Cranial Suture Regeneration Mitigates Skull and Neurocognitive Defects in Craniosynostosis.

Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1+/- mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.

Restoring the Sense of Touch Using a Sensorimotor Demultiplexing Neural Interface.

Paralyzed muscles can be reanimated following spinal cord injury (SCI) using a brain-computer interface (BCI) to enhance motor function alone. Importantly, the sense of touch is a key component of motor function. Here, we demonstrate that a human participant with a clinically complete SCI can use a BCI to simultaneously reanimate both motor function and the sense of touch, leveraging residual touch signaling from his own hand. In the primary motor cortex (M1), residual subperceptual hand touch signals are simultaneously demultiplexed from ongoing efferent motor intention, enabling intracortically controlled closed-loop sensory feedback. Using the closed-loop demultiplexing BCI almost fully restored the ability to detect object touch and significantly improved several sensorimotor functions. Afferent grip-intensity levels are also decoded from M1, enabling grip reanimation regulated by touch signaling. These results demonstrate that subperceptual neural signals can be decoded from the cortex and transformed into conscious perception, significantly augmenting function.

Protracted development of stick tool use skills extends into adulthood in wild western chimpanzees.

Tool use is considered a driving force behind the evolution of brain expansion and prolonged juvenile dependency in the hominin lineage. However, it remains rare across animals, possibly due to inherent constraints related to manual dexterity and cognitive abilities. In our study, we investigated the ontogeny of tool use in chimpanzees (Pan troglodytes), a species known for its extensive and flexible tool use behavior. We observed 70 wild chimpanzees across all ages and analyzed 1,460 stick use events filmed in the Taï National Park, Côte d'Ivoire during the chimpanzee attempts to retrieve high-nutrient, but difficult-to-access, foods. We found that chimpanzees increasingly utilized hand grips employing more than 1 independent digit as they matured. Such hand grips emerged at the age of 2, became predominant and fully functional at the age of 6, and ubiquitous at the age of 15, enhancing task accuracy. Adults adjusted their hand grip based on the specific task at hand, favoring power grips for pounding actions and intermediate grips that combine power and precision, for others. Highly protracted development of suitable actions to acquire hidden (i.e., larvae) compared to non-hidden (i.e., nut kernel) food was evident, with adult skill levels achieved only after 15 years, suggesting a pronounced cognitive learning component to task success. The prolonged time required for cognitive assimilation compared to neuromotor control points to selection pressure favoring the retention of learning capacities into adulthood.

Computation on Demand: Action-Specific Representations of Visual Task Features Arise during Distinct Movement Phases.

The intention to act influences the computations of various task-relevant features. However, little is known about the time course of these computations. Furthermore, it is commonly held that these computations are governed by conjunctive neural representations of the features. But, support for this view comes from paradigms arbitrarily combining task features and affordances, thus requiring representations in working memory. Therefore, the present study used electroencephalography and a well-rehearsed task with features that afford minimal working memory representations to investigate the temporal evolution of feature representations and their potential integration in the brain. Female and male human participants grasped objects or touched them with a knuckle. Objects had different shapes and were made of heavy or light materials with shape and weight being relevant for grasping, not for "knuckling." Using multivariate analysis showed that representations of object shape were similar for grasping and knuckling. However, only for grasping did early shape representations reactivate at later phases of grasp planning, suggesting that sensorimotor control signals feed back to the early visual cortex. Grasp-specific representations of material/weight only arose during grasp execution after object contact during the load phase. A trend for integrated representations of shape and material also became grasp-specific but only briefly during the movement onset. These results suggest that the brain generates action-specific representations of relevant features as required for the different subcomponents of its action computations. Our results argue against the view that goal-directed actions inevitably join all features of a task into a sustained and unified neural representation.

Differential Modulation of Local Field Potentials in the Primary and Premotor Cortices during Ipsilateral and Contralateral Reach to Grasp in Macaque Monkeys.

Hand movements are associated with modulations of neuronal activity across several interconnected cortical areas, including the primary motor cortex (M1) and the dorsal and ventral premotor cortices (PMd and PMv). Local field potentials (LFPs) provide a link between neuronal discharges and synaptic inputs. Our current understanding of how LFPs vary in M1, PMd, and PMv during contralateral and ipsilateral movements is incomplete. To help reveal unique features in the pattern of modulations, we simultaneously recorded LFPs in these areas in two macaque monkeys performing reach and grasp movements with either the right or left hand. The greatest effector-dependent differences were seen in M1, at low (≤13 Hz) and γ frequencies. In premotor areas, differences related to hand use were only present in low frequencies. PMv exhibited the greatest increase in low frequencies during instruction cues and the smallest effector-dependent modulation during movement execution. In PMd, δ oscillations were greater during contralateral reach and grasp, and ß activity increased during contralateral grasp. In contrast, ß oscillations decreased in M1 and PMv. These results suggest that while M1 primarily exhibits effector-specific LFP activity, premotor areas compute more effector-independent aspects of the task requirements, particularly during movement preparation for PMv and production for PMd. The generation of precise hand movements likely relies on the combination of complementary information contained in the unique pattern of neural modulations contained in each cortical area. Accordingly, integrating LFPs from premotor areas and M1 could enhance the performance and robustness of brain-machine interfaces.

Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis.

BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations. CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Learning the signatures of the human grasp using a scalable tactile glove.

Humans can feel, weigh and grasp diverse objects, and simultaneously infer their material properties while applying the right amount of force-a challenging set of tasks for a modern robot1. Mechanoreceptor networks that provide sensory feedback and enable the dexterity of the human grasp2 remain difficult to replicate in robots. Whereas computer-vision-based robot grasping strategies3-5 have progressed substantially with the abundance of visual data and emerging machine-learning tools, there are as yet no equivalent sensing platforms and large-scale datasets with which to probe the use of the tactile information that humans rely on when grasping objects. Studying the mechanics of how humans grasp objects will complement vision-based robotic object handling. Importantly, the inability to record and analyse tactile signals currently limits our understanding of the role of tactile information in the human grasp itself-for example, how tactile maps are used to identify objects and infer their properties is unknown6. Here we use a scalable tactile glove and deep convolutional neural networks to show that sensors uniformly distributed over the hand can be used to identify individual objects, estimate their weight and explore the typical tactile patterns that emerge while grasping objects. The sensor array (548 sensors) is assembled on a knitted glove, and consists of a piezoresistive film connected by a network of conductive thread electrodes that are passively probed. Using a low-cost (about US$10) scalable tactile glove sensor array, we record a large-scale tactile dataset with 135,000 frames, each covering the full hand, while interacting with 26 different objects. This set of interactions with different objects reveals the key correspondences between different regions of a human hand while it is manipulating objects. Insights from the tactile signatures of the human grasp-through the lens of an artificial analogue of the natural mechanoreceptor network-can thus aid the future design of prosthetics7, robot grasping tools and human-robot interactions1,8-10.

Active entanglement enables stochastic, topological grasping.

Grasping, in both biological and engineered mechanisms, can be highly sensitive to the gripper and object morphology, as well as perception and motion planning. Here, we circumvent the need for feedback or precise planning by using an array of fluidically actuated slender hollow elastomeric filaments to actively entangle with objects that vary in geometric and topological complexity. The resulting stochastic interactions enable a unique soft and conformable grasping strategy across a range of target objects that vary in size, weight, and shape. We experimentally evaluate the grasping performance of our strategy and use a computational framework for the collective mechanics of flexible filaments in contact with complex objects to explain our findings. Overall, our study highlights how active collective entanglement of a filament array via an uncontrolled, spatially distributed scheme provides options for soft, adaptable grasping.

Finger stability in precision grips.

