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Our ability to skillfully manipulate objects is supported by rapid corrective responses that are initiated when we experience perturbations that interfere with movement goals. For example, the corrective lifting response is triggered when an object is heavier than expected and fails to lift off the surface. In this situation, the absence of expected sensory feedback signalling lift off initiates, within ~ 90 ms, an increase in lifting force. Importantly, when people repeatedly lift an object that, on occasional catch trials, is heavier than expected, the gain of the corrective response, defined as the rate of force increase, adapts to the 'catch' weight. In the present study, we investigated whether this response adaption transfers intermanually. In the training phase, participants used either their left or right hand (counterbalanced) to repeatedly lift a 3 N object that unexpectedly increased to 9 N on catch trials, leading to an increase in the gain of the lifting response across catch trials. Participants then lifted the object with their other hand. On the first catch trial, the gain remained elevated and thus transferred across the hands. This finding suggests that the history of lifts performed by one hand updates the corrective responses for both hands., (© 2024. The Author(s).)

Introduction: Epilepsy is a common neurological disorder characterised by recurrent seizures. Almost half of patients who have an unprovoked first seizure (UFS) have additional seizures and develop epilepsy. No current predictive models exist to determine who has a higher risk of recurrence to guide treatment. Emerging evidence suggests alterations in cognition, mood and brain connectivity exist in the population with UFS. Baseline evaluations of these factors following a UFS will enable the development of the first multimodal biomarker-based predictive model of seizure recurrence in adults with UFS., Methods and Analysis: 200 patients and 75 matched healthy controls (aged 18-65) from the Kingston and Halifax First Seizure Clinics will undergo neuropsychological assessments, structural and functional MRI, and electroencephalography. Seizure recurrence will be assessed prospectively. Regular follow-ups will occur at 3, 6, 9 and 12 months to monitor recurrence. Comparisons will be made between patients with UFS and healthy control groups, as well as between patients with and without seizure recurrence at follow-up. A multimodal machine-learning model will be trained to predict seizure recurrence at 12 months., Ethics and Dissemination: This study was approved by the Health Sciences and Affiliated Teaching Hospitals Research Ethics Board at Queen's University (DMED-2681-22) and the Nova Scotia Research Ethics Board (1028519). It is supported by the Canadian Institutes of Health Research (PJT-183906). Findings will be presented at national and international conferences, published in peer-reviewed journals and presented to the public via patient support organisation newsletters and talks., Trial Registration Number: NCT05724719., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model (N = 31) and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the parietal and temporal cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of parietal and temporal regions in spontaneous behavioural recovery., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Motor errors can have both bias and noise components. Bias can be compensated for by adaptation and, in tasks in which the magnitude of noise varies across the environment, noise can be reduced by identifying and then acting in less noisy regions of the environment. Here we examine how these two processes interact when participants reach under a combination of an externally imposed visuomotor bias and noise. In a center-out reaching task, participants experienced noise (zero-mean random visuomotor rotations) that was target-direction dependent with a standard deviation that increased linearly from a least-noisy direction. They also experienced a constant bias, a visuomotor rotation that varied (across groups) from 0 to 40 degrees. Critically, on each trial, participants could select one of three targets to reach to, thereby allowing them to potentially select targets close to the least-noisy direction. The group who experienced no bias (0 degrees) quickly learned to select targets close to the least-noisy direction. However, groups who experienced a bias often failed to identify the least-noisy direction, even though they did partially adapt to the bias. When noise was introduced after participants experienced and adapted to a 40 degrees bias (without noise) in all directions, they exhibited an improved ability to find the least-noisy direction. We developed two models-one for reach adaptation and one for target selection-that could explain participants' adaptation and target-selection behavior. Our data and simulations indicate that there is a trade-off between adaptation and selection. Specifically, because bias learning is local, participants can improve performance, through adaptation, by always selecting targets that are closest to a chosen direction. However, this comes at the expense of improving performance, through selection, by reaching toward targets in different directions to find the least-noisy direction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zhu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (Copyright © 2023 the authors.)

Real world search tasks often involve action on a target object once it has been located. However, few studies have examined whether movement-related costs associated with acting on located objects influence visual search. Here, using a task in which participants reached to a target object after locating it, we examined whether people take into account obstacles that increase movement-related costs for some regions of the reachable search space but not others. In each trial, a set of 36 objects (4 targets and 32 distractors) were displayed on a vertical screen and participants moved a cursor to a target after locating it. Participants had to fixate on an object to determine whether it was a target or distractor. A rectangular obstacle, of varying length, location, and orientation, was briefly displayed at the start of the trial. Participants controlled the cursor by moving the handle of a robotic manipulandum in a horizontal plane. The handle applied forces to simulate contact between the cursor and the unseen obstacle. We found that search, measured using eye movements, was biased to regions of the search space that could be reached without moving around the obstacle. This result suggests that when deciding where to search, people can incorporate the physical structure of the environment so as to reduce the movement-related cost of subsequently acting on the located target.

Humans vary greatly in their motor learning abilities, yet little is known about the neural processes that underlie this variability. We identified distinct profiles of human sensorimotor adaptation that emerged across 2 days of learning, linking these profiles to the dynamics of whole-brain functional networks early on the first day when cognitive strategies toward sensorimotor adaptation are believed to be most prominent. During early learning, greater recruitment of a network of higher-order brain regions, involving prefrontal and anterior temporal cortex, was associated with faster learning. At the same time, greater integration of this "cognitive network" with a sensorimotor network was associated with slower learning, consistent with the notion that cognitive strategies toward adaptation operate in parallel with implicit learning processes of the sensorimotor system. On the second day, greater recruitment of a network that included the hippocampus was associated with faster learning, consistent with the notion that declarative memory systems are involved with fast relearning of sensorimotor mappings. Together, these findings provide novel evidence for the role of higher-order brain systems in driving variability in adaptation., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Real-world search behavior often involves limb movements, either during search or after search. Here we investigated whether movement-related costs influence search behavior in two kinds of search tasks. In our visual search tasks, participants made saccades to find a target object among distractors and then moved a cursor, controlled by the handle of a robotic manipulandum, to the target. In our manual search tasks, participants moved the cursor to perform the search, placing it onto objects to reveal their identity as either a target or a distractor. In all tasks, there were multiple targets. Across experiments, we manipulated either the effort or time costs associated with movement such that these costs varied across the search space. We varied effort by applying different resistive forces to the handle, and we varied time costs by altering the speed of the cursor. Our analysis of cursor and eye movements during manual and visual search, respectively, showed that effort influenced manual search but did not influence visual search. In contrast, time costs influenced both visual and manual search. Our results demonstrate that, in addition to perceptual and cognitive factors, movement-related costs can also influence search behavior. NEW & NOTEWORTHY Numerous studies have investigated the perceptual and cognitive factors that influence decision making about where to look, or move, in search tasks. However, little is known about how search is influenced by movement-related costs associated with acting on an object once it has been visually located or acting during manual search. In this article, we show that movement time costs can bias visual and manual search and that movement effort costs bias manual search.

