Topology, dynamics, and control of a muscle-architected soft arm.

Muscular hydrostats, such as octopus arms or elephant trunks, lack bones entirely, endowing them with exceptional dexterity and reconfigurability. Key to their unmatched ability to control nearly infinite degrees of freedom is the architecture into which muscle fibers are weaved. Their arrangement is, effectively, the instantiation of a sophisticated mechanical program that mediates, and likely facilitates, the control and realization of complex, dynamic morphological reconfigurations. Here, by combining medical imaging, biomechanical data, live behavioral experiments, and numerical simulations, an octopus-inspired arm made of [Formula: see text]200 continuous muscle groups is synthesized, exposing "mechanically intelligent" design and control principles broadly pertinent to dynamics and robotics. Such principles are mathematically understood in terms of storage, transport, and conversion of topological quantities, effected into complex 3D motions via simple muscle activation templates. These are in turn composed into higher-level control strategies that, compounded by the arm's compliance, are demonstrated across challenging manipulation tasks, revealing surprising simplicity and robustness.

A computational study of how an α- to γ-motoneurone collateral can mitigate velocity-dependent stretch reflexes during voluntary movement.

The primary motor cortex does not uniquely or directly produce alpha motoneurone (α-MN) drive to muscles during voluntary movement. Rather, α-MN drive emerges from the synthesis and competition among excitatory and inhibitory inputs from multiple descending tracts, spinal interneurons, sensory inputs, and proprioceptive afferents. One such fundamental input is velocity-dependent stretch reflexes in lengthening muscles, which should be inhibited to enable voluntary movement. It remains an open question, however, the extent to which unmodulated stretch reflexes disrupt voluntary movement, and whether and how they are inhibited in limbs with numerous multiarticular muscles. We used a computational model of a Rhesus Macaque arm to simulate movements with feedforward α-MN commands only, and with added velocity-dependent stretch reflex feedback. We found that velocity-dependent stretch reflex caused movement-specific, typically large and variable disruptions to arm movements. These disruptions were greatly reduced when modulating velocity-dependent stretch reflex feedback (i) as per the commonly proposed (but yet to be clarified) idealized alpha-gamma (α-γ) coactivation or (ii) an alternative α-MN collateral projection to homonymous γ-MNs. We conclude that such α-MN collaterals are a physiologically tenable propriospinal circuit in the mammalian fusimotor system. These collaterals could still collaborate with α-γ coactivation, and the few skeletofusimotor fibers (ß-MNs) in mammals, to create a flexible fusimotor ecosystem to enable voluntary movement. By locally and automatically regulating the highly nonlinear neuro-musculo-skeletal mechanics of the limb, these collaterals could be a critical low-level enabler of learning, adaptation, and performance via higher-level brainstem, cerebellar, and cortical mechanisms.

Motor Cortex Latent Dynamics Encode Spatial and Temporal Arm Movement Parameters Independently.

The fluid movement of an arm requires multiple spatiotemporal parameters to be set independently. Recent studies have argued that arm movements are generated by the collective dynamics of neurons in motor cortex. An untested prediction of this hypothesis is that independent parameters of movement must map to independent components of the neural dynamics. Using a task where three male monkeys made a sequence of reaching movements to randomly placed targets, we show that the spatial and temporal parameters of arm movements are independently encoded in the low-dimensional trajectories of population activity in motor cortex: each movement's direction corresponds to a fixed neural trajectory through neural state space and its speed to how quickly that trajectory is traversed. Recurrent neural network models show that this coding allows independent control over the spatial and temporal parameters of movement by separate network parameters. Our results support a key prediction of the dynamical systems view of motor cortex, and also argue that not all parameters of movement are defined by different trajectories of population activity.

Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.

Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.

Arm and ankle blood pressure indices, and peripheral artery disease, and mortality: a cohort study.