Stable precision grips using the fingertips are a cornerstone of human hand dexterity. However, our fingers become unstable sometimes and snap into a hyperextended posture. This is because multilink mechanisms like our fingers can buckle under tip forces. Suppressing this instability is crucial for hand dexterity, but how the neuromuscular system does so is unknown. Here we show that people rely on the stiffness from muscle contraction for finger stability. We measured buckling time constants of 50 ms or less during maximal force application with the index finger­quicker than feedback latencies­which suggests that muscle-induced stiffness may underlie stability. However, a biomechanical model of the finger predicts that muscle-induced stiffness cannot stabilize at maximal force unless we add springs to stiffen the joints or people reduce their force to enable cocontraction. We tested this prediction in 38 volunteers. Upon adding stiffness, maximal force increased by 34 ± 3%, and muscle electromyography readings were 21 ± 3% higher for the finger flexors (mean ± SE). Muscle recordings and mathematical modeling show that adding stiffness offloads the demand for muscle cocontraction, thus freeing up muscle capacity for fingertip force. Hence, people refrain from applying truly maximal force unless an external stabilizing stiffness allows their muscles to apply higher force without losing stability. But more stiffness is not always better. Stiff fingers would affect the ability to adapt passively to complex object geometries and precisely regulate force. Thus, our results show how hand function arises from neurally tuned muscle stiffness that balances finger stability with compliance.

Fast Feedback Responses to Categorical Sensorimotor Errors That Do Not Indicate Error Magnitude Are Optimized Based on Short- and Long-Term Memory.

Skilled motor performance depends critically on rapid corrective responses that act to preserve the goal of the movement in the face of perturbations. Although it is well established that the gain of corrective responses elicited while reaching toward objects adapts to different contexts, little is known about the adaptability of corrective responses supporting the manipulation of objects after they are grasped. Here, we investigated the adaptability of the corrective response elicited when an object being lifted is heavier than expected and fails to lift off when predicted. This response involves a monotonic increase in vertical load force triggered, within ∼90 ms, by the absence of expected sensory feedback signaling lift off and terminated when actual lift off occurs. Critically, because the actual weight of the object cannot be directly sensed at the moment the object fails to lift off, any adaptation of the corrective response would have to be based on memory from previous lifts. We show that when humans, including men and women, repeatedly lift an object that on occasional catch trials increases from a baseline weight to a fixed heavier weight, they scale the gain of the response (i.e., the rate of force increase) to the heavier weight within two to three catch trials. We also show that the gain of the response scales, on the first catch trial, with the baseline weight of the object. Thus, the gain of the lifting response can be adapted by both short- and long-term experience. Finally, we demonstrate that this adaptation preserves the efficacy of the response across contexts.SIGNIFICANCE STATEMENT Here, we present the first investigation of the adaptability of the corrective lifting response elicited when an object is heavier than expected and fails to lift off when predicted. A striking feature of the response, which is driven by a sensory prediction error arising from the absence of expected sensory feedback, is that the magnitude of the error is unknown. That is, the motor system only receives a categorical error indicating that the object is heavier than expected but not its actual weight. Although the error magnitude is not known at the moment the response is elicited, we show that the response can be scaled to predictions of error magnitude based on both recent and long-term memories.

Distinct Neural Components of Visually Guided Grasping during Planning and Execution.

