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Fingertip force scaling during hand-object interactions typically relies on visual information about the object and sensorimotor memories from previous object interactions. Here, we investigated whether contextual information, that is not explicitly linked to the intrinsic object properties (e.g., size or weight) but is informative for motor control requirements, can mediate force scaling. For this, we relied on two separate behavioral tasks during which we applied transcranial magnetic stimulation (TMS) to probe corticospinal excitability (CSE), as a window onto the primary motor cortex role in controlling fingertip forces. In experiment 1, participants performed a force tracking task, where we manipulated available implicit and explicit visual information. That is, either the force target was fully visible, or only the force error was displayed as a deviation from a horizontal line. We found that participants’ performance was better when the former condition, in which they had explicit access to predictive information. However, we did not find differences in CSE modulation based on the type of visual information. On the other hand, CSE was modulated by the change in muscle contraction, i.e., contraction vs. relaxation and fast vs. slow changes. In sum, these findings indicate that CSE only reflects the ongoing motor command. In experiment 2, other participants performed a sequential object lifting task of visually identical objects that were differently weighted, in a seemingly random order. Within this task, we hid short series of incrementally increasing object weights. This allowed us to investigate whether participants would scale their forces for specific object weights based on the previously lifted object (i.e., sensorimotor effect) or based on the implicit information about the hidden series of incrementally increasing weights (i.e., extrapolation beyond sensorimotor effects). Results showed that participants did not extrapolate fingertip forces based on the hidden series but scaled their forces solely on the previously lifted object. Unsurprisingly, CSE was not modulated differently when lifting series of random weights versus series of increasing weights. Altogether, these results in two different grasping tasks suggest that CSE encodes ongoing motor components but not sensorimotor cues that are hidden within contextual information.HighlightsExplicit visual cues and sensorimotor experience are key for object graspingInvestigating influence of implicit, contextual information on object graspingExplicit but not implicit cues improve motor performance during object graspingExplicit but not implicit cues modulate corticospinal excitability

Observation of object lifting allows updating of internal object representations for object weight, in turn enabling accurate scaling of fingertip forces when lifting the same object. Here, we investigated whether lift observation also enables updating of internal representations for an object's weight distribution. We asked participants to lift an inverted T-shaped manipulandum, of which the weight distribution could be changed, in turns with an actor. Participants were required to minimize object roll (i.e., "lift performance") during lifting and were allowed to place their fingertips at self-chosen locations. The center of mass changed unpredictably every third to sixth trial performed by the actor, and participants were informed that they would always lift the same weight distribution as the actor. Participants observed either erroneous (i.e., object rolling toward its heavy side) or skilled (i.e., minimized object roll) lifts. Lifting performance after observation was compared with lifts without prior observation and with lifts after active lifting, which provided haptic feedback about the weight distribution. Our results show that observing both skilled and erroneous lifts convey an object's weight distribution similar to active lifting, resulting in altered digit positioning strategies. However, minimizing object roll on novel weight distributions was only improved after observing error lifts and not after observing skilled lifts. In sum, these findings suggest that although observing motor errors and skilled motor performance enables updating of digit positioning strategy, only observing error lifts enables changes in predictive motor control when lifting objects with unexpected weight distributions.NEW & NOTEWORTHY Individuals are able to extract an object's size and weight by observing interactions with objects and subsequently integrate this information in their own motor repertoire. Here, we show that this ability extrapolates to weight distributions. Specifically, we highlighted that individuals can perceive an object's weight distribution during lift observation but can only partially embody this information when planning their own actions. ispartof: JOURNAL OF NEUROPHYSIOLOGY vol:125 issue:4 pages:1348-1366 ispartof: location:United States status: published