Sensorimotor learning is a dynamic, systems-level process that involves the combined action of multiple neural systems distributed across the brain. Although much is known about the specialized cortical systems that support specific components of action (such as reaching), we know less about how cortical systems function in a coordinated manner to facilitate adaptive behavior. To address this gap, our study measured human brain activity using functional MRI (fMRI) while participants performed a classic sensorimotor adaptation task and used a manifold learning approach to describe how behavioral changes during adaptation relate to changes in the landscape of cortical activity. During early adaptation, areas in the parietal and premotor cortices exhibited significant contraction along the cortical manifold, which was associated with their increased covariance with regions in the higher-order association cortex, including both the default mode and fronto-parietal networks. By contrast, during Late adaptation, when visuomotor errors had been largely reduced, a significant expansion of the visual cortex along the cortical manifold was associated with its reduced covariance with the association cortex and its increased intraconnectivity. Lastly, individuals who learned more rapidly exhibited greater covariance between regions in the sensorimotor and association cortices during early adaptation. These findings are consistent with a view that sensorimotor adaptation depends on changes in the integration and segregation of neural activity across more specialized regions of the unimodal cortex with regions in the association cortex implicated in higher-order processes. More generally, they lend support to an emerging line of evidence implicating regions of the default mode network (DMN) in task-based performance.

Error-based and reward-based processes are critical for motor learning and are thought to be mediated via distinct neural pathways. However, recent behavioral work in humans suggests that both learning processes can be bolstered by the use of cognitive strategies, which may mediate individual differences in motor learning ability. It has been speculated that medial temporal lobe regions, which have been shown to support motor sequence learning, also support the use of cognitive strategies in error-based and reinforcement motor learning. However, direct evidence in support of this idea remains sparse. Here we first show that better overall learning during error-based visuomotor adaptation is associated with better overall learning during the reward-based shaping of reaching movements. Given the cognitive contribution to learning in both of these tasks, these results support the notion that strategic processes, associated with better performance, drive intersubject variation in both error-based and reinforcement motor learning. Furthermore, we show that entorhinal cortex volume is larger in better learning individuals-characterized across both motor learning tasks-compared with their poorer learning counterparts. These results suggest that individual differences in learning performance during error and reinforcement learning are related to neuroanatomical differences in entorhinal cortex., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Humans vary greatly in their motor learning abilities, yet little is known about the neural mechanisms that underlie this variability. Recent neuroimaging and electrophysiological studies demonstrate that large-scale neural dynamics inhabit a low-dimensional subspace or manifold, and that learning is constrained by this intrinsic manifold architecture. Here, we asked, using functional MRI, whether subject-level differences in neural excursion from manifold structure can explain differences in learning across participants. We had subjects perform a sensorimotor adaptation task in the MRI scanner on 2 consecutive days, allowing us to assess their learning performance across days, as well as continuously measure brain activity. We find that the overall neural excursion from manifold activity in both cognitive and sensorimotor brain networks is associated with differences in subjects' patterns of learning and relearning across days. These findings suggest that off-manifold activity provides an index of the relative engagement of different neural systems during learning, and that subject differences in patterns of learning and relearning are related to reconfiguration processes occurring in cognitive and sensorimotor networks., Competing Interests: CA, DG, DS, JN, JF, JG No competing interests declared, (© 2022, Areshenkoff et al.)

Recent data and motor control theory argues that movement planning involves preparing the neural state of primary motor cortex (M1) for forthcoming action execution. Theories related to internal models, feedback control, and predictive coding also emphasize the importance of sensory prediction (and processing) prior to (and during) the movement itself, explaining why motor-related deficits can arise from damage to primary somatosensory cortex (S1). Motivated by this work, here we examined whether motor planning, in addition to changing the neural state of M1, changes the neural state of S1, preparing it for the sensory feedback that arises during action. We tested this idea in two human functional MRI studies (N=31, 16 female) involving delayed object manipulation tasks, focusing our analysis on pre-movement activity patterns in M1 and S1. We found that the motor effector to be used in the upcoming action could be decoded, well before movement, from neural activity in M1 in both studies. Critically, we found that this effector information was also present, well before movement, in S1. In particular, we found that the encoding of effector information in area 3b (S1 proper) was linked to the contralateral hand, similarly to that found in M1, whereas in areas 1 and 2 this encoding was present in both the contralateral and ipsilateral hemispheres. Together, these findings suggest that motor planning not only prepares the motor system for movement, but also changes the neural state of the somatosensory system, presumably allowing it to anticipate the sensory information received during movement. SIGNIFICANCE STATEMENT: Whereas recent work on motor cortex has emphasized the critical role of movement planning in preparing neural activity for movement generation, it has not investigated the extent to which planning also modulates the activity in adjacent primary somatosensory cortex (S1). This reflects a key gap in knowledge, given that recent motor control theories emphasize the importance of sensory feedback processing in effective movement generation. Here we find, through a convergence of experiments and analyses, that the planning of object manipulation tasks, in addition to modulating the activity in motor cortex, changes the state of neural activity in different subfields of human S1. We suggest that this modulation prepares S1 for the sensory information it will receive during action execution., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 the authors.)

