Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant.

We identified an emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California, a state in the western United States. Named B.1.427/B.1.429 to denote its two lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6%-24% increased transmissibility relative to wild-type circulating strains. The variant carries three mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0- to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation.

Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity.

Interferon-induced transmembrane proteins (IFITMs) are broad spectrum antiviral factors that inhibit the entry of a wide range of clinically important pathogens including influenza A virus, HIV-1, and Dengue virus. IFITMs are thought to act primarily by antagonizing virus-cell membrane fusion in this regard. However, recent work on these proteins has uncovered novel post-entry viral restriction mechanisms. IFITMs are also increasingly thought to have a role regulating immune responses, including innate antiviral and inflammatory responses as well as adaptive T-cell and B-cell responses. Further, IFITMs may have pathological activities in cancer, wherein IFITM expression can be a marker of therapeutically resistant and aggressive disease courses. In this review, we summarize the respective literatures concerning these apparently diverse functions with a view to identifying common themes and potentially yielding a more unified understanding of IFITM biology.

Working memory constraints for visuomotor retrieval strategies.

Recent work has shown the fundamental role that cognitive strategies play in visuomotor adaptation. While algorithmic strategies, such as mental rotation, are flexible and generalizable, they are computationally demanding. To avoid this computational cost, people can instead rely on memory retrieval of previously successful visuomotor solutions. However, such a strategy is likely subject to strict stimulus-response associations and rely heavily on working memory. In a series of five experiments, we sought to estimate the constraints in terms of capacity and precision of working memory retrieval for visuomotor adaptation. This was accomplished by leveraging different variations of visuomotor item-recognition and visuomotor rotation tasks where we associated unique rotations with specific targets in the workspace and manipulated the set size (i.e., number of rotation-target associations). Notably, from Experiment 1 to 4, we found key signatures of working memory retrieval and not mental rotation. In particular, participants were less accurate and slower for larger set sizes and less recent items. Using a Bayesian latent-mixture model, we found that such decrease in performance was the result of increasing guessing behavior and less precise memories. In addition we estimated that participants' working memory capacity was limited to 2-5 items, after which guessing increasingly dominated performance. Finally, in Experiment 5, we showed how the constraints observed across Experiments 1 to 4 can be overcome when relying on long-term memory retrieval. Our results point to the opportunity of studying other sources of memories where visuomotor solutions can be stored (e.g., episodic memories) to achieve successful adaptation.

Exploring the role of task success in implicit motor adaptation.

Although implicit motor adaptation is driven by sensory-prediction errors (SPEs), recent work has shown that task success modulates this process. Task success has typically been defined as hitting a target, which signifies the goal of the movement. Visuomotor adaptation tasks are uniquely situated to experimentally manipulate task success independently from SPE by changing the target size or the location of the target. These two, distinct manipulations may influence implicit motor adaptation in different ways, so, over four experiments, we sought to probe the efficacy of each manipulation. We found that changes in target size, which caused the target to fully envelop the cursor, only affected implicit adaptation for a narrow range of SPE sizes, while jumping the target to overlap with the cursor more reliably and robustly affected implicit adaptation. Taken together, our data indicate that, while task success exerts a small effect on implicit adaptation, these effects are susceptible to methodological variations. Future investigations of the effect of task success on implicit adaptation could benefit from employing target jump manipulations instead of target size manipulations.NEW & NOTEWORTHY Recent work has suggested that task success, namely, hitting a target, influences implicit motor adaptation. Here, we observed that implicit adaptation is modulated by target jump manipulations, where the target abruptly "jumps" to meet the cursor; however, implicit adaptation was only weakly modulated by target size manipulations, where a static target either envelops or excludes the cursor. We discuss how these manipulations may exert their effects through different mechanisms.

Continuous manipulation of mental representations is compromised in cerebellar degeneration.

