Changes in Sensorimotor Cortical Activation in Children Using Prostheses and Prosthetic Simulators

This study aimed to examine the neural responses of children using prostheses and prosthetic simulators to better elucidate the emulation abilities of the simulators. We utilized functional near-infrared spectroscopy (fNIRS) to evaluate the neural response in five children with a congenital upper limb reduction (ULR) using a body-powered prosthesis to complete a 60 s gross motor dexterity task. The ULR group was matched with five typically developing children (TD) using their non-preferred hand and a prosthetic simulator on the same hand. The ULR group had lower activation within the primary motor cortex (M1) and supplementary motor area (SMA) compared to the TD group, but nonsignificant differences in the primary somatosensory area (S1). Compared to using their non-preferred hand, the TD group exhibited significantly higher action in S1 when using the simulator, but nonsignificant differences in M1 and SMA. The non-significant differences in S1 activation between groups and the increased activation evoked by the simulator’s use may suggest rapid changes in feedback prioritization during tool use. We suggest that prosthetic simulators may elicit increased reliance on proprioceptive and tactile feedback during motor tasks. This knowledge may help to develop future prosthesis rehabilitative training or the improvement of tool-based skills

Developing and Testing of Low-cost 3D Printed Prostheses to Restore and Improve Function of Children with Congenital or Traumatic Amputations

The purpose of this investigation was to provide technical considerations and clinical evidence of the possible benefits and obstacles in the use of upper-limb 3D printed prostheses in paediatric populations. This information is crucial for clinicians interested in exploring the use of 3D printed prostheses for their patients. In the present study, children with congenital digit reductions (n=5); absent digits (one traumatic and four congenital) (n=5) and with upper-limb reductions (n=9). The perceived functionality of upper-limbs before the use of the prosthesis and after 4 months of use. In addition, gross dexterity, anthropometric measurements, active range of motion, and strength measurements were assessed before and after 6 month of using a low-cost 3D printed prosthetic hand. Their parents completed a survey at 1 and 3 months asking to quantify the time their child used the prosthesis on a daily basis in addition to the type of activities they performed with the prosthesis. The main finding of our studies is that the initial prosthesis design of the Cyborg Beast was not a functional solution for congenital paediatric patients with remnant opposition and pinch function, but significantly increased forearm circumference (Before=16.70±1.86 cm and After=17.80±1.48 cm), wrist active ROM flexion (Before=54.60±14.48° and After=68.40±14.29°), and active ROM extension (Before=40.40±37.75° and After=47.00±36.42° cm) after 6 months of use and can be incorporated in several activities at home and in school. However, 44% of our research participants reported durability issues and/or malfunctioning of these devices after 3 months of use

Use-Dependent Prosthesis Training Strengthens Contralateral Hemodynamic Brain Responses in a Young Adult With Upper Limb Reduction Deficiency: A Case Report

The purpose of the current case study was to determine the influence of an 8-week home intervention training utilizing a partial hand prosthesis on hemodynamic responses of the brain and gross dexterity in a case participant with congenital unilateral upper-limb reduction deficiency (ULD). The case participant (female, 19 years of age) performed a gross manual dexterity task (Box and Block Test) while measuring brain activity (functional near-infrared spectroscopy; fNIRS) before and after an 8-weeks home intervention training. During baseline, there was a broad cortical activation in the ipsilateral sensorimotor cortex and a non-focalized cortical activation in the contralateral hemisphere, which was non-focalized, while performing a gross manual dexterity task using a prosthesis. After the 8-week home intervention training, however, cortical activation shifted to the contralateral motor cortex while cortical activation was diminished in the ipsilateral hemisphere. Specifically, the oxygenated hemodynamics (HbO) responses increased in the medial aspects of the contralateral primary motor and somatosensory cortices. Thus, these results suggest that an 8-week prosthetic home intervention was able to strengthen contralateral connections in this young adult with congenital partial hand reduction. This was supported by the case participant showing after training an increased flexor tone, increased range of motion of the wrist, and decreased times to complete various gross dexterity tasks. Changes in HbO responses due to the home intervention training follow the mechanisms of use-dependent plasticity and further guide the use of prostheses as a rehabilitation strategy for individuals with ULD