It is well established that movement planning recruits motor-related cortical brain areas in preparation for the forthcoming action. Given that an integral component to the control of action is the processing of sensory information throughout movement, we predicted that movement planning might also modulate early sensory cortical areas, readying them for sensory processing during the unfolding action. To test this hypothesis, we performed 2 human functional magnetic resonance imaging studies involving separate delayed movement tasks and focused on premovement neural activity in early auditory cortex, given the area's direct connections to the motor system and evidence that it is modulated by motor cortex during movement in rodents. We show that effector-specific information (i.e., movements of the left vs. right hand in Experiment 1 and movements of the hand vs. eye in Experiment 2) can be decoded, well before movement, from neural activity in early auditory cortex. We find that this motor-related information is encoded in a separate subregion of auditory cortex than sensory-related information and is present even when movements are cued visually instead of auditorily. These findings suggest that action planning, in addition to preparing the motor system for movement, involves selectively modulating primary sensory areas based on the intended action., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Changes in resting-state functional connectivity (rs-FC) under general anesthesia have been widely studied with the goal of identifying neural signatures of consciousness. This work has commonly revealed an apparent fragmentation of whole-brain network structure during unconsciousness, which has been interpreted as reflecting a break-down in connectivity and a disruption of the brain's ability to integrate information. Here we show, by studying rs-FC under varying depths of isoflurane-induced anesthesia in nonhuman primates, that this apparent fragmentation, rather than reflecting an actual change in network structure, can be simply explained as the result of a global reduction in FC. Specifically, by comparing the actual FC data to surrogate data sets that we derived to test competing hypotheses of how FC changes as a function of dose, we found that increases in whole-brain modularity and the number of network communities - considered hallmarks of fragmentation - are artifacts of constructing FC networks by thresholding based on correlation magnitude. Taken together, our findings suggest that deepening levels of unconsciousness are instead associated with the increasingly muted expression of functional networks, an observation that constrains current interpretations as to how anesthesia-induced FC changes map onto existing neurobiological theories of consciousness., (Copyright © 2021. Published by Elsevier Inc.)

Everyday tasks such as catching a ball appear effortless, but in fact require complex interactions and tight temporal coordination between the brain's visual and motor systems. What makes such interceptive actions particularly impressive is the capacity of the brain to account for temporal delays in the central nervous system-a limitation that can be mitigated by making predictions about the environment as well as one's own actions. Here, we wanted to assess how well human participants can plan an upcoming movement based on a dynamic, predictable stimulus that is not the target of action. A central stationary or rotating stimulus determined the probability that each of two potential targets would be the eventual target of a rapid reach-to-touch movement. We examined the extent to which reach movement trajectories convey internal predictions about the future state of dynamic probabilistic information conveyed by the rotating stimulus. We show that movement trajectories reflect the target probabilities determined at movement onset, suggesting that humans rapidly and accurately integrate visuospatial predictions and estimates of their own reaction times to effectively guide action., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

General anesthetics are routinely used to induce unconsciousness, and much is known about their effects on receptor function and single neuron activity. Much less is known about how these local effects are manifest at the whole-brain level nor how they influence network dynamics, especially past the point of induced unconsciousness. Using resting-state functional magnetic resonance imaging (fMRI) with nonhuman primates, we investigated the dose-dependent effects of anesthesia on whole-brain temporal modular structure, following loss of consciousness. We found that higher isoflurane dose was associated with an increase in both the number and isolation of whole-brain modules, as well as an increase in the uncoordinated movement of brain regions between those modules. Conversely, we found that higher dose was associated with a decrease in the cohesive movement of brain regions between modules, as well as a decrease in the proportion of modules in which brain regions participated. Moreover, higher dose was associated with a decrease in the overall integrity of networks derived from the temporal modules, with the exception of a single, sensory-motor network. Together, these findings suggest that anesthesia-induced unconsciousness results from the hierarchical fragmentation of dynamic whole-brain network structure, leading to the discoordination of temporal interactions between cortical modules., (© The Author(s) 2020. Published by Oxford University Press.)

Skillful manipulation requires forming memories of object dynamics, linking applied force to motion. Although it has been assumed that such memories are linked to objects, a recent study showed that people can form separate memories when these are linked to different controlled points on an object (Heald JB, Ingram JN, Flanagan JR, Wolpert DM. Nat Hum Behav 2: 300-311, 2018). In that study, participants controlled the handle of a robotic device to move a virtual bar with circles (control points) on the left and right sides. Participants were instructed to move either the left or right control point to a target on the left or right, respectively, such that the required movement was constant. When these control points were paired with opposing force fields, adaptation was observed. In this previous study, both the controlled point and the target changed between contexts. To assess which of these factors is critical for learning, here, we used a similar paradigm but with a bar that automatically rotated as it was moved. In the first experiment, the bar rotated, such that the left and right control points moved to a common target. In the second experiment, the bar rotated such that a single control point moved to a target located on either the left or right. In both experiments, participants were able to learn opposing force fields applied in the two contexts. We conclude that separate memories of dynamics can be formed for different "contact goals," involving a unique combination of the controlled point on an object and the target location this point "contacts." NEW & NOTEWORTHY Skilled manipulation requires forming memories of object dynamics, previously assumed to be associated with entire objects. However, we recently demonstrated that people can form multiple motor memories when explicitly instructed to move different locations on an object to different targets. Here, we show that separate motor memories can be learned for different contact goals, which involve a unique combination of a control point and target.

Decision making is a fundamental cognitive function, which not only determines our day-to-day choices but also shapes the trajectories of our movements, our lives, and our societies. While immense progress has been made in recent years on our understanding of the mechanisms underlying decision making, research on this topic is still largely split into two halves. Good-based models largely state that decisions are made between representations of abstract value associated with available options; while action-based models largely state that decisions are made at the level of action representations. These models are further divided between those that state that a decision is made before an action is specified, and those that regard decision making as an evolving process that continues until movement completion. Here, we review computational models, behavioral findings, and results from neural recordings associated with these frameworks. In synthesizing this literature, we submit that decision making is best understood as a continuous, graded, and distributed process that traverses a landscape of behaviorally relevant options, from their presentation until movement completion. Identifying and understanding the intimate links between decision making and action processing has important implications for the study of complex, goal-directed behaviors such as social communication, and for elucidating the underlying mechanisms by which decisions are formed., (© 2018 New York Academy of Sciences.)