We introduce a novel perspective on how the cerebellum might contribute to cognition, hypothesizing that this structure supports dynamic transformations of mental representations. In support of this hypothesis, we report a series of neuropsychological experiments comparing the performance of individuals with degenerative cerebellar disorders on tasks that either entail continuous, movement-like mental operations or more discrete mental operations. In the domain of visual cognition, the cerebellar disorders group exhibited an impaired rate of mental rotation, an operation hypothesized to require the continuous manipulation of a visual representation. In contrast, the cerebellar disorders group showed a normal processing rate when scanning items in visual working memory, an operation hypothesized to require the maintenance and retrieval of remembered items. In the domain of mathematical cognition, the cerebellar disorders group was impaired at single-digit addition, an operation hypothesized to primarily require iterative manipulations along a mental number-line; this group was not impaired on arithmetic tasks linked to memory retrieval (e.g. single-digit multiplication). These results, obtained in tasks from two disparate domains, point to a potential constraint on the contribution of the cerebellum to cognitive tasks. Paralleling its role in motor control, the cerebellum may be essential for coordinating dynamic, movement-like transformations in a mental workspace.

Developmental control of polycomb subunit composition by GATA factors mediates a switch to non-canonical functions.

Polycomb repressive complex 2 (PRC2) plays crucial roles in transcriptional regulation and stem cell development. However, the context-specific functions associated with alternative subunits remain largely unexplored. Here we show that the related enzymatic subunits EZH1 and EZH2 undergo an expression switch during blood cell development. An erythroid-specific enhancer mediates transcriptional activation of EZH1, and a switch from GATA2 to GATA1 controls the developmental EZH1/2 switch by differential association with EZH1 enhancers. We further examine the in vivo stoichiometry of the PRC2 complexes by quantitative proteomics and reveal the existence of an EZH1-SUZ12 subcomplex lacking EED. EZH1 together with SUZ12 form a non-canonical PRC2 complex, occupy active chromatin, and positively regulate gene expression. Loss of EZH2 expression leads to repositioning of EZH1 to EZH2 targets. Thus, the lineage- and developmental stage-specific regulation of PRC2 subunit composition leads to a switch from canonical silencing to non-canonical functions during blood stem cell specification.

Using Social Media to Examine Themes Surrounding Fentanyl Misuse and Risk Indicators.

Background: Opioid misuse is a crisis in the United States, and synthetic opioids such as fentanyl pose risks for overdose and mortality. Individuals who misuse substances commonly seek information and support online due to stigma and legal concerns, and this online networking may provide insight for substance misuse prevention and treatment. We aimed to characterize topics in substance-misuse related discourse among members of an online fentanyl community. Method: We investigated posts on a fentanyl-specific forum on the platform Reddit to identify emergent substance misuse-related themes potentially indicative of heightened risk for overdose and other adverse health outcomes. We analyzed 27 posts and 338 comments with a qualitative codebook established using a subset of user posts via inductive and deductive methods. Posts and comments were independently reviewed by two coders with a third coder resolving discrepancies. The top 200 subreddits with the most activity by r/fentanyl members were also inductively analyzed to understand interests of r/fentanyl users. Results: Functional/quality of life impairments due to substance misuse (29%) was the most commonly occurring theme, followed by polysubstance use (27%) and tolerance/dependence/withdrawal (20%). Additional themes included drug identification with photos, substances cut with other drugs, injection drugs, and past overdoses. Media-focused subreddits and other drug focused communities were among the communities most often followed by r/fentanyl users. Conclusion: Themes closely align with DSM-V substance use disorder symptoms for fentanyl and other substances. High involvement in media-focused subreddits and other substance-misuse-related communities suggests digital platforms as acceptable for overdose prevention and recovery support interventions.

Revisiting the Role of the Medial Temporal Lobe in Motor Learning.

Classic taxonomies of memory distinguish explicit and implicit memory systems, placing motor skills squarely in the latter branch. This assertion is in part a consequence of foundational discoveries showing significant motor learning in amnesics. Those findings suggest that declarative memory processes in the medial temporal lobe (MTL) do not contribute to motor learning. Here, we revisit this issue, testing an individual (L. S. J.) with severe MTL damage on four motor learning tasks and comparing her performance to age-matched controls. Consistent with previous findings in amnesics, we observed that L. S. J. could improve motor performance despite having significantly impaired declarative memory. However, she tended to perform poorly relative to age-matched controls, with deficits apparently related to flexible action selection. Further supporting an action selection deficit, L. S. J. fully failed to learn a task that required the acquisition of arbitrary action-outcome associations. We thus propose a modest revision to the classic taxonomic model: Although MTL-dependent memory processes are not necessary for some motor learning to occur, they play a significant role in the acquisition, implementation, and retrieval of action selection strategies. These findings have implications for our understanding of the neural correlates of motor learning, the psychological mechanisms of skill, and the theory of multiple memory systems.

