ASU Scholarship Showcase
This growing collection consists of scholarly works authored by ASU-affiliated faculty, staff, and community members, and it contains many open access articles. ASU-affiliated authors are encouraged to Share Your Work in KEEP.
Filtering by
- Creators: Santello, Marco
- Creators: Johnston, Stephen
Humans are able to modulate digit forces as a function of position despite changes in digit placement that might occur from trial to trial or when changing grip type for object manipulation. Although this phenomenon is likely to rely on sensing the position of the digits relative to each other and the object, the underlying mechanisms remain unclear. To address this question, we asked subjects (n = 30) to match perceived vertical distance between the center of pressure (CoP) of the thumb and index finger pads (dy) of the right hand (“reference” hand) using the same hand (“test” hand). The digits of reference hand were passively placed collinearly (dy = 0 mm). Subjects were then asked to exert different combinations of normal and tangential digit forces (Fn and Ftan, respectively) using the reference hand and then match the memorized dy using the test hand. The reference hand exerted Ftan of thumb and index finger in either same or opposite direction. We hypothesized that, when the tangential forces of the digits are produced in opposite directions, matching error (1) would be biased toward the directions of the tangential forces; and (2) would be greater when the remembered relative contact points are matched with negligible digit force production. For the test hand, digit forces were either negligible (0.5–1 N, 0 ± 0.25 N; Experiment 1) or the same as those exerted by the reference hand (Experiment 2).Matching error was biased towards the direction of digit tangential forces: thumb CoP was placed higher than the index finger CoP when thumb and index finger Ftan were directed upward and downward, respectively, and vice versa (p < 0.001). However, matching error was not dependent on whether the reference and test hand exerted similar or different forces. We propose that the expected sensory consequence of motor commands for tangential forces in opposite directions overrides estimation of fingertip position through haptic sensory feedback.
Recent studies about sensorimotor control of the human hand have focused on how dexterous manipulation is learned and generalized. Here we address this question by testing the extent to which learned manipulation can be transferred when the contralateral hand is used and/or object orientation is reversed. We asked subjects to use a precision grip to lift a grip device with an asymmetrical mass distribution while minimizing object roll during lifting by generating a compensatory torque. Subjects were allowed to grasp anywhere on the object’s vertical surfaces, and were therefore able to modulate both digit positions and forces. After every block of eight trials performed in one manipulation context (i.e., using the right hand and at a given object orientation), subjects had to lift the same object in the second context for one trial (transfer trial).
Context changes were made by asking subjects to switch the hand used to lift the object and/or rotate the object 180° about a vertical axis. Therefore, three transfer conditions, hand switch (HS), object rotation (OR), and both hand switch and object rotation (HS+OR), were tested and compared with hand matched control groups who did not experience context changes. We found that subjects in all transfer conditions adapted digit positions across multiple transfer trials similar to the learning of control groups, regardless of different changes of contexts. Moreover, subjects in both HS and HS+OR group also adapted digit forces similar to the control group, suggesting independent learning of the left hand. In contrast, the OR group showed significant negative transfer of the compensatory torque due to an inability to adapt digit forces. Our results indicate that internal representations of dexterous manipulation tasks may be primarily built through the hand used for learning and cannot be transferred across hands.
Background: Cancer diagnosis in both dogs and humans is complicated by the lack of a non-invasive diagnostic test. To meet this clinical need, we apply the recently developed immunosignature assay to spontaneous canine lymphoma as clinical proof-of-concept. Here we evaluate the immunosignature as a diagnostic for spontaneous canine lymphoma at both at initial diagnosis and evaluating the disease free interval following treatment.
Methods: Sera from dogs with confirmed lymphoma (B cell n = 38, T cell n = 11) and clinically normal dogs (n = 39) were analyzed. Serum antibody responses were characterized by analyzing the binding pattern, or immunosignature, of serum antibodies on a non-natural sequence peptide microarray. Peptides were selected and tested for the ability to distinguish healthy dogs from those with lymphoma and to distinguish lymphoma subtypes based on immunophenotype. The immunosignature of dogs with lymphoma were evaluated for individual signatures. Changes in the immunosignatures were evaluated following treatment and eventual relapse.
Results: Despite being a clonal disease, both an individual immunosignature and a generalized lymphoma immunosignature were observed in each dog. The general lymphoma immunosignature identified in the initial set of dogs (n = 32) was able to predict disease status in an independent set of dogs (n = 42, 97% accuracy). A separate immunosignature was able to distinguish the lymphoma based on immunophenotype (n = 25, 88% accuracy). The individual immunosignature was capable of confirming remission three months following diagnosis. Immunosignature at diagnosis was able to predict which dogs with B cell lymphoma would relapse in less than 120 days (n = 33, 97% accuracy).
Conclusion: We conclude that the immunosignature can serve as a multilevel diagnostic for canine, and potentially human, lymphoma.