It is well-established that people can factor into account the distribution of their errors in motor performance so as to optimize reward. Here we asked whether, in the context of motor learning where errors decrease across trials, people take into account their future, improved performance so as to make optimal decisions to maximize reward. One group of participants performed a virtual throwing task in which, periodically, they were given the opportunity to select from a set of smaller targets of increasing value. A second group of participants performed a reaching task under a visuomotor rotation in which, after performing a initial set of trials, they selected a reward structure (ratio of points for target hits and misses) for different exploitation horizons (i.e., numbers of trials they might be asked to perform). Because movement errors decreased exponentially across trials in both learning tasks, optimal target selection (task 1) and optimal reward structure selection (task 2) required taking into account future performance. The results from both tasks indicate that people anticipate their future motor performance so as to make decisions that will improve their expected future reward., Competing Interests: The authors have declared that no competing interests exist.

The primate visual system contains myriad feedback projections from higher- to lower-order cortical areas, an architecture that has been implicated in the top-down modulation of early visual areas during working memory and attention. Here we tested the hypothesis that these feedback projections also modulate early visual cortical activity during the planning of visually guided actions. We show, across three separate human functional magnetic resonance imaging (fMRI) studies involving object-directed movements, that information related to the motor effector to be used (i.e., limb, eye) and action goal to be performed (i.e., grasp, reach) can be selectively decoded-prior to movement-from the retinotopic representation of the target object(s) in early visual cortex. We also find that during the planning of sequential actions involving objects in two different spatial locations, that motor-related information can be decoded from both locations in retinotopic cortex. Together, these findings indicate that movement planning selectively modulates early visual cortical activity patterns in an effector-specific, target-centric, and task-dependent manner. These findings offer a neural account of how motor-relevant target features are enhanced during action planning and suggest a possible role for early visual cortex in instituting a sensorimotor estimate of the visual consequences of movement., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Skillful manipulation requires forming and recalling memories of the dynamics of objects linking applied force to motion. It has been assumed that such memories are associated with entire objects. However, we often control different locations on an object, and these locations may be associated with different dynamics. We have previously demonstrated that multiple memories can be formed when participants are explicitly instructed to control different visual points marked on an object. A key question is whether this novel finding generalizes to more natural situations in which control points are implicitly defined by the task. To answer this question, we used objects with no explicit control points and tasks designed to encourage the use of distinct implicit control points. Participants moved a handle, attached to a robotic interface, to control the position of a rectangular object ("eraser") in the horizontal plane. Participants were required to move the eraser straight ahead to wipe away a column of dots ("dust"), located to either the left or right. We found that participants adapted to opposing dynamics when linked to the left and right dust locations, even though the movements required for these two contexts were the same. Control conditions showed this learning could not be accounted for by contextual cues or the fact that the task goal required moving in a straight line. These results suggest that people naturally control different locations on manipulated objects depending on the task context and that doing so affords the formation of separate motor memories. NEW & NOTEWORTHY Skilled manipulation requires forming motor memories of object dynamics, which have been assumed to be associated with entire objects. However, we recently demonstrated that people can form multiple memories when explicitly instructed to control different visual points on an object. In this article we show that this novel finding generalizes to more natural situations in which control points are implicitly defined by the task.

During goal-directed reaching, people typically direct their gaze to the target before the start of the hand movement and maintain fixation until the hand arrives. This gaze strategy improves reach accuracy in two ways. It enables the use of central vision at the end of movement, and it allows the use of extraretinal information in guiding the hand to the target. Here we tested whether fixating the reach target further facilitates reach accuracy by optimizing the use of peripheral vision in detecting, and rapidly responding to, reach errors during the ongoing movement. We examined automatic visuomotor corrections in response to displacements of the cursor representing the hand position as a function of gaze fixation location during unimanual goal-directed reaching. Eight fixation targets were positioned either in line with, or at different angles relative to, the straight-ahead movement direction (manipulation of fixation angle), and at different distances from the location of the visual perturbation (manipulation of fixation distance). We found that corrections were fastest and strongest when gaze was directed at the reach target compared with when gaze was directed to a different location in the workspace. We found that the gain of the visuomotor response was strongly affected by fixation angle, and to a smaller extent by fixation distance, with lower gains as the angle or distance increased. We submit that fixating the reach target improves reach accuracy by facilitating rapid visuomotor responses to reach errors viewed in peripheral vision. NEW & NOTEWORTHY It is well known that directing gaze to the reach target allows the use of foveal visual feedback and extraretinal information to improve the accuracy of reaching movements. Here we demonstrate that target fixation also optimizes rapid visuomotor corrections to reach errors viewed in peripheral vision, with the angle of gaze relative to the hand movement being a critical determinant in the gain of the visuomotor response.

Successful motor performance relies on our ability to adapt to changes in the environment by learning novel mappings between motor commands and sensory outcomes. Such adaptation is thought to involve two distinct mechanisms: an implicit, error-based component linked to slow learning and an explicit, strategic component linked to fast learning and savings (i.e., faster relearning). Because behavior, at any given moment, is the resultant combination of these two processes, it has remained a challenge to parcellate their relative contributions to performance. The explicit component to visuomotor rotation (VMR) learning has recently been measured by having participants verbally report their aiming strategy used to counteract the rotation. However, this procedure has been shown to magnify the explicit component. Here we tested whether task-specific eye movements, a natural component of reach planning, but poorly studied in motor learning tasks, can provide a direct readout of the state of the explicit component during VMR learning. We show, by placing targets on a visible ring and including a delay between target presentation and reach onset, that individual differences in gaze patterns during sensorimotor learning are linked to participants' rates of learning and their expression of savings. Specifically, we find that participants who, during reach planning, naturally fixate an aimpoint rotated away from the target location, show faster initial adaptation and readaptation 24 h later. Our results demonstrate that gaze behavior cannot only uniquely identify individuals who implement cognitive strategies during learning but also how their implementation is linked to differences in learning. NEW & NOTEWORTHY Although it is increasingly well appreciated that sensorimotor learning is driven by two separate components, an error-based process and a strategic process, it has remained a challenge to identify their relative contributions to performance. Here we demonstrate that task-specific eye movements provide a direct read-out of explicit strategies during sensorimotor learning in the presence of visual landmarks. We further show that individual differences in gaze behavior are linked to learning rate and savings.