Distinct Neural Signatures of Outcome Monitoring After Selection and Execution Errors.

Losing a point in tennis could result from poor shot selection or faulty stroke execution. To explore how the brain responds to these different types of errors, we examined feedback-locked EEG activity while participants completed a modified version of a standard three-armed bandit probabilistic reward task. Our task framed unrewarded outcomes as the result of either errors of selection or errors of execution. We examined whether amplitude of a medial frontal negativity (the feedback-related negativity [FRN]) was sensitive to the different forms of error attribution. Consistent with previous reports, selection errors elicited a large FRN relative to rewards, and amplitude of this signal correlated with behavioral adjustment after these errors. A different pattern was observed in response to execution errors. These outcomes produced a larger FRN, a frontocentral attenuation in activity preceding this component, and a subsequent enhanced error positivity in parietal sites. Notably, the only correlations with behavioral adjustment were with the early frontocentral attenuation and amplitude of the parietal signal; FRN differences between execution errors and rewarded trials did not correlate with subsequent changes in behavior. Our findings highlight distinct neural correlates of selection and execution error processing, providing insight into how the brain responds to the different classes of error that determine future action.

Implicit adaptation to mirror reversal is in the correct coordinate system but the wrong direction.

Learning in visuomotor adaptation tasks is the result of both explicit and implicit processes. Explicit processes, operationalized as reaiming an intended movement to a new goal, account for a significant proportion of learning. However, implicit processes, operationalized as error-dependent learning that gives rise to aftereffects, appear to be highly constrained. The limitations of implicit learning are highlighted in the mirror-reversal task, where implicit corrections act in opposition to performance. This is surprising given the mirror-reversal task has been viewed as emblematic of implicit learning. One potential issue not being considered in these studies is that both explicit and implicit processes were allowed to operate concurrently, which may interact, potentially in opposition. Therefore, we sought to further characterize implicit learning in a mirror-reversal task with a clamp design to isolate implicit learning from explicit strategies. We confirmed that implicit adaptation is in the wrong direction for mirror reversal and operates as if the perturbation were a rotation and only showed a moderate attenuation after 3 days of training. This result raised the question of whether implicit adaptation blindly operates as though perturbations were a rotation. In a separate experiment, which directly compared a mirror reversal and a rotation, we found that implicit adaptation operates in a proper coordinate system for different perturbations: adaptation to a mirror reversal and rotational perturbation is more consistent with Cartesian and polar coordinate systems, respectively. It remains an open question why implicit process would be flexible to the coordinate system of a perturbation but continue to be directed inappropriately.NEW & NOTEWORTHY Recent studies have found that implicit learning may operate inappropriately in some motor tasks, requiring explicit strategies to improve performance. However, this inappropriate adaptation could be attributable to competitive interactions between explicit and implicit processes. After isolating implicit processes, we found that implicit adaptation remained in the wrong direction for a mirror reversal, acting as if it were a rotation. Interestingly, however, the implicit system is sensitive to a particular coordinate system, treating mirror reversal and rotation differently.

Taking aim at the perceptual side of motor learning: exploring how explicit and implicit learning encode perceptual error information through depth vision.

Motor learning in visuomotor adaptation tasks results from both explicit and implicit processes, each responding differently to an error signal. Although the motor output side of these processes has been extensively studied, the visual input side is relatively unknown. We investigated if and how depth perception affects the computation of error information by explicit and implicit motor learning. Two groups of participants made reaching movements to bring a virtual cursor to a target in the frontoparallel plane. The Delayed group was allowed to reaim and their feedback was delayed to emphasize explicit learning, whereas the camped group received task-irrelevant clamped cursor feedback and continued to aim straight at the target to emphasize implicit adaptation. Both groups played this game in a highly detailed virtual environment (depth condition), leveraging a cover task of playing darts in a virtual tavern, and in an empty environment (no-depth condition). The delayed group showed an increase in error sensitivity under depth relative to no-depth. In contrast, the clamped group adapted to the same degree under both conditions. The movement kinematics of the delayed participants also changed under the depth condition, consistent with the target appearing more distant, unlike the Clamped group. A comparison of the delayed behavioral data with a perceptual task from the same individuals showed that the greater reaiming in the depth condition was consistent with an increase in the scaling of the error distance and size. These findings suggest that explicit and implicit learning processes may rely on different sources of perceptual information.NEW & NOTEWORTHY We leveraged a classic sensorimotor adaptation task to perform a first systematic assessment of the role of perceptual cues in the estimation of an error signal in the 3-D space during motor learning. We crossed two conditions presenting different amounts of depth information, with two manipulations emphasizing explicit and implicit learning processes. Explicit learning responded to the visual conditions, consistent with perceptual reports, whereas implicit learning appeared to be independent of them.