BACKGROUND AND AIMS: Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials. METHODS: Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death. RESULTS: Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3%, diabetes 50.2%) from 53 countries, 1071 (2.6%) developed PAD, and 4955 (12.2%) died during 5 years of follow-up. Incident PAD progressively rose with higher arm BP indices and fell with ankle BP indices. The strongest relationships were noted for ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, adjusted hazard ratios (95% confidence interval) for each lower fourth were 1.64 (1.31-2.04), 2.59 (2.10-3.20), and 4.23 (3.44-5.21) for ankle SBP; 1.19 (0.95-1.50), 1.66 (1.34-2.05), and 3.34 (2.75-4.06) for ABI; and 1.41 (1.11-1.78), 2.04 (1.64-2.54), and 3.63 (2.96-4.45) for APPD. Similar patterns were observed for mortality. Ankle BP indices provided the highest c-statistics and classification indices in predicting future PAD beyond established risk factors. CONCLUSIONS: Ankle BP indices including the ankle SBP and the APPD best predicted PAD and mortality.

Role of arm reaching movement kinematics in friction perception at initial contact with smooth surfaces.

When manipulating objects, humans begin adjusting their grip force to friction within 100 ms of contact. During motor adaptation, subjects become aware of the slipperiness of touched surfaces. Previously, we have demonstrated that humans cannot perceive frictional differences when surfaces are brought in contact with an immobilised finger, but can do so when there is submillimeter lateral displacement or subjects actively make the contact movement. Similarly, in, we investigated how humans perceive friction in the absence of intentional exploratory sliding or rubbing movements, to mimic object manipulation interactions. We used a two-alternative forced-choice paradigm in which subjects had to reach and touch one surface followed by another, and then indicate which felt more slippery. Subjects correctly identified the more slippery surface in 87 ± 8% of cases (mean ± SD; n = 12). Biomechanical analysis of finger pad skin displacement patterns revealed the presence of tiny (<1 mm) localised slips, known to be sufficient to perceive frictional differences. We tested whether these skin movements arise as a result of natural hand reaching kinematics. The task was repeated with the introduction of a hand support, eliminating the hand reaching movement and minimising fingertip movement deviations from a straight path. As a result, our subjects' performance significantly declined (66 ± 12% correct, mean ± SD; n = 12), suggesting that unrestricted reaching movement kinematics and factors such as physiological tremor, play a crucial role in enhancing or enabling friction perception upon initial contact. KEY POINTS: More slippery objects require a stronger grip to prevent them from slipping out of hands. Grip force adjustments to friction driven by tactile sensory signals are largely automatic and do not necessitate cognitive involvement; nevertheless, some associated awareness of grip surface slipperiness under such sensory conditions is present and helps to select a safe and appropriate movement plan. When gripping an object, tactile receptors provide frictional information without intentional rubbing or sliding fingers over the surface. However, we have discovered that submillimeter range lateral displacement might be required to enhance or enable friction sensing. The present study provides evidence that such small lateral movements causing localised partial slips arise and are an inherent part of natural reaching movement kinematics.

Dose Response to Upper Extremity Stroke Rehabilitation Varies by Individual: Early Indicators of Treatment Response.

BACKGROUND: Dose response has remained a priority area in motor rehabilitation research for decades, prompting several large randomized trials and meta-analyses. These between-subjects comparisons have revealed equivocal relationships between the duration of motor practice and rehabilitation response. Prior reliance on time-consuming clinical assessments made it infeasible to capture within-subjects dose response, as tracking the dose-response trajectory of an individual requires dozens of repeated administrations. METHODS: This secondary observational cohort analysis of existing data from the gaming arms of the VIGoROUS multisite trial (Video Game Rehabilitation for Outpatient Stroke) describes the rehabilitation dose response of 80 participants with mild-moderate chronic stroke. The 3-dimensional joint position data were captured via the Kinect v2 optical sensor as participants completed a prescribed 15 hours of in-home unsupervised game-based motor practice. Kinematic dose response trajectories were fitted from hundreds to thousands of in-game repetitions for 4 separate upper extremity movements for each participant. RESULTS: Of 75 participants with sufficient data for dose-response analysis, 85% showed improved motor capacity for at least 1 movement. Dose response was bimodal; 42% required <5 hours of motor practice before reaching a plateau in movement kinematics, whereas 55% required >10 and 34% required >30 hours. We could predict with 93% accuracy whether or not an individual would ultimately respond to game-based motor practice within 5 hours of gameplay. CONCLUSIONS: Dose response varies considerably between individuals. About half of chronic stroke patients benefit from higher doses of motor practice than the current standard of care. Individualized dose-response data from motion capture rehabilitation gaming can guide clinical decision-making early on in treatment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02631850.