Selecting suitable grasps on three-dimensional objects is a challenging visuomotor computation, which involves combining information about an object (e.g., its shape, size, and mass) with information about the actor's body (e.g., the optimal grasp aperture and hand posture for comfortable manipulation). Here, we used functional magnetic resonance imaging to investigate brain networks associated with these distinct aspects during grasp planning and execution. Human participants of either sex viewed and then executed preselected grasps on L-shaped objects made of wood and/or brass. By leveraging a computational approach that accurately predicts human grasp locations, we selected grasp points that disentangled the role of multiple grasp-relevant factors, that is, grasp axis, grasp size, and object mass. Representational Similarity Analysis revealed that grasp axis was encoded along dorsal-stream regions during grasp planning. Grasp size was first encoded in ventral stream areas during grasp planning then in premotor regions during grasp execution. Object mass was encoded in ventral stream and (pre)motor regions only during grasp execution. Premotor regions further encoded visual predictions of grasp comfort, whereas the ventral stream encoded grasp comfort during execution, suggesting its involvement in haptic evaluation. These shifts in neural representations thus capture the sensorimotor transformations that allow humans to grasp objects.SIGNIFICANCE STATEMENT Grasping requires integrating object properties with constraints on hand and arm postures. Using a computational approach that accurately predicts human grasp locations by combining such constraints, we selected grasps on objects that disentangled the relative contributions of object mass, grasp size, and grasp axis during grasp planning and execution in a neuroimaging study. Our findings reveal a greater role of dorsal-stream visuomotor areas during grasp planning, and, surprisingly, increasing ventral stream engagement during execution. We propose that during planning, visuomotor representations initially encode grasp axis and size. Perceptual representations of object material properties become more relevant instead as the hand approaches the object and motor programs are refined with estimates of the grip forces required to successfully lift the object.

Grasping with a Twist: Dissociating Action Goals from Motor Actions in Human Frontoparietal Circuits.

In daily life, prehension is typically not the end goal of hand-object interactions but a precursor for manipulation. Nevertheless, functional MRI (fMRI) studies investigating manual manipulation have primarily relied on prehension as the end goal of an action. Here, we used slow event-related fMRI to investigate differences in neural activation patterns between prehension in isolation and prehension for object manipulation. Sixteen (seven males and nine females) participants were instructed either to simply grasp the handle of a rotatable dial (isolated prehension) or to grasp and turn it (prehension for object manipulation). We used representational similarity analysis (RSA) to investigate whether the experimental conditions could be discriminated from each other based on differences in task-related brain activation patterns. We also used temporal multivoxel pattern analysis (tMVPA) to examine the evolution of regional activation patterns over time. Importantly, we were able to differentiate isolated prehension and prehension for manipulation from activation patterns in the early visual cortex, the caudal intraparietal sulcus (cIPS), and the superior parietal lobule (SPL). Our findings indicate that object manipulation extends beyond the putative cortical grasping network (anterior intraparietal sulcus, premotor and motor cortices) to include the superior parietal lobule and early visual cortex.SIGNIFICANCE STATEMENT A simple act such as turning an oven dial requires not only that the CNS encode the initial state (starting dial orientation) of the object but also the appropriate posture to grasp it to achieve the desired end state (final dial orientation) and the motor commands to achieve that state. Using advanced temporal neuroimaging analysis techniques, we reveal how such actions unfold over time and how they differ between object manipulation (turning a dial) versus grasping alone. We find that a combination of brain areas implicated in visual processing and sensorimotor integration can distinguish between the complex and simple tasks during planning, with neural patterns that approximate those during the actual execution of the action.

How we perceive the width of grasped objects: Insights into the central processes that govern proprioceptive judgements.