Direct and indirect cues can enable dual adaptation, but through different learning processes.

Switching between motor tasks requires accurate adjustments for changes in dynamics (grasping a cup) or sensorimotor transformations (moving a computer mouse). Dual-adaptation studies have investigated how learning of context-dependent dynamics or transformations is enabled by sensory cues. However, certain cues, such as color, have shown mixed results. We propose that these mixed results may arise from two major classes of cues: "direct" cues, which are part of the dynamic state and "indirect" cues, which are not. We hypothesized that explicit strategies would primarily account for the adaptation of an indirect color cue but would be limited to simple tasks, whereas a direct visual separation cue would allow implicit adaptation regardless of task complexity. To test this idea, we investigated the relative contribution of implicit and explicit learning in relation to contextual cue type (colored or visually shifted workspace) and task complexity (1 or 8 targets) in a dual-adaptation task. We found that the visual workspace location cue enabled adaptation across conditions primarily through implicit adaptation. In contrast, we found that the color cue was largely ineffective for dual adaptation, except in a small subset of participants who appeared to use explicit strategies. Our study suggests that the previously inconclusive role of color cues in dual adaptation may be explained by differential contribution of explicit strategies across conditions.NEW & NOTEWORTHY We present evidence that learning of context-dependent dynamics proceeds via different processes depending on the type of sensory cue used to signal the context. Visual workspace location enabled learning different dynamics implicitly, presumably because it directly enters the dynamic state estimate. In contrast, a color cue was only successful where learners were apparently able to leverage explicit strategies to account for changed dynamics. This suggests a unification for the previously inconclusive role of color cues.

Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function.

Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1) facilitates rapid propagation of action potentials necessary for each heartbeat. Gap junctions also propagate innate and adaptive antiviral immune responses, but how viruses may target these structures is not understood. Given this immunological role of Cx43, we hypothesized that gap junctions would be targeted during adenovirus type 5 (Ad5) infection. We find reduced Cx43 protein levels due to decreased GJA1 mRNA transcripts dependent upon ß-catenin transcriptional activity during Ad5 infection, with early viral protein E4orf1 sufficient to induce ß-catenin phosphorylation. Loss of gap junction function occurs prior to reduced Cx43 protein levels with Ad5 infection rapidly inducing Cx43 phosphorylation events consistent with altered gap junction conductance. Direct Cx43 interaction with ZO-1 plays a critical role in gap junction regulation. We find loss of Cx43/ZO-1 complexing during Ad5 infection by co-immunoprecipitation and complementary studies in human induced pluripotent stem cell derived-cardiomyocytes reveal Cx43 gap junction remodeling by reduced ZO-1 complexing. These findings reveal specific targeting of gap junction function by Ad5 leading to loss of intercellular communication which would contribute to dangerous pathological states including arrhythmias in infected hearts.

Epinephrine and glucose regulation of leptin synthesis and secretion in a teleost fish, the tilapia (Oreochromis mossambicus).

Acute stress is regulated through the sympathetic adrenergic axis where catecholamines mobilize energy stores including carbohydrates as a principal element of the endocrine stress response. Leptin is a cytokine critical for regulating energy expenditure in vertebrates and is stimulated by various stressors in fish such as fasting, hyperosmotic challenge, and hypoxia. However, little is known about the regulatory interactions between leptin and the endocrine stress axis in fishes and other ectothermic vertebrates. We evaluated the actions of epinephrine and glucose in regulating leptin A (LepA) in vivo and in vitro in tilapia. Using hepatocyte incubations and a homologous LepA ELISA, we show that LepA synthesis and secretion decline as ambient glucose levels increase (10-25 mM). By contrast, bolus glucose administration in tilapia increases lepa mRNA levels 14-fold at 6 h, suggesting systemic factors regulated by glucose may counteract the direct inhibitory effects of glucose on hepatic lepa mRNA observed in vitro. Epinephrine stimulated glucose and LepA secretion from hepatocytes in a dose-dependent fashion within 15 min but had little effect on lepa mRNA levels. An in vivo injection of epinephrine into tilapia stimulated a rapid rise in blood glucose which was followed by a 4-fold increase in hepatic lepa mRNA levels at 2.5 and 6 h. Plasma LepA was also elevated by 6 h relative to controls. Recombinant tilapia LepA administration in vivo did not have any significant effect on plasma epinephrine levels. The results of this study demonstrate LepA is negatively regulated by rises in extracellular glucose at the level of the hepatocyte but stimulated by hyperglycemia in vivo. Further, epinephrine increases LepA. This, along with previous work demonstrating a hyperglycemic and glycogenolytic effect of LepA in tilapia, suggests that epinephrine may stimulate leptin secretion to augment and fine tune glucose mobilization and homeostasis as part of the integrated, adaptive stress response.