Skilled sensorimotor interactions with the world result from a series of decision-making processes that determine, on the basis of information extracted during the unfolding sequence of events, which movements to make and when and how to make them. Despite this inherent link between decision-making and sensorimotor control, research into each of these two areas has largely evolved in isolation, and it is only fairly recently that researchers have begun investigating how they interact and, together, influence behaviour. Here, we review recent behavioural, neurophysiological and computational research that highlights the role of decision-making processes in the selection, planning and control of goal-directed movements in humans and nonhuman primates.

Several lines of evidence point to areas in the occipitotemporal pathway as being critical in the processes of visual perception and object recognition. Much less appreciated, however, is the role that this pathway plays in object-related processing for the purposes of visually guided action. Here, using functional MRI (fMRI) and functional connectivity (FC) measures, we examined interactions between areas in frontoparietal cortex (FPC) involved in grasping, reaching, eye movements, and tool use and areas in occipitotemporal cortex (OTC) involved in object-, face-, scene-, body-, tool-, and motion-related processing, both during the performance of sensorimotor and visual-perceptual tasks, as well as during passive fixation (resting-state). Cluster analysis of regional time course data identified correspondence in the patterns of FPC and OTC connectivity during the visual-perceptual tasks and rest that both tended to segregate regions along traditional dorsal/ventral pathway boundaries. During the sensorimotor tasks, however, we observed a notable separation in functional coupling between ventral-medial and ventral-lateral regions of OTC, with several of the latter areas often being clustered together with sensorimotor-defined areas in parietal cortex. These findings indicate that the functional coupling of ventral-lateral OTC areas to dorsal parietal and ventral-medial structures is flexible and task-dependent, and suggests that regions in lateral occipital cortex, in particular, may play an important role in mediating interactions between the dorsal and ventral pathways during tasks involving sensorimotor control., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In 1992, Goodale and Milner proposed a division of labor in the visual pathways of the primate cerebral cortex. According to their account, the ventral pathway, which projects to occipitotemporal cortex, constructs our visual percepts, while the dorsal pathway, which projects to posterior parietal cortex, mediates the visual control of action. Although the framing of the two-visual-system hypothesis has not been without controversy, it is clear that vision for action and vision for perception have distinct computational requirements, and significant support for the proposed neuroanatomic division has continued to emerge over the last two decades from human neuropsychology, neuroimaging, behavioral psychophysics, and monkey neurophysiology. In this chapter, we review much of this evidence, with a particular focus on recent findings from human neuroimaging and monkey neurophysiology, demonstrating a specialized role for parietal cortex in visually guided behavior. But even though the available evidence suggests that dedicated circuits mediate action and perception, in order to produce adaptive goal-directed behavior there must be a close coupling and seamless integration of information processing across these two systems. We discuss such ventral-dorsal-stream interactions and argue that the two pathways play different, yet complementary, roles in the production of skilled behavior., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The role of the early visual cortex and higher-order occipitotemporal cortex has been studied extensively for visual recognition and to a lesser degree for haptic recognition and visually guided actions. Using a slow event-related fMRI experiment, we investigated whether tactile and visual exploration of objects recruit the same "visual" areas (and in the case of visual cortex, the same retinotopic zones) and if these areas show reactivation during delayed actions in the dark toward haptically explored objects (and if so, whether this reactivation might be due to imagery). We examined activation during visual or haptic exploration of objects and action execution (grasping or reaching) separated by an 18 s delay. Twenty-nine human volunteers (13 females) participated in this study. Participants had their eyes open and fixated on a point in the dark. The objects were placed below the fixation point and accordingly visual exploration activated the cuneus, which processes retinotopic locations in the lower visual field. Strikingly, the occipital pole (OP), representing foveal locations, showed higher activation for tactile than visual exploration, although the stimulus was unseen and location in the visual field was peripheral. Moreover, the lateral occipital tactile-visual area (LOtv) showed comparable activation for tactile and visual exploration. Psychophysiological interaction analysis indicated that the OP showed stronger functional connectivity with anterior intraparietal sulcus and LOtv during the haptic than visual exploration of shapes in the dark. After the delay, the cuneus, OP, and LOtv showed reactivation that was independent of the sensory modality used to explore the object. These results show that haptic actions not only activate "visual" areas during object touch, but also that this information appears to be used in guiding grasping actions toward targets after a delay. SIGNIFICANCE STATEMENT Visual presentation of an object activates shape-processing areas and retinotopic locations in early visual areas. Moreover, if the object is grasped in the dark after a delay, these areas show "reactivation." Here, we show that these areas are also activated and reactivated for haptic object exploration and haptically guided grasping. Touch-related activity occurs not only in the retinotopic location of the visual stimulus, but also at the occipital pole (OP), corresponding to the foveal representation, even though the stimulus was unseen and located peripherally. That is, the same "visual" regions are implicated in both visual and haptic exploration; however, touch also recruits high-acuity central representation within early visual areas during both haptic exploration of objects and subsequent actions toward them. Functional connectivity analysis shows that the OP is more strongly connected with ventral and dorsal stream areas when participants explore an object in the dark than when they view it., (Copyright © 2017 the authors 0270-6474/17/3711572-20$15.00/0.)