Low-level proprioceptive judgements involve a single frame of reference, whereas high-level proprioceptive judgements are made across different frames of reference. The present study systematically compared low-level (grasp → $\rightarrow$ grasp) and high-level (vision → $\rightarrow$ grasp, grasp → $\rightarrow$ vision) proprioceptive tasks, and quantified the consistency of grasp → $\rightarrow$ vision and possible reciprocal nature of related high-level proprioceptive tasks. Experiment 1 (n = 30) compared performance across vision → $\rightarrow$ grasp, a grasp → $\rightarrow$ vision and a grasp → $\rightarrow$ grasp tasks. Experiment 2 (n = 30) compared performance on the grasp → $\rightarrow$ vision task between hands and over time. Participants were accurate (mean absolute error 0.27 cm [0.20 to 0.34]; mean [95% CI]) and precise ( R 2 $R^2$ = 0.95 [0.93 to 0.96]) for grasp → $\rightarrow$ grasp judgements, with a strong correlation between outcomes (r = -0.85 [-0.93 to -0.70]). Accuracy and precision decreased in the two high-level tasks ( R 2 $R^2$ = 0.86 and 0.89; mean absolute error = 1.34 and 1.41 cm), with most participants overestimating perceived width for the vision → $\rightarrow$ grasp task and underestimating it for grasp → $\rightarrow$ vision task. There was minimal correlation between accuracy and precision for these two tasks. Converging evidence indicated performance was largely reciprocal (inverse) between the vision → $\rightarrow$ grasp and grasp → $\rightarrow$ vision tasks. Performance on the grasp → $\rightarrow$ vision task was consistent between dominant and non-dominant hands, and across repeated sessions a day or week apart. Overall, there are fundamental differences between low- and high-level proprioceptive judgements that reflect fundamental differences in the cortical processes that underpin these perceptions. Moreover, the central transformations that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. KEY POINTS: Low-level proprioceptive judgements involve a single frame of reference (e.g. indicating the width of a grasped object by selecting from a series of objects of different width), whereas high-level proprioceptive judgements are made across different frames of reference (e.g. indicating the width of a grasped object by selecting from a series of visible lines of different length). We highlight fundamental differences in the precision and accuracy of low- and high-level proprioceptive judgements. We provide converging evidence that the neural transformations between frames of reference that govern high-level proprioceptive judgements of grasp are personalised, stable and reciprocal for reciprocal tasks. This stability is likely key to precise judgements and accurate predictions in high-level proprioception.

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.

Dexterous manipulation: differential sensitivity of manipulation and grasp forces to task requirements.

How humans coordinate digit forces to perform dexterous manipulation is not well understood. This gap is due to the use of tasks devoid of dexterity requirements and/or the use of analytical techniques that cannot isolate the roles that digit forces play in preventing object slip and controlling object position and orientation (pose). In our recent work, we used a dexterous manipulation task and decomposed digit forces into FG, the internal force that prevents object slip, and FM, the force responsible for object pose control. Unlike FG, FM was modulated from object lift onset to hold, suggesting their different sensitivity to sensory feedback acquired during object lift. However, the extent to which FG and FM can be controlled independently remains to be determined. Importantly, how FG and FM change as a function of object property is mathematically indeterminate and therefore requires active modulation. To address this gap, we systematically changed either object mass or external torque. The FM normal component responsible for object orientation control was modulated to changes in object torque but not mass. In contrast, FG was distinctly modulated to changes in object mass and torque. These findings point to a differential sensitivity of FG and FM to task requirements and provide novel insights into the neural control of dexterous manipulation. Importantly, our results indicate that the proposed digit force decomposition has the potential to capture important differences in how sensory inputs are processed and integrated to simultaneously ensure grasp stability and dexterous object pose control.NEW & NOTEWORTHY Successful dexterous object manipulation requires simultaneous prevention of object slip and object pose control. How these two task goals are attained can be investigated by decomposing digit forces into grasp and manipulation forces, respectively. We found that these forces were characterized by differential sensitivity to changes in object properties (mass and torque). This finding suggests the involvement of distinct sensorimotor mechanisms that, combined, simultaneously ensure grasp stability and dexterous control of object pose.

Repeated context-specific actions disrupt feedforward adjustments in motor commands in younger and older adults.