Sensorimotor control theories propose that the central nervous system exploits expected sensory consequences generated by motor commands for movement planning, as well as online sensory feedback for comparison with expected sensory feedback for monitoring and correcting, if needed, ongoing motor output. In our study, we tested this theoretical framework by quantifying the functional role of expected vs. actual proprioceptive feedback for planning and regulation of gait in humans. We addressed this question by using a novel methodological approach to deliver fast perturbations of the walking surface stiffness, in conjunction with a virtual reality system that provided visual feedback of upcoming changes of surface stiffness. In the “predictable” experimental condition, we asked subjects to learn associating visual feedback of changes in floor stiffness (sand patch) during locomotion to quantify kinematic and kinetic changes in gait prior to and during the gait cycle. In the “unpredictable” experimental condition, we perturbed floor stiffness at unpredictable instances during the gait to characterize the gait-phase dependent strategies in recovering the locomotor cycle. For the “unpredictable” conditions, visual feedback of changes in floor stiffness was absent or inconsistent with tactile and proprioceptive feedback. The investigation of these perturbation-induced effects on contralateral leg kinematics revealed that visual feedback of upcoming changes in floor stiffness allows for both early (preparatory) and late (post-perturbation) changes in leg kinematics. However, when proprioceptive feedback is not available, the early responses in leg kinematics do not occur while the late responses are preserved although in a, slightly attenuated form. The methods proposed in this study and the preliminary results of the kinematic response of the contralateral leg open new directions for the investigation of the relative role of visual, tactile, and proprioceptive feedback on gait control, with potential implications for designing novel robot-assisted gait rehabilitation approaches.
The intact nervous system has an exquisite ability to modulate the activity of multiple muscles acting at one or more joints to produce an enormous range of actions. Seemingly simple tasks, such as reaching for an object or walking, in fact rely on very complex spatial and temporal patterns of muscle activations. Neurological disorders such as stroke and focal dystonia affect the ability to coordinate multi-joint movements. This article reviews the state of the art of research of muscle synergies in the intact and damaged nervous system, their implications for recovery and rehabilitation, and proposes avenues for research aimed at restoring the nervous system’s ability to control movement.
Studies have shown that internal representations of manipulations of objects with asymmetric mass distributions that are generated within a specific orientation are not generalizable to novel orientations, i.e., subjects fail to prevent object roll on their first grasp-lift attempt of the object following 180° object rotation. This suggests that representations of these manipulations are specific to the reference frame in which they are formed. However, it is unknown whether that reference frame is specific to the hand, the body, or both, because rotating the object 180° modifies the relation between object and body as well as object and hand. An alternative, untested explanation for the above failure to generalize learned manipulations is that any rotation will disrupt grasp performance, regardless if the reference frame in which the manipulation was learned is maintained or modified. We examined the effect of rotations that (1) maintain and (2) modify relations between object and body, and object and hand, on the generalizability of learned two-digit manipulation of an object with an asymmetric mass distribution. Following rotations that maintained the relation between object and body and object and hand (e.g., rotating the object and subject 180°), subjects continued to use appropriate digit placement and load force distributions, thus generating sufficient compensatory moments to minimize object roll. In contrast, following rotations that modified the relation between (1) object and hand (e.g. rotating the hand around to the opposite object side), (2) object and body (e.g. rotating subject and hand 180°), or (3) both (e.g. rotating the subject 180°), subjects used the same, yet inappropriate digit placement and load force distribution, as those used prior to the rotation. Consequently, the compensatory moments were insufficient to prevent large object rolls. These findings suggest that representations of learned manipulation of objects with asymmetric mass distributions are specific to the body- and hand-reference frames in which they were learned.
Antigen-antibody complexes are central players in an effective immune response. However, finding those interactions relevant to a particular disease state can be arduous. Nonetheless many paths to discovery have been explored since deciphering these interactions can greatly facilitate the development of new diagnostics, therapeutics, and vaccines. In silico B cell epitope mapping approaches have been widely pursued, though success has not been consistent. Antibody mixtures in immune sera have been used as handles for biologically relevant antigens, but these and other experimental approaches have proven resource intensive and time consuming. In addition, these methods are often tailored to individual diseases or a specific proteome, rather than providing a universal platform. Most of these methods are not able to identify the specific antibody’s epitopes from unknown antigens, such as un-annotated neo antigens in cancer. Alternatively, a peptide library comprised of sequences unrestricted by naturally-found protein space provides for a universal search for mimotopes of an antibody’s epitope. Here we present the utility of such a non-natural random sequence library of 10,000 peptides physically addressed on a microarray for mimotope discovery without sequence information of the specific antigen. The peptide arrays were probed with serum from an antigen-immunized rabbit, or alternatively probed with serum pre-absorbed with the same immunizing antigen. With this positive and negative screening scheme, we identified the library-peptides as the mimotopes of the antigen. The unique library peptides were successfully used to isolate antigen-specific antibodies from complete immune serum. Sequence analysis of these peptides revealed the epitopes in the immunized antigen. We present this method as an inexpensive, efficient method for identifying mimotopes of any antibody’s targets. These mimotopes should be useful in defining both components of the antigen-antibody complex.
