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BackgroundThough the US civilian trauma care system plays a critical role in disaster response, there is currently no systems-based strategy that enables hospital emergency management and local and regional emergency planners to quantify, and potentially prepare for, surges in trauma care demand that accompany mass-casualty disasters.ObjectiveA proof-of-concept model that estimates the geographic distributions of patients, trauma center resource usage, and mortality rates for varying disaster sizes, in and around the 25 largest US cities, is presented. The model was designed to be scalable, and its inputs can be modified depending on the planning assumptions of different locales and for different types of mass-casualty events.MethodsTo demonstrate the model’s potential application to real-life planning scenarios, sample disaster responses for 25 major US cities were investigated using a hybrid of geographic information systems and dynamic simulation-optimization. In each city, a simulated, fast-onset disaster epicenter, such as might occur with a bombing, was located randomly within one mile of its population center. Patients then were assigned and transported, in simulation, via the new model to Level 1, 2, and 3 trauma centers, in and around each city, over a 48-hour period for disaster scenario sizes of 100, 500, 5000, and 10,000 casualties.ResultsAcross all 25 cities, total mean mortality rates ranged from 26.3% in the smallest disaster scenario to 41.9% in the largest. Out-of-hospital mortality rates increased (from 21.3% to 38.5%) while in-hospital mortality rates decreased (from 5.0% to 3.4%) as disaster scenario sizes increased. The mean number of trauma centers involved ranged from 3.0 in the smallest disaster scenario to 63.4 in the largest. Cities that were less geographically isolated with more concentrated trauma centers in their surrounding regions had lower total and out-of-hospital mortality rates. The nine US cities listed as being the most likely targets of terrorist attacks involved, on average, more trauma centers and had lower mortality rates compared with the remaining 16 cities.ConclusionsThe disaster response simulation model discussed here may offer insights to emergency planners and health systems in more realistically planning for mass-casualty events. Longer wait and transport times needed to distribute high numbers of patients to distant trauma centers in fast-onset disasters may create predictable increases in mortality and trauma center resource consumption. The results of the modeled scenarios indicate the need for a systems-based approach to trauma care management during disasters, since the local trauma center network was often too small to provide adequate care for the projected patient surge. Simulation of out-of-hospital resources that might be called upon during disasters, as well as guidance in the appropriate execution of mutual aid agreements and prevention of over-response, could be of value to preparedness planners and emergency response leaders. Study assumptions and limitations are discussed.CarrBG, WalshL, WilliamsJC, PryorJP, BranasCC. A geographic simulation model for the treatment of trauma patients in disasters. Prehosp Disaster Med.2016;31(4):413–421.

This chapter explores the relationship between environmental thought and geographic spatial theory. Both lines of thought problematize the role of non-humans in political and ethical life. Although both environmental and spatial thinkers argue for a dynamic exchange between humans and nature, the environment, the built environment, or their non-human surroundings, they tend to focus on different elements of those non-human surroundings and deploy different conceptual frameworks to analyze them. Additionally, environmental thinkers attend more to the ability of the non-human world to thwart, interfere with, or otherwise constitute social action, a trend that, when combined with spatial thinkers’ broad understanding of non-humans and developed conceptual categories, such as place and scale, can produce richer, fuller accounts of how non-humans figure into political life.

The Seventh International Workshop on Advances in Electrocorticography (ECoG) convened in Washington, DC, on November 13-14, 2014. Electrocorticography-based research continues to proliferate widely across basic science and clinical disciplines. The 2014 workshop highlighted advances in neurolinguistics, brain-computer interface, functional mapping, and seizure termination facilitated by advances in the recording and analysis of the ECoG signal. The following proceedings document summarizes the content of this successful multidisciplinary gathering.

Deep brain stimulation (DBS) efficacy is related to optimal electrode placement. Several authors have quantified brain shift related to surgical targeting; yet, few reports document and discuss the effects of brain shift after insertion. Objective: To quantify brain shift and electrode displacement after device insertion. Twelve patients were retrospectively reviewed, and one post-operative MRI and one time-delayed CT were obtained for each patient and their implanted electrodes modeled in 3D. Two competing methods were employed to measure the electrode tip location and deviation from the prototypical linear implant after the resolution of acute surgical changes, such as brain shift and pneumocephalus. In the interim between surgery and a pneumocephalus free postoperative scan, electrode deviation was documented in all patients and all electrodes. Significant shift of the electrode tip was identified in rostral, anterior, and medial directions (p < 0.05). Shift was greatest in the rostral direction, measuring an average of 1.41 mm. Brain shift and subsequent electrode displacement occurs in patients after DBS surgery with the reversal of intraoperative brain shift. Rostral displacement is on the order of the height of one DBS contact. Further investigation into the time course of intraoperative brain shift and its potential effects on procedures performed with rigid and non-rigid devices in supine and semi-sitting surgical positions is needed.