The flexibility of the motor system to adjust a planned action before or during the execution of the movement in response to sensory information is critical for preventing errors in motor control. As individuals age, this function declines, leading to an increased incidence of motor errors. Although sensory processing and cognitive decline are known contributors to this impairment, here, we test the hypothesis that repetition of context-specific planned actions interferes with the adjustment of feedforward motor commands. Younger and older participants were instructed to grasp and lift a T-shaped object with a concealed, off-sided center of mass and minimize its roll through anticipatory force control, relying predominantly on predictive model-driven planning (i.e., sensorimotor memories) developed through repeated lifts. We selectively manipulate the number of trial repeats with the center of mass on one side before switching it to the other side of the T-shaped object. The results showed that increasing the number of repetitions improved performance in manipulating an object with a given center of mass but led to increased errors when the object's center of mass was switched. This deleterious effect of repetition on feedforward motor adjustment was observed in younger and older adults. Critically, we show these effects on an internal model-driven motor planning task that relies predominantly on sensorimotor memory, with no differences in sensory inputs from the repetition manipulation. The findings indicate that feedforward motor adjustments are hampered by repetitive stereotyped planning and execution of motor behavior.NEW & NOTEWORTHY Adjusting planned actions in response to sensory stimuli degrades with age contributing to increased incidence of errors ranging from clumsy spills to catastrophic falls. Multiple factors likely contribute to age-related motor inflexibility, including sensory- and cognition-supporting system declines. Here, we present compelling evidence for repetition to disrupt feedforward adjusting of motor commands in younger and older adults, which suggests increases in stereotypy as a deleterious potentiator of motor control errors.

Activity in the pontine reticular nuclei scales with handgrip force in humans.

The neural pathways that contribute to force production in humans are currently poorly understood, as the relative roles of the corticospinal tract and brainstem pathways, such as the reticulospinal tract (RST), vary substantially across species. Using functional magnetic resonance imaging (fMRI), we aimed to measure activation in the pontine reticular nuclei (PRN) during different submaximal handgrip contractions to determine the potential role of the PRN in force modulation. Thirteen neurologically intact participants (age: 28 ± 6 yr) performed unilateral handgrip contractions at 25%, 50%, 75% of maximum voluntary contraction during brain scans. We quantified the magnitude of PRN activation from the contralateral and ipsilateral sides during each of the three contraction intensities. A repeated-measures ANOVA demonstrated a significant main effect of force (P = 0.012, [Formula: see text] = 0.307) for PRN activation, independent of side (i.e., activation increased with force for both contralateral and ipsilateral nuclei). Further analyses of these data involved calculating the linear slope between the magnitude of activation and handgrip force for each region of interest (ROI) at the individual-level. One-sample t tests on the slopes revealed significant group-level scaling for the PRN bilaterally, but only the ipsilateral PRN remained significant after correcting for multiple comparisons. We show evidence of task-dependent activation in the PRN that was positively related to handgrip force. These data build on a growing body of literature that highlights the RST as a functionally relevant motor pathway for force modulation in humans.NEW & NOTEWORTHY In this study, we used a task-based functional magnetic resonance imaging (fMRI) paradigm to show that activity in the pontine reticular nuclei scales linearly with increasing force during a handgrip task. These findings directly support recently proposed hypotheses that the reticulospinal tract may play an important role in modulating force production in humans.

Elevated sympathetic-mediated vasoconstriction at rest but intact functional sympatholysis during exercise in heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.

Blood pressure responses to handgrip exercise but not apnea or mental stress are enhanced in women with a recent history of preeclampsia.