When presented with competing potential reach targets and required to launch a movement before knowing which one will be cued as the target, people initially reach in the average target direction. Although this spatial averaging could arise from executing a weighted average of motor plans for the potential targets, it could also arise from planning a single, optimal movement. To test between these alternatives we used a task in which participants were required to reach to either a single target or towards two potential targets while grasping an object. A robotic device applied a lateral elastic load to the object requiring large grip forces for reaches to targets either side of midline and a minimal grip force for midline movements. As expected, in trials with two targets located either side of midline, participants initially reached straight ahead. Critically, on these trials the initial grip force was minimal, appropriate for the midline movement, and not the average of the large grip forces required for movements to the individual targets. These results indicate that under conditions of target uncertainty, people do not execute an average of planned actions but rather a single movement that optimizes motor costs.

Multiple cortical regions are crucial for perceiving the visual world, yet the processes shaping representations in these regions are unclear. To address this issue, we must elucidate how perceptual features shape representations of the environment. Here, we explore how the weighting of different visual features affects neural representations of objects and scenes, focusing on the scene-selective parahippocampal place area (PPA), but additionally including the retrosplenial complex (RSC), occipital place area (OPA), lateral occipital (LO) area, fusiform face area (FFA) and occipital face area (OFA). Across three experiments, we examined functional magnetic resonance imaging (fMRI) activity while human observers viewed scenes and objects that varied in geometry (shape/layout) and surface properties (texture/material). Interestingly, we found equal sensitivity in the PPA for these properties within a scene, revealing that spatial-selectivity alone does not drive activation within this cortical region. We also observed sensitivity to object texture in PPA, but not to the same degree as scene texture, and representations in PPA varied when objects were placed within scenes. We conclude that PPA may process surface properties in a domain-specific manner, and that the processing of scene texture and geometry is equally-weighted in PPA and may be mediated by similar underlying neuronal mechanisms., (Copyright © 2017 Elsevier Inc. All rights reserved.)

During goal-directed reaching, rapid visuomotor feedback processes enable the human motor system to quickly correct for errors in the trajectory of the hand that arise from motor noise and, in some cases, external perturbations. To date, these visuomotor responses, the gain of which is sensitive to features of the task and environment, have primarily been examined in the context of unimanual reaching movements toward a single target. However, many natural tasks involve moving both hands together, often to separate targets, such that errors can occur in parallel and at different spatial locations. Here, we examined the resource capacity of automatic visuomotor corrective mechanisms by comparing feedback gains during bimanual reaches, toward two targets, to feedback gains during unimanual reaches toward single targets. To investigate the sensitivity of the feedback gains and their relation to visual-spatial processing, we manipulated the widths of the targets and participants' gaze location. We found that the gain of corrective responses to cursor displacements, while strongly modulated by target width and gaze position, were only slightly reduced during bimanual control. Our results show that automatic visuomotor corrective mechanisms can efficiently operate in parallel across multiple spatial locations., Competing Interests: No conflicts of interest, financial or otherwise, are declared by the authors.

Recent neural and behavioral findings provide support for the influential idea that in situations in which multiple action options are presented simultaneously, we prepare action plans for each competing option before deciding between and executing one of those plans. However, in natural, everyday environments, our available action options frequently change from one moment to the next, and there is often uncertainty as to whether additional options will become available before having to select a particular course of action. Here, with the use of a target-directed reaching task, we show that in this situation, the brain specifies a competing action for each new, sequentially presented potential target and that recently formed action plans can be revisited and updated so as to conform with separate, more newly developed, plans. These findings indicate that the brain forms labile motor plans for sequentially arising target options that can be flexibly restructured to accommodate new motor plans., (Copyright © 2016 the American Physiological Society.)

Introduction & Aim: Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor. The STARTVerso1 and STARTVerso2 phase 3 studies evaluated faldaprevir plus peginterferon alfa-2a/ribavirin (PegIFN/RBV) in treatment-naïve patients with chronic HCV genotype-1 infection., Material and Methods: Patients were randomized 1:2:2 to receive placebo, faldaprevir 120 mg q.d. (12 or 24 weeks) or faldaprevir 240 mg q.d. (12 weeks) all with PegIFN/RBV (24-48 weeks). Faldaprevir 120 mg for 12 weeks only (STARTVerso1 only) required early treatment success (ETS, HCV RNA < 25 IU/mL at week 4 and undetected at week 8). All faldaprevir-treated patients with ETS stopped PegIFN/RBV at week 24. Primary endpoint: sustained virologic response 12 weeks post-treatment (SVR12)., Results: SVR12 rates were significantly higher for patients treated with faldaprevir 120 or 240 mg (72% and 73%, respectively) compared with placebo (50%); estimated differences (adjusted for trial, race, and genotype-1 subtype) faldaprevir 120 mg 24% (95% CI: 17-31%, P < 0.0001), faldaprevir 240 mg 23% (95% CI: 16-30%, P < 0.0001). Subgroup analyses consistently showed higher SVR12 rates for patients receiving faldaprevir compared with placebo. The incidence of adverse events (AEs) was similar in faldaprevir 120-mg and placebo groups and slightly higher in the faldaprevir 240-mg group. Serious Aes were reported in 6%, 7%, and 8% of patients in placebo, faldaprevir 120-mg, and faldaprevir 240-mg groups, respectively., Conclusion: Addition of faldaprevir to PegIFN/RBV increased SVR12 in patients with HCV genotype-1, and was well tolerated. Faldaprevir 120 mg is effective in the treatment of HCV genotype-1. ClinicalTrials.gov: NCT01343888 and NCT01297270.

Recent theory proposes that the brain, when confronted with several action possibilities, prepares multiple competing movements before deciding among them. Psychophysical supporting evidence for this idea comes from the observation that when reaching towards multiple potential targets, the initial movement is directed towards the average location of the targets, consistent with multiple prepared reaches being executed simultaneously. However, reach planning involves far more than specifying movement direction; it requires the specification of a sensorimotor control policy that sets feedback gains shaping how the motor system responds to errors induced by noise or external perturbations. Here we found that, when a subject is reaching towards multiple potential targets, the feedback gain corresponds to an average of the gains specified when reaching to each target presented alone. Our findings provide evidence that the brain, when presented with multiple action options, computes multiple competing sensorimotor control policies in parallel before implementing one of them.