Transcranial magnetic stimulation (TMS) studies showed that corticospinal excitability (CSE) is modulated during observation of object lifting, an effect termed 'motor resonance'. Specifically, motor resonance is driven by movement features indicating object weight, such as object size or observed movement kinematics. We investigated in 16 humans (8 females) whether motor resonance is also modulated by an object's weight distribution. Participants were asked to lift an inverted T-shaped manipulandum with interchangeable center of mass after first observing an actor lift the same manipulandum. Participants and actor were instructed to minimize object roll and rely on constrained digit positioning during lifting. Constrained positioning was either collinear (i.e., fingertips on the same height) or noncollinear (i.e., fingertip on the heavy side higher than the one on the light side). The center of mass changed unpredictably before the actor's lifts and participants were explained that their weight distribution always matched the actor's one. Last, TMS was applied during both lift observation and planning of lift actions. Our results showed that CSE was similarly modulated during lift observation and planning: when participants observed or planned lifts in which the weight distribution was asymmetrically right-sided, CSE recorded from the thumb muscles was significantly increased compared to when the weight distribution was left-sided. During both lift observation and planning, this increase seemed to be primarily driven by the weight distribution and not specifically by the (observed) digit positioning or muscle contraction. In conclusion, our results indicate that complex intrinsic object properties such as weight distributions can modulate activation of the motor system during both observation and planning of lifting actions. ispartof: Neuropsychologia vol:156 ispartof: location:England status: published

Skillful object lifting relies on scaling fingertip forces according to the object's weight. When no visual cues about weight are available, force planning relies on previous lifting experience. Recently, we showed that previously lifted objects also affect weight estimation, as objects are perceived to be lighter when lifted after heavy objects compared with after light ones. Here, we investigated the underlying neural mechanisms mediating these effects. We asked participants to lift objects and estimate their weight. Simultaneously, we applied transcranial magnetic stimulation (TMS) during the dynamic loading or static holding phase. Two subject groups received TMS over either the anterior intraparietal sulcus (aIPS) or the lateral occipital area (LO), known to be important nodes in object grasping and perception. We hypothesized that TMS over aIPS and LO during object lifting would alter force scaling and weight perception. Contrary to our hypothesis, we did not find effects of aIPS or LO stimulation on force planning or weight estimation caused by previous lifting experience. However, we found that TMS over both areas increased grip forces, but only when applied during dynamic loading, and decreased weight estimation, but only when applied during static holding, suggesting time-specific effects. Interestingly, our results also indicate that TMS over LO, but not aIPS, affected load force scaling specifically for heavy objects, which further indicates that load and grip forces might be controlled differently. These findings provide new insights on the interactions between brain networks mediating action and perception during object manipulation.NEW & NOTEWORTHY This article provides new insights into the neural mechanisms underlying object lifting and perception. Using transcranial magnetic stimulation during object lifting, we show that effects of previous experience on force scaling and weight perception are not mediated by the anterior intraparietal sulcus or the lateral occipital cortex (LO). In contrast, we highlight a unique role for LO in load force scaling, suggesting different brain processes for grip and load force scaling in object manipulation. ispartof: JOURNAL OF NEUROPHYSIOLOGY vol:124 issue:2 pages:557-573 ispartof: location:United States status: published

Transcranial magnetic stimulation (TMS) studies have highlighted that corticospinal excitability (CSE) is increased during observation of object lifting, an effect termed ‘motor resonance’. This facilitation is driven by movement features indicative of object weight, such as object size or observed movement kinematics. Here, we investigated in 35 humans (23 females) how motor resonance is altered when the observer’s weight expectations, based on visual information, do not match the actual object weight as revealed by the observed movement kinematics. Our results highlight that motor resonance is not robustly driven by object weight but easily masked by a suppressive mechanism reflecting the correctness of the weight expectations. Subsequently, we investigated in 24 humans (14 females) whether this suppressive mechanism was driven by higher-order cortical areas. For this, we induced ‘virtual lesions’ to either the posterior superior temporal sulcus (pSTS) or dorsolateral prefrontal cortex (DLPFC) prior to having participants perform the task. Importantly, virtual lesion of pSTS eradicated this suppressive mechanism and restored object weight-driven motor resonance. In addition, DLPFC virtual lesion eradicated any modulation of motor resonance. This indicates that motor resonance is heavily mediated by top-down inputs from both pSTS and DLPFC. Altogether, these findings shed new light on the theorized cortical network driving motor resonance. That is, our findings highlight that motor resonance is not only driven by the putative human mirror neuron network consisting of the primary motor and premotor cortices as well as the anterior intraparietal sulcus, but also by top-down input from pSTS and DLPFC.Significance StatementObservation of object lifting activates the observer’s motor system in a weight-specific fashion: Corticospinal excitability is larger when observing lifts of heavy objects compared to light ones. Interestingly, here we demonstrate that this weight-driven modulation of corticospinal excitability is easily suppressed by the observer’s expectations about object weight and that this suppression is mediated by the posterior superior temporal sulcus. Thus, our findings show that modulation of corticospinal excitability during observed object lifting is not robust but easily altered by top-down cognitive processes. Finally, our results also indicate how cortical inputs, originating remotely from motor pathways and processing action observation, overlap with bottom-up motor resonance effects.

Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19&minus, ), combined hepatocellular&ndash, cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19&minus, HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19&minus, HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.

Changes in both brain structure and neurophysiological function regulating homotopic as well as heterotopic interhemispheric interactions (IHIs) are assumed to be responsible for the bimanual performance deficits in older adults. However, how the structural and functional networks regulating bimanual performance decline in older adults, as well as the interplay between brain structure and function remain largely unclear. Using a dual-site transcranial magnetic stimulation paradigm, we examined the age-related changes in the interhemispheric effects from the dorsolateral prefrontal cortex and dorsal premotor cortex onto the contralateral primary motor cortex (M1) during the preparation of a complex bimanual coordination task in human. Structural properties of these interactions were assessed with diffusion-based fiber tractography. Compared with young adults, older adults showed performance declines in the more difficult bimanual conditions, less optimal brain white matter (WM) microstructure, and a decreased ability to regulate the interaction between dorsolateral prefrontal cortex and M1. Importantly, we found that WM microstructure, neurophysiological function, and bimanual performance were interrelated in older adults, whereas only the task-related changes in IHI predicted bimanual performance in young adults. These results reflect unique interactions between structure and function in the aging brain, such that declines in WM microstructural organization likely lead to dysfunctional regulation of IHI, ultimately accounting for bimanual performance deficits.SIGNIFICANCE STATEMENTThe structural and functional changes in the aging brain are associated with a decline in movement control, compromising functional independence. We used MRI and noninvasive brain stimulation techniques to investigate white matter microstructural organization and neurophysiological function in the aging brain, in relation to bimanual movement control. We found that less optimal brain microstructural organization and task-related modulations in neurophysiological function resulted in poor bimanual performance in older adults. By interrelating brain structure, neurophysiological function, and behavior, the current study provides a comprehensive picture of biological alterations in the aging brain that underlie declines in bimanual performance.

Even though it has been suggested that the dorsolateral prefrontal cortex (DLPFC) and dorsal premotor cortex (PMd) are highly involved in the planning of bimanual movements, the exact nature (facilitatory or inhibitory) of their role is not well understood. Using a dual-site transcranial magnetic stimulation (TMS) paradigm, we examined the functional influence from DLPFC and PMd to the contralateral primary cortex (M1) during the preparation of a complex bimanual coordination task in which inter-hand movement frequency was manipulated. Only the left PMd showed inter-hand frequency-specific modulations in the interaction with the contralateral M1. Left PMd-right M1 interaction became facilitatory during the preparation phase when the left hand had to move faster than the right hand, while inhibitory modulation was observed when the movement frequency arrangement was reversed. Interestingly, bilateral DLPFC showed a facilitatory interaction with the contralateral M1s during the preparation period only in difficult conditions, irrespective of the inter-hand frequency ratio, suggesting a less task-specific role in the organization of complex bimanual actions. Observed task-related modulations in DLPFC-M1 and left PMd-right M1 interactions during preparation were significantly correlated with up-coming performance, predicting successful bimanual movements. These observations highlight the distinct roles of DLPFC and left PMd in the preparation of bimanual movements that require a differential contribution of each limb.