The anterior cingulate cortex is involved in intero-exteroceptive integration for spatial image transformation of the self-body.

Spatial image transformation of the self-body is a fundamental function of visual perspective-taking. Recent research underscores the significance of intero-exteroceptive information integration to construct representations of our embodied self. This raises the intriguing hypothesis that interoceptive processing might be involved in the spatial image transformation of the self-body. To test this hypothesis, the present study used functional magnetic resonance imaging to measure brain activity during an arm laterality judgment (ALJ) task. In this task, participants were tasked with discerning whether the outstretched arm of a human figure, viewed from the front or back, was the right or left hand. The reaction times for the ALJ task proved longer when the stimulus presented orientations of 0°, 90°, and 270° relative to the upright orientation, and when the front view was presented rather than the back view. Reflecting the increased reaction time, increased brain activity was manifested in a cluster centered on the dorsal anterior cingulate cortex (ACC), suggesting that the activation reflects the involvement of an embodied simulation in ALJ. Furthermore, this cluster of brain activity exhibited overlap with regions where the difference in activation between the front and back views positively correlated with the participants' interoceptive sensitivity, as assessed through the heartbeat discrimination task, within the pregenual ACC. These results suggest that the ACC plays an important role in integrating intero-exteroceptive cues to spatially transform the image of our self-body.

The control of the arm's equilibrium position.

To generate a force, the brain activates muscles that act like springs to pull the arm toward a new equilibrium position. The equilibrium position (EP) is central to our understanding of the biological control of viscoelastic muscles. Although there is evidence of the EP during the control of limb posture, EPs have not been directly identified when the limb exerts a force against the environment. Here, we asked participants to apply a constant force in one of eight directions against a point-like constraint. This constraint was released abruptly to observe the final position to which the arm converged. Importantly, the same force magnitude was maintained while changing the arm's stiffness by modulating the strength of the hand's power grasp. The final position moved further away from the constraint as the arm became less stiff and was inversely proportional to the arm's stiffness, thereby confirming that the final position was the arm's EP. These results demonstrate how the EP changes with the arm's stiffness to produce a desired force in different directions.NEW & NOTEWORTHY According to numerous theories, the brain controls posture and movement by activating muscles that attract the limb toward a so-called equilibrium position, but the universality of this mechanism has not been shown for different motor behaviors. Here, we show that even when pushing or pulling against the environment, the brain achieves the desired force through an equilibrium position that lies beyond the physical constraint.

Arm cooling selectively impacts sensorimotor control.

The benefits of cold have long been recognized in sport and medicine. However, it also brings costs, which have more rarely been investigated, notably in terms of sensorimotor control. We hypothesized that, in addition to peripheral effects, cold slows down the processing of proprioceptive cues, which has an impact on both feedback and feedforward control. We therefore compared the performances of participants whose right arm had been immersed in either cold water (arm temperature: 14°C) or lukewarm water (arm temperature: 34°C). In experiment 1, we administered a Fitts's pointing task and performed a kinematic analysis to determine whether sensorimotor control processes were affected by the cold. Results revealed 1) modifications in late kinematic parameters, suggesting changes in the use of proprioceptive feedback, and 2) modifications in early kinematic parameters, suggesting changes in action representations and/or feedforward processes. To explore our hypothesis further, we ran a second experiment in which no physical movement was involved, and thus no peripheral effects. Participants were administrated a hand laterality task, known to involve implicit motor imagery and assess the internal representation of the hand. They were shown left- and right-hand images randomly displayed in different orientations in the picture plane and had to identify as quickly and as accurately as possible whether each image was of the left hand or the right hand. Results revealed slower responses and more errors when participants had to mentally rotate the cooled hand in the extreme orientation of 160°, further suggesting the impact of cold on action representations.NEW & NOTEWORTHY We investigated how arm cooling modulates sensorimotor representations and sensorimotor control. Arm cooling induced changes in early kinematic parameters of pointing, suggesting an impact on feedforward processes or hand representation. Arm cooling induced changes in late kinematic parameters of pointing, suggesting an impact on feedback processes. Arm cooling also affected performance on a hand laterality task, suggesting that action representations were modified.