Object-manipulation tasks (e.g., drinking from a cup) typically involve sequencing together a series of distinct motor acts (e.g., reaching toward, grasping, lifting, and transporting the cup) in order to accomplish some overarching goal (e.g., quenching thirst). Although several studies in humans have investigated the neural mechanisms supporting the planning of visually guided movements directed toward objects (such as reaching or pointing), only a handful have examined how manipulatory sequences of actions-those that occur after an object has been grasped-are planned and represented in the brain. Here, using event-related functional MRI and pattern decoding methods, we investigated the neural basis of real-object manipulation using a delayed-movement task in which participants first prepared and then executed different object-directed action sequences that varied either in their complexity or final spatial goals. Consistent with previous reports of preparatory brain activity in non-human primates, we found that activity patterns in several frontoparietal areas reliably predicted entire action sequences in advance of movement. Notably, we found that similar sequence-related information could also be decoded from pre-movement signals in object- and body-selective occipitotemporal cortex (OTC). These findings suggest that both frontoparietal and occipitotemporal circuits are engaged in transforming object-related information into complex, goal-directed movements., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Scenes are constructed from multiple visual features, yet previous research investigating scene processing has often focused on the contributions of single features in isolation. In the real world, features rarely exist independently of one another and likely converge to inform scene identity in unique ways. Here, we utilize fMRI and pattern classification techniques to examine the interactions between task context (i.e., attend to diagnostic global scene features; texture or layout) and high-level scene attributes (content and spatial boundary) to test the novel hypothesis that scene-selective cortex represents multiple visual features, the importance of which varies according to their diagnostic relevance across scene categories and task demands. Our results show for the first time that scene representations are driven by interactions between multiple visual features and high-level scene attributes. Specifically, univariate analysis of scene-selective cortex revealed that task context and feature diagnosticity shape activity differentially across scene categories. Examination using multivariate decoding methods revealed results consistent with univariate findings, but also evidence for an interaction between high-level scene attributes and diagnostic visual features within scene categories. Critically, these findings suggest visual feature representations are not distributed uniformly across scene categories but are shaped by task context and feature diagnosticity. Thus, we propose that scene-selective cortex constructs a flexible representation of the environment by integrating multiple diagnostically relevant visual features, the nature of which varies according to the particular scene being perceived and the goals of the observer., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background & Aim: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin., Methods: HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression., Results: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12., Conclusions: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes., Trial Registration: ClinicalTrials.gov: NCT01132313.

Many earlier human functional MRI (fMRI) studies that investigated the neural circuits involved in sensorimotor control were motivated by previous non-human primate (NHP) work and focused on the specialization of brain areas for particular actions like reaching, grasping and eye movements. More recently, newer, more sensitive analysis techniques have enabled researchers to move beyond this simple functional mapping approach and begin exploring a wide range of novel research questions in humans that have not been well addressed in NHPs. This work, which we review here, reveals that action-related information is coded across a much broader range of brain regions than expected from earlier studies and offers new insights into the highly distributed hierarchical neural architecture that supports human goal-directed behavior., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Decision making revolves around weighing potential gains and losses. Research in economic decision making has emphasized that humans exercise disproportionate caution when making explicit choices involving loss. By comparison, research in perceptual decision making has revealed a processing advantage for targets associated with potential gain, though the effects of loss have been explored less systematically. Here, we use a rapid reaching task to measure the relative sensitivity (Experiment 1) and the time course (Experiments 2 and 3) of rapid actions with regard to the reward valence and probability of targets. We show that targets linked to a high probability of gain influence actions about 100 ms earlier than targets associated with equivalent probability and value of loss. These findings are well accounted for by a model of stimulus response in which reward modulates the late, postpeak phase of the activity. We interpret our results within a neural framework of biased competition that is resolved in spatial maps of behavioral relevance. As implied by our model, all visual stimuli initially receive positive activation. Gain stimuli can build off of this initial activation when selected as a target, whereas loss stimuli have to overcome this initial activation in order to be avoided, accounting for the observed delay between valences. Our results bring clarity to the perceptual effects of losses versus gains and highlight the importance of considering the timeline of different biasing factors that influence decisions., ((c) 2015 APA, all rights reserved).)

Based on its diverse and wide-spread patterns of connectivity, primate posteromedial cortex (PMC) is well positioned to support roles in several aspects of sensory-, cognitive- and motor-related processing. Previous work in both humans and non-human primates (NHPs) using resting-state functional MRI (rs-fMRI) suggests that a subregion of PMC, the medial parieto-occipital cortex (mPOC), by virtue of its intrinsic functional connectivity (FC) with visual cortex, may only play a role in higher-order visual processing. Recent neuroanatomical tracer studies in NHPs, however, demonstrate that mPOC also has prominent cortico-cortical connections with several frontoparietal structures involved in movement planning and control, a finding consistent with increasing observations of reach- and grasp-related activity in the mPOC of both NHPs and humans. To reconcile these observations, here we used rs-fMRI data collected from both awake humans and anesthetized macaque monkeys to more closely examine and compare parcellations of mPOC across species and explore the FC patterns associated with these subdivisions. Seed-based and voxel-wise hierarchical cluster analyses revealed four broad spatially separated functional boundaries that correspond with graded differences in whole-brain FC patterns in each species. The patterns of FC observed are consistent with mPOC forming a critical hub of networks involved in action planning and control, spatial navigation, and working memory. In addition, our comparison between species indicates that while there are several similarities, there may be some species-specific differences in functional neural organization. These findings and the associated theoretical implications are discussed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Several influential cognitive theories propose that in situations affording more than one possible target of action, we prepare multiple competing movements before selecting one. Here we provide direct evidence for this provocative but largely untested idea and demonstrate why preparing multiple movements is computationally advantageous. Using a reaching task in which movements are initiated after one of two potential targets is cued, we show that the movement generated for the cued target borrows components of the movement that would have been required for the other, competing target. This interaction can only arise if multiple potential movements are fully specified in advance and we demonstrate that it reduces the time required to launch a given action plan. Our findings suggest that this co-optimization of motor plans is highly automatic and largely occurs outside conscious awareness.

