Quantifying kinematics of purposeful movements to real, imagined, or absent functional objects: Implications for modelling trajectories for robot-assisted ADL tasks**

BACKGROUND: Robotic therapy is at the forefront of stroke rehabilitation. The Activities of Daily Living Exercise Robot (ADLER) was developed to improve carryover of gains after training by combining the benefits of Activities of Daily Living (ADL) training (motivation and functional task practice with real objects), with the benefits of robot mediated therapy (repeatability and reliability). In combining these two therapy techniques, we seek to develop a new model for trajectory generation that will support functional movements to real objects during robot training. We studied natural movements to real objects and report on how initial reaching movements are affected by real objects and how these movements deviate from the straight line paths predicted by the minimum jerk model, typically used to generate trajectories in robot training environments. We highlight key issues that to be considered in modelling natural trajectories. METHODS: Movement data was collected as eight normal subjects completed ADLs such as drinking and eating. Three conditions were considered: object absent, imagined, and present. This data was compared to predicted trajectories generated from implementing the minimum jerk model. The deviations in both the plane of the table (XY) and the saggital plane of torso (XZ) were examined for both reaches to a cup and to a spoon. Velocity profiles and curvature were also quantified for all trajectories. RESULTS: We hypothesized that movements performed with functional task constraints and objects would deviate from the minimum jerk trajectory model more than those performed under imaginary or object absent conditions. Trajectory deviations from the predicted minimum jerk model for these reaches were shown to depend on three variables: object presence, object orientation, and plane of movement. When subjects completed the cup reach their movements were more curved than for the spoon reach. The object present condition for the cup reach showed more curvature than in the object imagined and absent conditions. Curvature in the XZ plane of movement was greater than curvature in the XY plane for all movements. CONCLUSION: The implemented minimum jerk trajectory model was not adequate for generating functional trajectories for these ADLs. The deviations caused by object affordance and functional task constraints must be accounted for in order to allow subjects to perform functional task training in robotic therapy environments. The major differences that we have highlighted include trajectory dependence on: object presence, object orientation, and the plane of movement. With the ability to practice ADLs on the ADLER environment we hope to provide patients with a therapy paradigm that will produce optimal results and recovery

Perceptual Learning in the Absence of Task or Stimulus Specificity

Performance on most sensory tasks improves with practice. When making particularly challenging sensory judgments, perceptual improvements in performance are tightly coupled to the trained task and stimulus configuration. The form of this specificity is believed to provide a strong indication of which neurons are solving the task or encoding the learned stimulus. Here we systematically decouple task- and stimulus-mediated components of trained improvements in perceptual performance and show that neither provides an adequate description of the learning process. Twenty-four human subjects trained on a unique combination of task (three-element alignment or bisection) and stimulus configuration (vertical or horizontal orientation). Before and after training, we measured subjects' performance on all four task-configuration combinations. What we demonstrate for the first time is that learning does actually transfer across both task and configuration provided there is a common spatial axis to the judgment. The critical factor underlying the transfer of learning effects is not the task or stimulus arrangements themselves, but rather the recruitment of commons sets of neurons most informative for making each perceptual judgment

Vision First? The Development of Primary Visual Cortical Networks Is More Rapid Than the Development of Primary Motor Networks in Humans

The development of cortical functions and the capacity of the mature brain to learn are largely determined by the establishment and maintenance of neocortical networks. Here we address the human development of long-range connectivity in primary visual and motor cortices, using well-established behavioral measures - a Contour Integration test and a Finger-tapping task - that have been shown to be related to these specific primary areas, and the long-range neural connectivity within those. Possible confounding factors, such as different task requirements (complexity, cognitive load) are eliminated by using these tasks in a learning paradigm. We find that there is a temporal lag between the developmental timing of primary sensory vs. motor areas with an advantage of visual development; we also confirm that human development is very slow in both cases, and that there is a retained capacity for practice induced plastic changes in adults. This pattern of results seems to point to human-specific development of the “canonical circuits” of primary sensory and motor cortices, probably reflecting the ecological requirements of human life

A working model of stroke recovery from rehabilitation robotics practitioners

We reviewed some of our initial insights about the process of upper-limb behavioral recovery following stroke. Evidence to date indicates that intensity, task specificity, active engagement, and focusing training on motor coordination are key factors enabling efficacious recovery. On modeling, experience with over 400 stroke patients has suggested a working model of recovery similar to implicit motor learning. Ultimately, we plan to apply these insights in the development of customized training paradigms to enhance recovery

Dissociation of Motor Task-Induced Cortical Excitability and Pain Perception Changes in Healthy Volunteers