Force reserve predicts compensation in reaching movement with induced shoulder strength deficit.

Following events such as fatigue or stroke, individuals often move their trunks forward during reaching, leveraging a broader muscle group even when only arm movement would suffice. In previous work, we showed the existence of a "force reserve": a phenomenon where individuals, when challenged with a heavy weight, adjusted their motor coordination to preserve approximately 40% of their shoulder's force. Here, we investigated if such reserve can predict hip, shoulder, and elbow movements and torques resulting from an induced shoulder strength deficit. We engaged 20 healthy participants in a reaching task with incrementally heavier dumbbells, analyzing arm and trunk movements via motion capture and joint torques through inverse dynamics. We simulated these movements using an optimal control model of a 3-degree-of-freedom upper body, contrasting three cost functions: traditional sum of squared torques, a force reserve function incorporating a nonlinear penalty, and a normalized torque function. Our results demonstrate a clear increase in trunk movement correlated with heavier dumbbell weights, with participants employing compensatory movements to maintain a shoulder force reserve of approximately 40% of maximum torque. Simulations showed that while traditional and reserve functions accurately predicted trunk compensation, only the reserve function effectively predicted joint torques under heavier weights. These findings suggest that compensatory movements are strategically employed to minimize shoulder effort and distribute load across multiple joints in response to weakness. We discuss the implications of the force reserve cost function in the context of optimal control of human movements and its relevance for understanding compensatory movements poststroke.NEW & NOTEWORTHY Our study reveals key findings on compensatory movements during upper limb reaching tasks under shoulder strength deficits, as observed poststroke. Using heavy dumbbells with healthy volunteers, we demonstrate how forward trunk displacement conserves around 40% of shoulder strength reserve during reaching. We show that an optimal controller employing a cost function combining squared motor torque and a nonlinear penalty for excessive muscle activation outperforms traditional controllers in predicting torques and compensatory movements in these scenarios.

Change of function and brain activity in patients of right spastic arm paralysis combined with aphasia after contralateral cervical seventh nerve transfer surgery.

Left hemisphere injury can cause right spastic arm paralysis and aphasia, and recovery of both motor and language functions shares similar compensatory mechanisms and processes. Contralateral cervical seventh cross transfer (CC7) surgery can provide motor recovery for spastic arm paralysis by triggering interhemispheric plasticity, and self-reports from patients indicate spontaneous improvement in language function but still need to be verified. To explore the improvements in motor and language function after CC7 surgery, we performed this prospective observational cohort study. The Upper Extremity part of Fugl-Meyer scale (UEFM) and Modified Ashworth Scale were used to evaluate motor function, and Aphasia Quotient calculated by Mandarin version of the Western Aphasia Battery (WAB-AQ, larger score indicates better language function) was assessed for language function. In 20 patients included, the average scores of UEFM increased by .40 and 3.70 points from baseline to 1-week and 6-month post-surgery, respectively. The spasticity of the elbow and fingers decreased significantly at 1-week post-surgery, although partially recurred at 6-month follow-up. The average scores of WAB-AQ were increased by 9.14 and 10.69 points at 1-week and 6-month post-surgery (P < .001 for both), respectively. Post-surgical fMRI scans revealed increased activity in the bilateral hemispheres related to language centrals, including the right precentral cortex and right gyrus rectus. These findings suggest that CC7 surgery not only enhances motor function but may also improve the aphasia quotient in patients with right arm paralysis and aphasia due to left hemisphere injuries.