Background & Aims: The safety and efficacy of the interferon-free combination of faldaprevir (NS3/A4 protease inhibitor), deleobuvir (BI 207127, non-nucleoside polymerase inhibitor), and ribavirin in treatment-naïve patients chronically infected with HCV genotype-1 was explored., Methods: SOUND-C3 was a multicenter, open-label Phase 2b study. Treatment-naïve patients chronically infected with HCV genotype-1a (IL28B CC genotype only; n = 12) and genotype-1b (n = 20) were assigned to 16 weeks of treatment with faldaprevir 120 mg once daily, deleobuvir 600 mg twice daily, and weight-based ribavirin. Patients with compensated liver disease, including cirrhosis, were eligible for inclusion in this study. The primary endpoint was sustained virological response 12 weeks after completion of therapy., Results: Sustained virological response rates 12 weeks after completion of therapy were 17% and 95% in patients infected with HCV genotype-1a and genotype-1b respectively. All four patients with cirrhosis achieved sustained virological response 12 weeks after completion of therapy. The most frequently reported adverse events of at least moderate intensity were anaemia (16%), nausea, vomiting and fatigue (9% each). Three (9%) patients discontinued because of adverse events., Conclusions: The interferon-free regimen of faldaprevir, deleobuvir and ribavirin was efficacious in patients infected with genotype-1b and generally well tolerated., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.)., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Skilled manipulation requires the ability to predict the weights of viewed objects based on learned associations linking object weight to object visual appearance. However, the neural mechanisms involved in extracting weight information from viewed object properties are unknown. Given that ventral visual pathway areas represent a wide variety of object features, one intriguing but as yet untested possibility is that these areas also represent object weight, a nonvisual motor-relevant object property. Here, using event-related fMRI and pattern classification techniques, we tested the novel hypothesis that object-sensitive regions in occipitotemporal cortex (OTC), in addition to traditional motor-related brain areas, represent object weight when preparing to lift that object. In two studies, the same participants prepared and then executed lifting actions with objects of varying weight. In the first study, we show that when lifting visually identical objects, where predicted weight is based solely on sensorimotor memory, weight is represented in object-sensitive OTC. In the second study, we show that when object weight is associated with a particular surface texture, that texture-sensitive OTC areas also come to represent object weight. Notably, these texture-sensitive areas failed to carry information about weight in the first study, when object surface properties did not specify weight. Our results indicate that the integration of visual and motor-relevant object information occurs at the level of single OTC areas and provide evidence that the ventral visual pathway is actively and flexibly engaged in processing object weight, an object property critical for action planning and control., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Primate occipitotemporal cortex (OTC) is composed of a mosaic of highly specialized brain regions each involved in the high-level visual analysis and recognition of particular stimulus categories (e.g., objects, faces, scenes, bodies and tools). Whereas theories attempting to account for this modular organization of category-selective responses in OTC have largely focused on visually driven, bottom-up inputs to OTC (e.g., dimensions related to the visual structure of the world and how it is experienced), other proposals have instead focused on the connectivity of OTC's outputs, emphasizing how the information processed by different OTC regions might be used by the rest of the brain. The latter proposals underscore the importance of interpreting the activity (and selectivity) of individual OTC areas within the greater context of the widely distributed network of areas in which they are embedded and that use OTC information to support behavior. Here, using resting-state fMRI, we investigated the functional connectivity (FC) patterns of OTC regions associated with object-, face-, scene-, body- and tool-related processing defined from task-based localizers acquired in the same cohort of participants. We observed notable differences in the whole-brain FC patterns, not only across OTC regions, but even between areas thought to form part of the same category-selective network. Furthermore, we found that the neuroanatomical location of OTC regions (e.g., adjacency) had little, if any, bearing on the FC networks observed. FC between certain OTC areas and other regions traditionally implicated in sensory-, motor-, affective- and/or cognitive-related processing and the associated theoretical implications is discussed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Though several features of cognitive processing can be inferred from the discrete measurement [e.g., reaction time (RT), accuracy, etc.] of participants' conscious reports (e.g., verbal or key-press responses), it is becoming increasingly clear that a much richer understanding of these features can be captured from continuous measures of rapid, largely non-conscious behaviors like hand or eye movements. Here, using new experimental data, we describe in detail both the approach and analyses implemented in some of our previous studies that have used rapid reaching movements under cases of target uncertainty in order to probe the features, constraints and dynamics of stimulus-related processing in the brain. This work, as well as that of others, shows that when individuals are simultaneously presented with multiple potential targets-only one of which will be cued after reach onset-they produce initial reach trajectories that are spatially biased in accordance with the probabilistic distribution of targets. Such "spatial averaging" effects are consistent with observations from neurophysiological studies showing that neuronal populations in sensorimotor brain structures represent multiple target choices in parallel and they compete for selection. These effects also confirm and help extend computational models aimed at understanding the underlying mechanisms that support action-target selection. We suggest that the use of this simple, yet powerful behavioral paradigm for providing a "real-time" visualization of ongoing cognitive processes occurring at the neural level offers great promise for studying processes related to a wide range of psychological phenomena, such as decision-making and the representation of objects.

Riboswitches are sequences of RNA that control gene expression via RNA-ligand interactions, without the need for accessory proteins. Riboswitches consist of an aptamer that recognizes the ligand and an expression platform that couples ligand binding to a change in gene expression. Using in vitro selection, it is possible to screen large (∼ 10(13) members) libraries of RNA sequences to discover new aptamers. However, limitations in bacterial transformation efficiency make screening such large libraries for riboswitch function in intact cells impractical. Here we show that synthetic riboswitches function in an E. coli S30 extract in a manner similar to how they function in intact E. coli cells. We discovered that, although this family of riboswitches regulates the initiation of protein translation, the fate of whether an RNA message is translated is determined during transcription. Thus, ligand binding does not bias a population of rapidly equilibrating RNA structures, but rather, co-transcriptional ligand binding kinetically traps the RNA in a conformation that supports efficient translation. In addition to providing new insights into the mechanisms of action of a family of synthetic riboswitches, our experiments suggest that it may be possible to perform selections for novel synthetic riboswitches in an in vitro system., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)