Preeclampsia is a risk factor for future cardiovascular diseases. However, the mechanisms underlying this association remain unclear, limiting effective prevention strategies. Blood pressure responses to acute stimuli may reveal cardiovascular dysfunction not apparent at rest, identifying individuals at elevated cardiovascular risk. Therefore, we compared blood pressure responsiveness with acute stimuli between previously preeclamptic (PPE) women (34 ± 5 yr old, 13 ± 6 mo postpartum) and women following healthy pregnancies (Ctrl; 29 ± 3 yr old, 15 ± 4 mo postpartum). Blood pressure (finger photoplethysmography calibrated to manual sphygmomanometry-derived values; PPE: n = 12, Ctrl: n = 12) was assessed during end-expiratory apnea, mental stress, and isometric handgrip exercise protocols. Integrated muscle sympathetic nerve activity (MSNA) was assessed in a subset of participants (peroneal nerve microneurography; PPE: n = 6, Ctrl: n = 8). Across all protocols, systolic blood pressure (SBP) was higher in PPE than Ctrl (main effects of group all P < 0.05). Peak changes in SBP were stressor specific: peak increases in SBP were not different between PPE and Ctrl during apnea (8 ± 6 vs. 6 ± 5 mmHg, P = 0.32) or mental stress (9 ± 5 vs. 4 ± 7 mmHg, P = 0.06). However, peak exercise-induced increases in SBP were greater in PPE than Ctrl (11 ± 5 vs. 7 ± 7 mmHg, P = 0.04). MSNA was higher in PPE than Ctrl across all protocols (main effects of group all P < 0.05), and increases in peak MSNA were greater in PPE than Ctrl during apnea (44 ± 6 vs. 27 ± 14 burst/100 hb, P = 0.04) and exercise (25 ± 8 vs. 13 ± 11 burst/100 hb, P = 0.01) but not different between groups during mental stress (2 ± 3 vs. 0 ± 5 burst/100 hb, P = 0.41). Exaggerated pressor and sympathetic responses to certain stimuli may contribute to the elevated long-term risk for cardiovascular disease in PPE.NEW & NOTEWORTHY Women with recent histories of preeclampsia demonstrated higher systolic blood pressures across sympathoexcitatory stressors relative to controls. Peak systolic blood pressure reactivity was exacerbated in previously preeclamptic women during small muscle-mass exercises, although not during apneic or mental stress stimuli. These findings underscore the importance of assessing blood pressure control during a variety of experimental conditions in previously preeclamptic women to elucidate mechanisms that may contribute to their elevated cardiovascular disease risk.

Growth Hormone Therapy in Decompensated Cirrhosis: An Open-Label, Randomized Control Trial.

INTRODUCTION: Effect of long-term growth-hormone (GH) therapy in decompensated cirrhosis (DC) is unknown. We studied the safety and efficacy of GH therapy on malnutrition, nitrogen metabolism, and hormonal changes in patients with DC. METHODS: Patients with DC were randomized to standard medical therapy plus GH (group A; n = 38) or standard medical therapy alone (group B; n = 38). Body mass index, midarm muscle circumference (MAMC), hand grip strength (HGS), liver frailty index (LFI), skeletal muscle index (SMI), nitrogen balance, Child-Turcotte-Pugh, model for end-stage liver disease, quality of life (QOL), serum albumin, GH, insulin like growth factor-1, and acid labile subunit (ALS) were assessed at baseline and at 12 months. RESULTS: The mean difference between baseline and 12-months in SMI (-6.122 [-9.460 to -2.785] cm 2 /m 2 ), body mass index (-2.078 [-3.584 to -0.5718] kg/m 2 ), MAMC (-1.960 [-2.928 to -0.9908] cm), HGS (-5.595 [-7.159 to -4.031] kg), albumin (-0.3967 [-0.6876 to -0.1057] g/dL), LFI (0.3328 [0.07786-0.5878]), Child-Turcotte-Pugh (0.9624 [0.1435-1.781]), model for end-stage liver disease (1.401 [0.04698-2.75]), insulin-like growth factor-1 (-6.295 [-11.09 to -1.495] ng/dL), and ALS (-8.728 [-14.12 to -3.341] pg/mL) were statistically significantly better ( P < 0.05) in group A. There was no improvement in nutritional parameters, clinical scores, QOL scores, or nitrogen balance in group B. The mean difference between group A and B in SMI, HGS, MAMC, LFI, ALS, physical component summary, and mental component summary at 12 months was also statistically significant. Survival at 12 months was similar in both groups ( P = 0.35). No serious adverse events were observed. DISCUSSION: Long-term use of GH is safe in DC and leads to improvement in malnutrition and possibly QOL. However, there is no improvement in 12-month survival (NCT03420144).