Antecubital venous endothelial ETB receptor protein expression is preserved with aging in men.

Changes in endothelial function precede the development of cardiovascular disease (CVD). We have previously shown that age-related declines in endothelial function in women are due in part to a reduction in endothelial cell endothelin-B receptor (ETBR) protein expression. However, it is not known if ETBR protein expression changes with aging in men. The purpose of this study was to test the hypothesis that ETBR protein expression is attenuated in older men (OM) compared with younger men (YM). Primary endothelial cells were harvested from the antecubital vein of 14 OM (60 ± 6 yr; 26 ± 3 kg/m2) and 17 YM (24 ± 5 yr; 24 ± 2 kg/m2). Cells were stained with 4',6-diamidino-2-phenylindole, vascular endothelial cadherin, and ETBR. Images were quantified using immunocytochemistry. Endothelial function was assessed using brachial artery flow-mediated dilation (FMD). Systolic BP was similar (OM, 123 ± 11 vs. YM, 122 ± 10 mmHg) whereas diastolic BP was higher in OM (OM, 77 ± 7 vs. YM, 70 ± 6 mmHg; P < 0.01). Total testosterone was lower in OM (OM, 6.28 ± 4.21 vs. YM, 9.10 ± 2.68 ng/mL; P = 0.03). As expected, FMD was lower in OM (OM, 3.85 ± 1.51 vs. YM, 6.40 ± 2.68%; P < 0.01). However, ETBR protein expression was similar between OM and YM (OM, 0.39 ± 0.17 vs. YM, 0.42 ± 0.17 AU; P = 0.66). These data suggest that ETBR protein expression is not altered with age in men. These findings contrast with our previous data in women and further support sex differences in the endothelin system.NEW & NOTEWORTHY Our laboratory has previously shown that age-related declines in endothelial function are associated with a reduction in endothelial cell ETBR protein expression in women. However, it is unclear if endothelial cell ETBR protein expression is reduced with aging in men. This study demonstrates that endothelial cell ETBR protein expression is preserved with aging in men, and provides additional evidence for sex differences in the endothelin system.

Long-Term Patient-Reported Arm Symptoms in Breast Cancer Survivors.

BACKGROUND: Understanding long-term arm symptoms in breast cancer survivors is critical given excellent survival in the modern era. METHODS: This cross-sectional study included patients treated for stage 0-III breast cancer at our institution from 2002 to 2012. Patient-reported arm symptoms were collected from the EORTC QLQ-BR23 questionnaire. We used linear regression to evaluate adjusted associations between locoregional treatments and the continuous Arm Symptom (AS) score (0-100; higher score reflects more symptoms). RESULTS: A total of 1126 patients expressed interest in participating and 882 (78.3%) completed the questionnaire. Mean time since surgery was 10.5 years. There was a broad distribution of locoregional treatments, including axillary lymph node dissection (ALND) in 37.1% of patients, mastectomy with reconstruction in 36.5% of patients, and post-mastectomy radiation in 38.2% of patients. Overall, 64.3% (95% confidence interval [CI] 61.1-67.4%) of patients reported no arm symptoms, 17.0% (95% CI 14.7-19.6%) had one mild symptom, 9.4% (95% CI 7.7-11.5%) had two or more mild symptoms, and 9.3% (95% CI 7.6-11.4%) reported one or more severe symptoms. Adjusted AS scores were significantly higher with ALND versus sentinel node biopsy (ß 3.5, p = 0.01), and with autologous reconstruction versus all other breast/reconstructive surgery types (ß 4.5-5.5, all p < 0.05). There was a significant interaction between axillary and breast/reconstructive surgery, with the greatest effect of ALND in those with mastectomy with implant (ß 9.7) or autologous (ß 5.7) reconstruction. CONCLUSIONS: One in three patients reported arm symptoms at a mean of 10 years from treatment for breast cancer, although rates of severe symptoms were low (<10%). Attention is warranted to the arm morbidity related to both axillary and breast surgery during treatment counseling and survivorship.