Who will receive the last ventilator: why COVID-19 policies should not prioritise healthcare workers.

Policies promoted and adopted for allocating ventilators during the COVID-19 pandemic have often prioritised healthcare workers or other essential workers. While the need for such policies has so far been largely averted, renewed stress on health systems from continuing surges, as well as the experience of allocating another scarce resource-vaccination-counsel revisiting the justifications for such prioritisation. Prioritising healthcare workers may have intuitive appeal, but the ethical justifications for doing so and the potential harms that could follow require careful analysis. Ethical justifications commonly offered for healthcare worker prioritisation for ventilators rest on two social value criteria: (1) instrumental value, also known as the 'multiplier effect', which may preserve the ability of healthcare workers to help others, and (2) reciprocity, which rewards past usefulness or sacrifice. We argue that these justifications are insufficient to over-ride the common moral commitment to value each person's life equally. Institutional policies prioritising healthcare workers over other patients also violate other ethical norms of the healthcare professions, including the commitment to put patients first. Furthermore, policy decisions to prioritise healthcare workers for ventilators could engender or deepen existing distrust of the clinicians, hospitals and health systems where those policies exist, even if they are never invoked.

Small surgeries, big smiles: using virtual reality to reduce the need for sedation or general anesthesia during minor surgical procedures.

PURPOSE: Children often require anesthesia for simple diagnostic and therapeutic procedures. The aim of this study was to evaluate the feasibility of using virtual reality (VR) to reduce sedation in children undergoing minor surgical procedures. METHOD: In this prospective, non-randomized clinical trial, pediatric patients at a free-standing children's hospital undergoing hormone implant placement, removal, or exchange were recruited to use VR and local anesthesia instead of procedural sedation or general anesthesia (GA). Patients were enrolled between November 2017 and March 2020, and were compared to historic controls who underwent similar procedures without VR between April 2016 and February 2020. Primary outcome measure was successful procedure completion without sedation or GA. Secondary measures included assessments of pain, fear and anxiety, patient compliance, procedural and recovery times. RESULTS: Twenty-eight patients underwent 29 procedures with VR. Hormone implants (72%), removals (7%), or exchanges (21%) were completed without GA, sedation or IV placement. Procedure lengths and pain scores were similar between VR patients and historic controls, but recovery times were significantly shorter in VR patients (18 vs 65 min, p < 0.001). Participant satisfaction scores were high, with 95% recommending VR to others. CONCLUSIONS: VR is a feasible alternative to sedation or GA for select pediatric patients undergoing minor surgical procedures.

Sensorimotor adaptation and cue reweighting compensate for distorted 3D shape information, accounting for paradoxical perception-action dissociations.

Visually guided movements can show surprising accuracy even when the perceived three-dimensional (3D) shape of the target is distorted. One explanation of this paradox is that an evolutionarily specialized "vision-for-action" system provides accurate shape estimates by relying selectively on stereo information and ignoring less reliable sources of shape information like texture and shading. However, the key support for this hypothesis has come from studies that analyze average behavior across many visuomotor interactions where available sensory feedback reinforces stereo information. The present study, which carefully accounts for the effects of feedback, shows that visuomotor interactions with slanted surfaces are actually planned using the same cue-combination function as slant perception and that apparent dissociations can arise due to two distinct supervised learning processes: sensorimotor adaptation and cue reweighting. In two experiments, we show that when a distorted slant cue biases perception (e.g., surfaces appear flattened by a fixed amount), sensorimotor adaptation rapidly adjusts the planned grip orientation to compensate for this constant error. However, when the distorted slant cue is unreliable, leading to variable errors across a set of objects (i.e., some slants are overestimated, others underestimated), then relative cue weights are gradually adjusted to reduce the misleading effect of the unreliable cue, consistent with previous perceptual studies of cue reweighting. The speed and flexibility of these two forms of learning provide an alternative explanation of why perception and action are sometimes found to be dissociated in experiments where some 3D shape cues are consistent with sensory feedback while others are faulty.NEW & NOTEWORTHY When interacting with three-dimensional (3D) objects, sensory feedback is available that could improve future performance via supervised learning. Here we confirm that natural visuomotor interactions lead to sensorimotor adaptation and cue reweighting, two distinct learning processes uniquely suited to resolve errors caused by biased and noisy 3D shape cues. These findings explain why perception and action are often found to be dissociated in experiments where some cues are consistent with sensory feedback while others are faulty.