Assessing the causal role of body mass index on cardiovascular health in young adults:Mendelian randomization and recall-by-genotype analyses

Background:Body mass index (BMI) has been suggested to be causally related to cardiovascular health in mid-to-late life, but this has not been explored systematically at younger ages - nor with detailed cardiovascular phenotyping. Recall-by-Genotype (RbG) is an approach that enables the collection of precise phenotypic measures in smaller studies, whilst maintaining statistical power and ability for causal inference. Methods:In this study, we used a combination of conventional multivariable regression analysis, Mendelian randomization (MR) and sub-sample RbG methodologies to estimate the causal effect of BMI on gross-level and detailed cardiovascular health in healthy participants from the Avon Longitudinal Study of Parents and Children at age 17 (N=1420-3108 for different outcomes) and an independent sample from the same cohort (for RbG) study at age 21 (N=386-418). Results:In both MR and RbG analyses, results suggested that higher BMI causes higher blood pressure (BP) and left ventricular mass index (LVMI) in young adults (e.g., difference in LVMI per kg/m2 using MR: 1.07g/m2.7; 95% CI: 0.62, 1.52; P=3.87x10-06 and per 3.58kg/m2 using RbG: 1.65g/m2.7 95% CI: 0.83, 2.47; P=0.0001). Additionally, RbG results suggested a causal role of higher BMI on higher stroke volume (SV: difference per 3.58kg/m2: 1.49ml/m2.04; 95% CI: 0.62, 2.35; P=0.001) and cardiac output (CO: difference per 3.58kg/m2: 0.11l/min/m1.83; 95% CI: 0.03, 0.19; P=0.01) but no strong evidence for a causal role on systemic vascular resistance or total arterial compliance. Neither analysis supported a causal role of higher BMI on heart rate. Conclusions:Complementary MR and RbG causal methodologies, together with a range of sensitivity analyses, suggest that higher BMI is likely to cause worse cardiovascular health, specifically higher BP and LVMI, even in youth. Higher BMI also resulted in increased CO in the RbG study, which appeared to be solely driven by SV, as neither MR nor RbG analyses suggested a causal effect of BMI on heart rate. These consistent results support efforts to reduce BMI from a young age to prevent later adverse cardiovascular health and illustrate the potential for phenotypic resolution with maintained analytical power using RbG

Genetic risk for autism spectrum disorders and neuropsychiatric variation in the general population

Almost all genetic risk factors for autism spectrum disorders (ASDs) can be found in the general population, but the effects of that risk are unclear in people not ascertained for neuropsychiatric symptoms. Using several large ASD consortia and population based resources, we find genetic links between ASDs and typical variation in social behavior and adaptive functioning. This finding is evidenced through both inherited and de novo variation, indicating that multiple types of genetic risk for ASDs influence a continuum of behavioral and developmental traits, the severe tail of which can result in an ASD or other neuropsychiatric disorder diagnosis. A continuum model should inform the design and interpretation of studies of neuropsychiatric disease biology

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Motor dexterity and cortical laterality in chronically ill children after isolation

Objective: The main objective of this study was to describe the cortical patterns of brain activity during a gross manual dexterity task conducted by chronically ill children after experiencing isolation. Methods: Four pediatric participants completed the Box and Blocks test of gross manual dexterity with each hand while undergoing imaging of the motor cortex with functional near infrared spectroscopy. Results: All participants displayed gross manual dexterity levels lower than previously predicted based on normative data. Three out of the four participants displayed ipsilateral dominance of the motor cortex during the dexterity task. This research quantifies the motor behavior and motor cortex laterality of children following hospitalized isolation for chronic conditions. These results coupled with future research can be useful to further elucidate the specific impacts of isolation on children in the short and long term to aid in the development of hospital policies and interventions to prevent deleterious impacts from hospitalized isolation

Ipsilateral motor control of prosthesis during first use

To better understand the neurological mechanisms associated with prosthetic usage, a study was conducted during an initial fitting for children with congenital upper limb reductions body powered prosthetics. The aim of the current study was to examine the differences between hemispheric dominance at specific regions of interest between the affected and non-affected hands. fNIRS activity was recorded (NIRSport 2, NIRx Medical Technologies, Berlin, Germany) over 20 channels in regions associated with motor control and motor planning in the frontal and parietal lobes (specifically the premotor cortex, primary motor cortex, and primary sensory cortex). The hemodynamic activity was recorded for 9 participants (11±3.9 years old, 4 female, right-hand affected) during three one-minute-long gross motor dexterity tasks completed with a non-affected hand and an affected (prosthetic) hand. The hemodynamic activity for the first ten seconds of the task was block averaged in Homer3 before laterality index calculation and graphing were conducted in Matlab (The Mathworks Inc, Natick, MA, USA). The participants moved more blocks with their non-affected hands regardless of side (left non-affected: 43.52 ± 16.04, right non-affected: 34.76 ± 16.43 blocks) than with their affected hands (right affected: 7.33 ± 3.18, left affected 7.0 ± 5.32 blocks) (p = 0.001). During the time that the participants were completing the tasks, usage of the non-affected hand was associated with contralateral control in each region of interest. However, during usage of the affected hand with a prosthesis, the participants displayed ipsilateral control in all regions of interest but the premotor cortex. The main findings of this study include ipsilateral dominance of the primary motor and sensory cortices during control of an affected hand while wearing a prosthesis. This ipsilateral dominance in this group supports previous case study findings where a participant’s initial ipsilateral dominance was reversed through training. Accordingly, hemispheric laterality should be further studied to determine whether neuroplastic changes are associated with better functionality or perceived comfort. These insights might be used when determining dosage of prosthesis training in children

Effective Connectivity of Neural Networks During Motor Imagery and Execution of a Gross Manual Dexterity Task using Dynamic Causal Modeling: an fNIRS Study

Motor Imagery is the mental rehearsal of a movement, without actually performing the movement. Previous work has shown that motor imagery activates similar areas within the brain as actual motor execution. However, the majority of these studies have been performed using brain imaging modalities that restrict movement and have been limited to movements such as finger-tapping. Functional near-infrared spectroscopy, or fNIRS is a rapidly developing brain imaging technique that tolerates movement and allows for imaging during a wide array of naturalistic tasks. In this study, we propose to utilize fNIRS to measure the activity of the motor areas of 15 participants during a modified Box and Blocks task. Participants will be tasked to move 16 blocks in standardized positions from one side of a partitioned box to another during the motor execution condition and imagine doing the same task during the motor imagery condition. Activity within the brain will be investigated by measuring effective connectivity using Dynamic Causal Modeling. Effective connectivity is the assessment of how one neural network influences another. Dynamic Causal Modeling produces a generative model of how information flows within the brain, which can then be explored to make inferences on how different brain regions interact. Previous literature using tapping has shown that during motor imagery, the primary motor cortex (M1) has significantly reduced activation due to a suppressive influence placed on it from the supplementary motor area (SMA), which remains highly active. We expect to find similar results during the Box and Block Task, where the SMA will remain active during motor imagery, but suppress the primary motor cortex. We additionally expect that during motor execution, the SMA and M1 will work in tandem, positively influencing each other in a closed feedback loop. Verification of how these networks communicate during a more naturalistic task will expand the literature on the motor system within the brain and can form the basis for future studies seeking to understand differences in connectivity in pathologies such as stroke or amputation