The addition of a leaded arm sleeve to leaded aprons further decreases operator upper outer quadrant chest wall radiation dose during fluoroscopically guided interventions.

OBJECTIVE: Breast cancer most commonly occurs in the upper outer quadrant (UOQ) chest wall (CW). The effectiveness of routine leaded aprons to protect this region of the body in interventionalists during fluoroscopically guided interventions (FGIs) is unknown. Given the high lifetime attributable risks of prolonged occupational exposure to ionizing radiation and the increasing number of practicing female vascular surgeons and interventionalists, we sought to determine if the use of a leaded arm shield would offer additional protection to the lateral CW and axilla in operators compared with routine leaded aprons. METHODS: Effectiveness of leaded sleeves in attenuating radiation dose to the axilla and UOQ was evaluated in clinical practice and simulated scenarios. In the clinical setting, optically stimulated luminescence nanoDot detectors were placed at the UOQ lateral CW position, both over and under a standard leaded apron vest with and without the addition of an antimony/bismuth Enviro-Lite sleeve on two vascular surgeons performing FGIs. In the simulation, nanoDots were similarly placed on an anthropomorphic phantom positioned to represent a primary operator performing right femoral access. Fluorography was performed on 12-inch-thick acrylic scatter phantom at 80 kVp for an exposure of 3 Gy reference air kerma. Experiments were done with and without the sleeve. Paired Wilcoxon and χ2 tests were performed to identify the statistical significance of radiation attenuation. RESULTS: Operator UOQ CW dose was measured during 61 FGIs: 33 cases (54%) with and 28 cases (46%) without the sleeve. Median procedure reference air kerma and fluoroscopy time was 180 mGy (interquartile range [IQR], 85-447 mGy) and 21 minutes (IQR, 11-39 minutes) when the sleeve was worn vs 100 mGy (IQR, 67-270 mGy) and 11 minutes (IQR, 6.3-25 minutes) without the sleeve. Radiation dose to the operator's UOQ was reduced by 96% (IQR, 85%-96%) when the sleeve was present and by 62% (IQR, 44%-82%; P < .001) without the sleeve. In the simulated setting, the sleeve reduced the radiation dose to the UOQ compared with the apron alone (96% vs 67%; P < .001). CONCLUSIONS: Routine leaded aprons do attenuate the majority of UOQ chest wall radiation dose; however, the addition of a lead-equivalent sleeve further significantly reduces this dose. Because this area of the body has a high incidence of cancer formation, additional protection, especially to female interventionalists, seems prudent. Vascular surgeons should consider using a protective sleeve with their personal protective equipment when performing complex fluoroscopically guided procedures.

Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial.

BACKGROUND: Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. METHODS: The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. DISCUSSION: Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05848765; 08-May-2023. EUDRACT: 2022-000677-75; 10-Feb-2022.

Tissue Doppler ultrasound of arm muscles to assess myotonia in myotonic dystrophies: An exploratory study.