Assessing explicit strategies in force field adaptation.

In recent years, it has become increasingly clear that a number of learning processes are at play in visuomotor adaptation tasks. In addition to implicitly adapting to a perturbation, learners can develop explicit knowledge allowing them to select better actions in responding to it. Advances in visuomotor rotation experiments have underscored the important role of such "explicit learning" in shaping adaptation to kinematic perturbations. Yet, in adaptation to dynamic perturbations, its contribution has been largely overlooked. We therefore sought to approach the assessment of explicit learning in adaptation to dynamic perturbations, by developing two novel modifications of a force field experiment. First, we asked learners to abandon any cognitive strategy before selected force channel trials to expose consciously accessible parts of overall learning. Here, learners indeed reduced compensatory force compared with standard Catch channels. Second, we instructed a group of learners to mimic their right hand's adaptation by moving with their naïve left hand. While a control group displayed negligible left hand force compensation, the mimicking group reported forces that approximated right hand adaptation but appeared to under-report the velocity component of the force field in favor of a more position-based component. Our results highlight the viability of explicit learning as a potential contributor to force field adaptation, though the fraction of learning under participants' deliberate control on average remained considerably smaller than that of implicit learning, despite task conditions favoring explicit learning. The methods we employed provide a starting point for investigating the contribution of explicit strategies to force field adaptation.NEW & NOTEWORTHY While the contribution of explicit learning has been increasingly studied in visuomotor adaptation, its contribution to force field adaptation has not been studied extensively. We employed two novel methods to assay explicit learning in a force field adaptation task and found that learners can voluntarily control aspects of compensatory force production and manually report it with their untrained limb. This supports the general viability of the contribution of explicit learning also in force field adaptation.

Can patients with cerebellar disease switch learning mechanisms to reduce their adaptation deficits?

Systematic perturbations in motor adaptation tasks are primarily countered by learning from sensory-prediction errors, with secondary contributions from other learning processes. Despite the availability of these additional processes, particularly the use of explicit re-aiming to counteract observed target errors, patients with cerebellar degeneration are surprisingly unable to compensate for their sensory-prediction error deficits by spontaneously switching to another learning mechanism. We hypothesized that if the nature of the task was changed-by allowing vision of the hand, which eliminates sensory-prediction errors-patients could be induced to preferentially adopt aiming strategies to solve visuomotor rotations. To test this, we first developed a novel visuomotor rotation paradigm that provides participants with vision of their hand in addition to the cursor, effectively setting the sensory-prediction error signal to zero. We demonstrated in younger healthy control subjects that this promotes a switch to strategic re-aiming based on target errors. We then showed that with vision of the hand, patients with cerebellar degeneration could also switch to an aiming strategy in response to visuomotor rotations, performing similarly to age-matched participants (older controls). Moreover, patients could retrieve their learned aiming solution after vision of the hand was removed (although they could not improve beyond what they retrieved), and retain it for at least 1 year. Both patients and older controls, however, exhibited impaired overall adaptation performance compared to younger healthy controls (age 18-33 years), likely due to age-related reductions in spatial and working memory. Patients also failed to generalize, i.e. they were unable to adopt analogous aiming strategies in response to novel rotations. Hence, there appears to be an inescapable obligatory dependence on sensory-prediction error-based learning-even when this system is impaired in patients with cerebellar disease. The persistence of sensory-prediction error-based learning effectively suppresses a switch to target error-based learning, which perhaps explains the unexpectedly poor performance by patients with cerebellar degeneration in visuomotor adaptation tasks.