Background: The success of new sequencing technologies and informatic methods for identifying genes has made establishing gene product function a critical rate limiting step in progressing the molecular sciences. We present a method to functionally mine genomes for useful activities in vivo, using an unusual property of a member of the poxvirus family to demonstrate this screening approach.
Results: The genome of Parapoxvirus ovis (Orf virus) was sequenced, annotated, and then used to PCR-amplify its open-reading-frames. Employing a cloning-independent protocol, a viral expression-library was rapidly built and arrayed into sub-library pools. These were directly delivered into mice as expressible cassettes and assayed for an immune-modulating activity associated with parapoxvirus infection. The product of the B2L gene, a homolog of vaccinia F13L, was identified as the factor eliciting immune cell accumulation at sites of skin inoculation. Administration of purified B2 protein also elicited immune cell accumulation activity, and additionally was found to serve as an adjuvant for antigen-specific responses. Co-delivery of the B2L gene with an influenza gene-vaccine significantly improved protection in mice. Furthermore, delivery of the B2L expression construct, without antigen, non-specifically reduced tumor growth in murine models of cancer.
Conclusion: A streamlined, functional approach to genome-wide screening of a biological activity in vivo is presented. Its application to screening in mice for an immune activity elicited by the pathogen genome of Parapoxvirus ovis yielded a novel immunomodulator. In this inverted discovery method, it was possible to identify the adjuvant responsible for a function of interest prior to a mechanistic study of the adjuvant. The non-specific immune activity of this modulator, B2, is similar to that associated with administration of inactivated particles to a host or to a live viral infection. Administration of B2 may provide the opportunity to significantly impact host immunity while being itself only weakly recognized. The functional genomics method used to pinpoint B2 within an ORFeome may be more broadly applicable to screening for other biological activities in an animal.
Background: Immunosignaturing is a new peptide microarray based technology for profiling of humoral immune responses. Despite new challenges, immunosignaturing gives us the opportunity to explore new and fundamentally different research questions. In addition to classifying samples based on disease status, the complex patterns and latent factors underlying immunosignatures, which we attempt to model, may have a diverse range of applications.
Methods: We investigate the utility of a number of statistical methods to determine model performance and address challenges inherent in analyzing immunosignatures. Some of these methods include exploratory and confirmatory factor analyses, classical significance testing, structural equation and mixture modeling.
Results: We demonstrate an ability to classify samples based on disease status and show that immunosignaturing is a very promising technology for screening and presymptomatic screening of disease. In addition, we are able to model complex patterns and latent factors underlying immunosignatures. These latent factors may serve as biomarkers for disease and may play a key role in a bioinformatic method for antibody discovery.
Conclusion: Based on this research, we lay out an analytic framework illustrating how immunosignatures may be useful as a general method for screening and presymptomatic screening of disease as well as antibody discovery.
Background: Carpal tunnel syndrome (CTS) is a compression neuropathy of the median nerve that results in sensorimotor deficits in the hand. Until recently, the effects of CTS on hand function have been studied using mostly two-digit grip tasks. The purpose of this study was to investigate the coordination of multi-digit forces as a function of object center of mass (CM) during whole-hand grasping.
Methods: Fourteen CTS patients and age- and gender-matched controls were instructed to grasp, lift, hold, and release a grip device with five digits for seven consecutive lifts while maintaining its vertical orientation. The object CM was changed by adding a mass at different locations at the base of the object. We measured forces and torques exerted by each digit and object kinematics and analyzed modulation of these variables to object CM at object lift onset and during object hold. Our task requires a modulation of digit forces at and after object lift onset to generate a compensatory moment to counteract the external moment caused by the added mass and to minimize object tilt.
Results: We found that CTS patients learned to generate a compensatory moment and minimized object roll to the same extent as controls. However, controls fully exploited the available degrees of freedom (DoF) in coordinating their multi-digit forces to generate a compensatory moment, i.e., digit normal forces, tangential forces, and the net center of pressure on the finger side of the device at object lift onset and during object hold. In contrast, patients modulated only one of these DoFs (the net center of pressure) to object CM by modulating individual normal forces at object lift onset. During object hold, however, CTS patients were able to modulate digit tangential force distribution to object CM.
Conclusions: Our findings suggest that, although CTS did not affect patients’ ability to perform our manipulation task, it interfered with the modulation of specific grasp control variables. This phenomenon might be indicative of a lower degree of flexibility of the sensorimotor system in CTS to adapt to grasp task conditions.