INTRODUCTION/AIMS: Myotonia is a key symptom of myotonic dystrophies (DM), and its quantification is challenging. This exploratory study evaluated the utility of tissue Doppler ultrasound (TDU) to assess myotonia in DM. METHODS: Twelve DM patients (seven type-1 DM [DM1] and five type-2 DM [DM2]) and 20 age-matched healthy subjects were included in this cross-sectional study. After measuring cross-sectional areas of the flexor digitorum superficialis (FDS) and extensor digitorum communis (EDC) muscles in a resting state, muscle contraction/relaxation time, time to peak tissue velocity, peak tissue velocity and velocity gradients of these muscles were measured via TDU while performing forced fist unclenching after fist closure. Additionally, grip strength, Medical Research Council Sum score and patient-reported myotonia severity scores were assessed. RESULTS: DM1 and DM2 patients had a lower grip strength than healthy subjects (p = .0001/p = .002). Patient-reported myotonia did not differ between DM1 and DM2 patients. DM1 patients revealed FDS and EDC atrophy compared to DM2 patients and healthy subjects (p = .003/p = .004). TDU revealed prolonged muscle contraction and relaxation times in both DM subtypes, with prolonged time to reach FDS peak relaxation velocity and altered peak FDS relaxation velocity only in DM1 patients (p = .03/p = .003). Peak FDS relaxation velocity correlated inversely with C(C)TG repeat numbers in DM patients. Sensitivity of TDU parameters to detect myotonic dystrophy varied between 50% and 75%, with a specificity of 95%. DISCUSSION: Our exploratory study suggests that TDU could serve as a novel tool to quantify myotonia in DM patients, but larger follow-up studies are warranted to validate its diagnostic accuracy.

Learning context shapes bimanual control strategy and generalization of novel dynamics.

Bimanual movements are fundamental components of everyday actions, yet the underlying mechanisms coordinating adaptation of the two hands remain unclear. Although previous studies highlighted the contextual effect of kinematics of both arms on internal model formation, we do not know how the sensorimotor control system associates the learned memory with the experienced states in bimanual movements. More specifically, can, and if so, how, does the sensorimotor control system combine multiple states from different effectors to create and adapt a motor memory? Here, we tested motor memory formation in two groups with a novel paradigm requiring the encoding of the kinematics of the right hand to produce the appropriate predictive force on the left hand. While one group was provided with training movements in which this association was evident, the other group was trained on conditions in which this association was ambiguous. After adaptation, we tested the encoding of the learned motor memory by measuring the generalization to new movement combinations. While both groups adapted to the novel dynamics, the evident group showed a weighted encoding of the learned motor memory based on movements of the other (right) hand, whereas the ambiguous group exhibited mainly same (left) hand encoding in bimanual trials. Despite these differences, both groups demonstrated partial generalization to unimanual movements of the left hand. Our results show that motor memories can be encoded depending on the motion of other limbs, but that the training conditions strongly shape the encoding of the motor memory formation and determine the generalization to novel contexts.

Interactions between arm and leg neuronal circuits following paired cervical and lumbosacral transspinal stimulation in healthy humans.

Transspinal (or transcutaneous spinal cord) stimulation is a promising noninvasive method that may strengthen the intrinsic spinal neural connectivity in neurological disorders. In this study we assessed the effects of cervical transspinal stimulation on the amplitude of leg transspinal evoked potentials (TEPs), and the effects of lumbosacral transspinal stimulation on the amplitude of arm TEPs. Control TEPs were recorded following transspinal stimulation with one cathode electrode placed either on Cervical 3 (21.3 ± 1.7 mA) or Thoracic 10 (23.6 ± 16.5 mA) vertebrae levels. Associated anodes were placed bilaterally on clavicles or iliac crests. Cervical transspinal conditioning stimulation produced short latency inhibition of TEPs recorded from left soleus (ranging from - 6.11 to -3.87% of control TEP at C-T intervals of -50, -25, -20, -15, -10, 15 ms), right semitendinosus (ranging from - 11.1 to -4.55% of control TEP at C-T intervals of -20, -15, 15 ms), and right vastus lateralis (ranging from - 13.3 to -8.44% of control TEP at C-T intervals of -20 and - 15 ms) (p < 0.05). Lumbosacral transspinal conditioning stimulation produced no significant effects on arm TEPs. We conclude that in the resting state, cervical transspinal stimulation affects the net motor output of leg motoneurons under the experimental conditions used in this study. Further investigations are warranted to determine whether this protocol may reactivate local spinal circuitry after stroke or spinal cord injury and may have a significant effect in synchronization of upper and lower limb muscle synergies during rhythmic activities like locomotion or cycling.