Background: There is evidence that interventions aiming at modulation of the motor cortex activity lead to pain reduction. In order to understand further the role of the motor cortex on pain modulation, we aimed to compare the behavioral (pressure pain threshold) and neurophysiological effects (transcranial magnetic stimulation (TMS) induced cortical excitability) across three different motor tasks. Methodology/Principal Findings Fifteen healthy male subjects were enrolled in this randomized, controlled, blinded, cross-over designed study. Three different tasks were tested including motor learning with and without visual feedback, and simple hand movements. Cortical excitability was assessed using single and paired-pulse TMS measures such as resting motor threshold (RMT), motor-evoked potential (MEP), intracortical facilitation (ICF), short intracortical inhibition (SICI), and cortical silent period (CSP). All tasks showed significant reduction in pain perception represented by an increase in pressure pain threshold compared to the control condition (untrained hand). ANOVA indicated a difference among the three tasks regarding motor cortex excitability change. There was a significant increase in motor cortex excitability (as indexed by MEP increase and CSP shortening) for the simple hand movements. Conclusions/Significance: Although different motor tasks involving motor learning with and without visual feedback and simple hand movements appear to change pain perception similarly, it is likely that the neural mechanisms might not be the same as evidenced by differential effects in motor cortex excitability induced by these tasks. In addition, TMS-indexed motor excitability measures are not likely good markers to index the effects of motor-based tasks on pain perception in healthy subjects as other neural networks besides primary motor cortex might be involved with pain modulation during motor training

Expressions of Multiple Neuronal Dynamics during Sensorimotor Learning in the Motor Cortex of Behaving Monkeys

Previous studies support the notion that sensorimotor learning involves multiple processes. We investigated the neuronal basis of these processes by recording single-unit activity in motor cortex of non-human primates (Macaca fascicularis), during adaptation to force-field perturbations. Perturbed trials (reaching to one direction) were practiced along with unperturbed trials (to other directions). The number of perturbed trials relative to the unperturbed ones was either low or high, in two separate practice schedules. Unsurprisingly, practice under high-rate resulted in faster learning with more pronounced generalization, as compared to the low-rate practice. However, generalization and retention of behavioral and neuronal effects following practice in high-rate were less stable; namely, the faster learning was forgotten faster. We examined two subgroups of cells and showed that, during learning, the changes in firing-rate in one subgroup depended on the number of practiced trials, but not on time. In contrast, changes in the second subgroup depended on time and practice; the changes in firing-rate, following the same number of perturbed trials, were larger under high-rate than low-rate learning. After learning, the neuronal changes gradually decayed. In the first subgroup, the decay pace did not depend on the practice rate, whereas in the second subgroup, the decay pace was greater following high-rate practice. This group shows neuronal representation that mirrors the behavioral performance, evolving faster but also decaying faster at learning under high-rate, as compared to low-rate. The results suggest that the stability of a new learned skill and its neuronal representation are affected by the acquisition schedule.United States-Israel Binational Science FoundationIsrael Science FoundationIda Baruch FundRosetrees Trus

Mirror Symmetric Bimanual Movement Priming Can Increase Corticomotor Excitability and Enhance Motor Learning

Repetitive mirror symmetric bilateral upper limb may be a suitable priming technique for upper limb rehabilitation after stroke. Here we demonstrate neurophysiological and behavioural after-effects in healthy participants after priming with 20 minutes of repetitive active-passive bimanual wrist flexion and extension in a mirror symmetric pattern with respect to the body midline (MIR) compared to an control priming condition with alternating flexion-extension (ALT). Transcranial magnetic stimulation (TMS) indicated that corticomotor excitability (CME) of the passive hemisphere remained elevated compared to baseline for at least 30 minutes after MIR but not ALT, evidenced by an increase in the size of motor evoked potentials in ECR and FCR. Short and long-latency intracortical inhibition (SICI, LICI), short afferent inhibition (SAI) and interhemispheric inhibition (IHI) were also examined using pairs of stimuli. LICI differed between patterns, with less LICI after MIR compared with ALT, and an effect of pattern on IHI, with reduced IHI in passive FCR 15 minutes after MIR compared with ALT and baseline. There was no effect of pattern on SAI or FCR H-reflex. Similarly, SICI remained unchanged after 20 minutes of MIR. We then had participants complete a timed manual dexterity motor learning task with the passive hand during, immediately after, and 24 hours after MIR or control priming. The rate of task completion was faster with MIR priming compared to control conditions. Finally, ECR and FCR MEPs were examined within a pre-movement facilitation paradigm of wrist extension before and after MIR. ECR, but not FCR, MEPs were consistently facilitated before and after MIR, demonstrating no degradation of selective muscle activation. In summary, mirror symmetric active-passive bimanual movement increases CME and can enhance motor learning without degradation of muscle selectivity. These findings rationalise the use of mirror symmetric bimanual movement as a priming modality in post-stroke upper limb rehabilitation

Identifying Alternative Hyper-Splicing Signatures in MG-Thymoma by Exon Arrays

BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing signatures specific to particular tumor types are still lacking. Here, we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. METHODOLOGY/PRINCIPAL FINDINGS: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight various exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Ontology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. CONCLUSIONS/SIGNIFICANCE: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL)19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acetylcholinesterase ACHE gene. Corresponding changes in spliceosome composition were indicated by co-decreases in the splicing factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Fluorescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches

Obtaining Adequate Surgical Margins in Breast-Conserving Therapy for Patients with Early-Stage Breast Cancer: Current Modalities and Future Directions

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT