Cyber-Workstation for Computational Neuroscience

A Cyber-Workstation (CW) to study in vivo, real-time interactions between computational models and large-scale brain subsystems during behavioral experiments has been designed and implemented. The design philosophy seeks to directly link the in vivo neurophysiology laboratory with scalable computing resources to enable more sophisticated computational neuroscience investigation. The architecture designed here allows scientists to develop new models and integrate them with existing models (e.g. recursive least-squares regressor) by specifying appropriate connections in a block-diagram. Then, adaptive middleware transparently implements these user specifications using the full power of remote grid-computing hardware. In effect, the middleware deploys an on-demand and flexible neuroscience research test-bed to provide the neurophysiology laboratory extensive computational power from an outside source. The CW consolidates distributed software and hardware resources to support time-critical and/or resource-demanding computing during data collection from behaving animals. This power and flexibility is important as experimental and theoretical neuroscience evolves based on insights gained from data-intensive experiments, new technologies and engineering methodologies. This paper describes briefly the computational infrastructure and its most relevant components. Each component is discussed within a systematic process of setting up an in vivo, neuroscience experiment. Furthermore, a co-adaptive brain machine interface is implemented on the CW to illustrate how this integrated computational and experimental platform can be used to study systems neurophysiology and learning in a behavior task. We believe this implementation is also the first remote execution and adaptation of a brain-machine interface

Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants

Pt/Ir electrodes have been extensively used in neurophysiology research in recent years as they provide a more inert recording surface as compared to tungsten or stainless steel. While floating microelectrode arrays (FMA) consisting of Pt/Ir electrodes are an option for neuroprosthetic applications, long-term in vivo functional performance characterization of these FMAs is lacking. In this study, we have performed comprehensive abiotic-biotic characterization of Pt/Ir arrays in 12 rats with implant periods ranging from 1 week up to 6 months. Each of the FMAs consisted of 16-channel, 1.5 mm long, and 75 μm diameter microwires with tapered tips that were implanted into the somatosensory cortex. Abiotic characterization included (1) pre-implant and post-explant scanning electron microscopy (SEM) to study recording site changes, insulation delamination and cracking, and (2) chronic in vivo electrode impedance spectroscopy. Biotic characterization included study of microglial responses using a panel of antibodies, such as Iba1, ED1, and anti-ferritin, the latter being indicative of blood-brain barrier (BBB) disruption. Significant structural variation was observed pre-implantation among the arrays in the form of irregular insulation, cracks in insulation/recording surface, and insulation delamination. We observed delamination and cracking of insulation in almost all electrodes post-implantation. These changes altered the electrochemical surface area of the electrodes and resulted in declining impedance over the long-term due to formation of electrical leakage pathways. In general, the decline in impedance corresponded with poor electrode functional performance, which was quantified via electrode yield. Our abiotic results suggest that manufacturing variability and insulation material as an important factor contributing to electrode failure. Biotic results show that electrode performance was not correlated with microglial activation (neuroinflammation) as we were able to observe poor performance in the absence of neuroinflammation, as well as good performance in the presence of neuroinflammation. One biotic change that correlated well with poor electrode performance was intraparenchymal bleeding, which was evident macroscopically in some rats and presented microscopically by intense ferritin immunoreactivity in microglia/macrophages. Thus, we currently consider intraparenchymal bleeding, suboptimal electrode fabrication, and insulation delamination as the major factors contributing toward electrode failure

Runtime translation of OCL-like statements on Simulink models : Expanding domains and optimising queries

Open-source model management frameworks such as OCL and ATL tend to focus on manipulating models built atop the Eclipse Modelling Framework (EMF), a de facto standard for domain specific modelling. MATLAB Simulink is a widely used proprietary modelling framework for dynamic systems that is built atop an entirely different technical stack to EMF. To leverage the facilities of open-source model management frameworks with Simulink models, these can be transformed into an EMF-compatible representation. Downsides of this approach include the synchronisation of the native Simulink model and its EMF representation as they evolve; the completeness of the EMF representation, and the transformation cost which can be crippling for large Simulink models. We propose an alternative approach to bridge Simulink models with open-source model management frameworks that uses an “on-the-fly” translation of model management constructs into MATLAB statements. Our approach does not require an EMF representation and can mitigate the cost of the upfront transformation on large models. To evaluate both approaches we measure the performance of a model validation process with Epsilon (a model management framework) on a sample of large Simulink models available on GitHub. Our previous results suggest that, with our approach, the total validation time can be reduced by up to 80%. In this paper, we expand our approach to support the management of Simulink requirements and dictionaries, and we improve the approach to perform queries on collections of model elements more efficiently. We demonstrate the use of the Simulink requirements and dictionaries with a case study and we evaluate the optimisations on collection queries with an experiment that compares the performance of a set of queries on models with different sizes. Our results suggest an improvement by up to 99% on some queries

Commensal Microbes and Hair Follicle Morphogenesis Coordinately Drive Treg Migration into Neonatal Skin

Regulatory T cells (Tregs) are required to establish immune tolerance to commensal microbes. Tregs accumulate abruptly in the skin during a defined window of postnatal tissue development. However, the mechanisms mediating Treg migration to neonatal skin are unknown. Here we show that hair follicle (HF) development facilitates the accumulation of Tregs in neonatal skin and that upon skin entry these cells localize to HFs, a primary reservoir for skin commensals. Further, germ-free neonates had reduced skin Tregs indicating that commensal microbes augment Treg accumulation. We identified Ccl20 as a HF-derived, microbiota-dependent chemokine and found its receptor, Ccr6, to be preferentially expressed by Tregs in neonatal skin. The Ccl20-Ccr6 pathway mediated Treg migration in vitro and in vivo. Thus, HF morphogenesis, commensal microbe colonization, and local chemokine production work in concert to recruit Tregs into neonatal skin, thereby establishing this tissue Treg niche early in life

Expression of the transcription factor Klf6 by thymic epithelial cells is required for thymus development

Thymic epithelial cells (TEC) control T cell development and play essential roles in establishing self-tolerance. By using Foxn1-Cre–driven ablation of Klf6 gene in TEC, we identified Klf6 as a critical factor in TEC development. Klf6 deficiency resulted in a hypoplastic thymus—evident from fetal stages into adulthood—in which a dramatic increase in the frequency of apoptotic TEC was observed. Among cortical TEC (cTEC), a previously unreported cTEC population expressing the transcription factor Sox10 was relatively expanded. Within medullary TEC (mTEC), mTEC I and Tuft-like mTEC IV were disproportionately decreased. Klf6 deficiency altered chromatin accessibility and affected TEC chromatin configuration. Consistent with these defects, naïve conventional T cells and invariant natural killer T cells were reduced in the spleen. Late stages of T cell receptor–dependent selection of thymocytes were affected, and mice exhibited autoimmunity. Thus, Klf6 has a prosurvival role and affects the development of specific TEC subsets contributing to thymic function

Higher-order non-symmetric counterterms in pure Yang-Mills theory

We analyze the restoration of the Slavnov-Taylor (ST) identities for pure massless Yang-Mills theory in the Landau gauge within the BPHZL renormalization scheme with IR regulator. We obtain the most general form of the action-like part of the symmetric regularized action, obeying the relevant ST identities and all other relevant symmetries of the model, to all orders in the loop expansion. We also give a cohomological characterization of the fulfillment of BPHZL IR power-counting criterion, guaranteeing the existence of the limit where the IR regulator goes to zero. The technique analyzed in this paper is needed in the study of the restoration of the ST identities for those models, like the MSSM, where massless particles are present and no invariant regularization scheme is known to preserve the full set of ST identities of the theory.Comment: Final version published in the journa

Pannexin 3 deletion reduces fat accumulation and inflammation in a sex-specific manner

Background: Pannexin 3 (PANX3) is a channel-forming glycoprotein that enables nutrient-induced inflammation in vitro, and genetic linkage data suggest that it regulates body mass index. Here, we characterized inflammatory and metabolic parameters in global Panx3 knockout (KO) mice in the context of forced treadmill running (FEX) and high-fat diet (HFD). Methods: C57BL/6N (WT) and KO mice were randomized to either a FEX running protocol or no running (SED) from 24 until 30 weeks of age. Body weight was measured biweekly, and body composition was measured at 24 and 30 weeks of age. Male WT and KO mice were fed a HFD from 12 to 28 weeks of age. Metabolic organs were analyzed for a panel of inflammatory markers and PANX3 expression. Results: In females there were no significant differences in body composition between genotypes, which could be due to the lack of PANX3 expression in female white adipose tissue, while male KOs fed a chow diet had lower body weight and lower fat mass at 24 and 30 weeks of age, which was reduced to the same extent as 6 weeks of FEX in WT mice. In addition, male KO mice exhibited significantly lower expression of multiple pro-inflammatory genes in white adipose tissue compared to WT mice. While on a HFD body weight differences were insignificant, multiple inflammatory genes were significantly different in quadriceps muscle and white adipose tissue resulting in a more anti-inflammatory phenotype in KO mice compared to WT. The lower fat mass in male KO mice may be due to significantly fewer adipocytes in their subcutaneous fat compared to WT mice. Mechanistically, adipose stromal cells (ASCs) cultured from KO mice grow significantly slower than WT ASCs. Conclusion: PANX3 is expressed in male adult mouse adipose tissue and may regulate adipocyte numbers, influencing fat accumulation and inflammation

The HAND-Q : Psychometrics of a New Patient-reported Outcome Measure for Clinical and Research Applications

Background: The perspective of the patient in measuring the outcome of their hand treatment is of key importance. We developed a hand-specific patient-reported outcome measure to provide a means to measure outcomes and experiences of care from the patient perspective, that is, HAND-Q. Methods: Data were collected from people with a broad range of hand conditions in hand clinics in six countries between April 2018 and January 2021. Rasch measurement theory analysis was used to perform item reduction and to examine reliability and validity of each HAND-Q scale. Results: A sample of 1277 patients was recruited. Participants ranged in age from 16 to 89 years, 54% were women, and a broad range of congenital and acquired hand conditions were represented. Rasch measurement theory analysis led to the refinement of 14 independently functioning scales that measure hand appearance, health-related quality of life, experience of care, and treatment outcome. Each scale evidenced reliability and validity. Examination of differential item functioning by age, gender, language, and type of hand condition (ie, nontraumatic versus traumatic) confirmed that a common scoring algorithm for each scale could be implemented. Conclusions: The HAND-Q was developed following robust psychometric methods to provide a comprehensive modular independently functioning set of scales. HAND-Q scales can be used to assess and compare evidence-based outcomes in patients with any type of hand condition.Peer reviewe

A Symbiotic Brain-Machine Interface through Value-Based Decision Making

BACKGROUND: In the development of Brain Machine Interfaces (BMIs), there is a great need to enable users to interact with changing environments during the activities of daily life. It is expected that the number and scope of the learning tasks encountered during interaction with the environment as well as the pattern of brain activity will vary over time. These conditions, in addition to neural reorganization, pose a challenge to decoding neural commands for BMIs. We have developed a new BMI framework in which a computational agent symbiotically decoded users' intended actions by utilizing both motor commands and goal information directly from the brain through a continuous Perception-Action-Reward Cycle (PARC). METHODOLOGY: The control architecture designed was based on Actor-Critic learning, which is a PARC-based reinforcement learning method. Our neurophysiology studies in rat models suggested that Nucleus Accumbens (NAcc) contained a rich representation of goal information in terms of predicting the probability of earning reward and it could be translated into an evaluative feedback for adaptation of the decoder with high precision. Simulated neural control experiments showed that the system was able to maintain high performance in decoding neural motor commands during novel tasks or in the presence of reorganization in the neural input. We then implanted a dual micro-wire array in the primary motor cortex (M1) and the NAcc of rat brain and implemented a full closed-loop system in which robot actions were decoded from the single unit activity in M1 based on an evaluative feedback that was estimated from NAcc. CONCLUSIONS: Our results suggest that adapting the BMI decoder with an evaluative feedback that is directly extracted from the brain is a possible solution to the problem of operating BMIs in changing environments with dynamic neural signals. During closed-loop control, the agent was able to solve a reaching task by capturing the action and reward interdependency in the brain