It is not well understood how people perceive the difficulty of performing brain-computer interface (BCI) tasks, which specific aspects of mental workload contribute the most, and whether there is a difference in perceived workload between participants who are able-bodied and disabled. This study evaluated mental workload using the NASA Task Load Index (TLX), a multi-dimensional rating procedure with six subscales: Mental Demands, Physical Demands, Temporal Demands, Performance, Effort, and Frustration. Able-bodied and motor disabled participants completed the survey after performing EEG-based BCI Fitts' law target acquisition and phrase spelling tasks. The NASA-TLX scores were similar for able-bodied and disabled participants. For example, overall workload scores (range 0-100) for 1D horizontal tasks were 48.5 (SD = 17.7) and 46.6 (SD 10.3), respectively. The TLX can be used to inform the design of BCIs that will have greater usability by evaluating subjective workload between BCI tasks, participant groups, and control modalities.Mental workload of brain-computer interfaces (BCI) can be evaluated with the NASA Task Load Index (TLX). The TLX is an effective tool for comparing subjective workload between BCI tasks, participant groups (able-bodied and disabled), and control modalities. The data can inform the design of BCIs that will have greater usability.

In many neural culture studies, neurite migration on a flat, open surface does not reflect the three-dimensional (3D) microenvironment in vivo. With that in mind, we fabricated arrays of semiconductor tubes using strained silicon (Si) and germanium (Ge) nanomembranes and employed them as a cell culture substrate for primary cortical neurons. Our experiments show that the SiGe substrate and the tube fabrication process are biologically viable for neuron cells. We also observe that neurons are attracted by the tube topography, even in the absence of adhesion factors, and can be guided to pass through the tubes during outgrowth. Coupled with selective seeding of individual neurons close to the tube opening, growth within a tube can be limited to a single axon. Furthermore, the tube feature resembles the natural myelin, both physically and electrically, and it is possible to control the tube diameter to be close to that of an axon, providing a confined 3D contact with the axon membrane and potentially insulating it from the extracellular solution.

Since the 1940s electrocorticography (ECoG) devices and, more recently, in the last decade, micro-electrocorticography (µECoG) cortical electrode arrays were used for a wide set of experimental and clinical applications, such as epilepsy localization and brain–computer interface (BCI) technologies. Miniaturized implantable µECoG devices have the advantage of providing greater-density neural signal acquisition and stimulation capabilities in a minimally invasive fashion. An increased spatial resolution of the µECoG array will be useful for greater specificity diagnosis and treatment of neuronal diseases and the advancement of basic neuroscience and BCI research. In this review, recent achievements of ECoG and µECoG are discussed. The electrode configurations and varying material choices used to design µECoG arrays are discussed, including advantages and disadvantages of µECoG technology compared to electroencephalography (EEG), ECoG, and intracortical electrode arrays. Electrode materials that are the primary focus include platinum, iridium oxide, poly(3,4-ethylenedioxythiophene) (PEDOT), indium tin oxide (ITO), and graphene. We discuss the biological immune response to µECoG devices compared to other electrode array types, the role of µECoG in clinical pathology, and brain–computer interface technology. The information presented in this review will be helpful to understand the current status, organize available knowledge, and guide future clinical and research applications of µECoG technologies.

It is known that conventional scaffold manufacturing techniques have low reproducibility and control of the micro-architecture features. Although there have been advances in bone tissue engineering fabrication, there is no consensus on the optimized parameter designs or clear understanding of the microfluidic interactions required for tissue regeneration. In this work, we introduce a new inexpensive fabrication method of producing pore designs of 3D-elastomeric structures with high controlled geometry of orthogonal arrays. The present fabrication method utilizes a permanent and reusable micro-machined mould along with a micro-casted process to efficiently fabricate diverse 3D feature directly. This fabrication method, without multiple process steps, would be suitable to support experiments of controlled environment for flow effects in 3D bone scaffolds.

Current methods to examine and regulate the functional integration and plasticity of human ESC (hESC)-derived neurons are cumbersome and technically challenging. Here, we engineered hESCs and their derivatives to express the light-gated channelrhodopsin-2 (ChR2) protein to overcome these deficiencies. Optogenetic targeting of hESC-derived neurons with ChR2 linked to the mCherry fluorophore allowed reliable cell tracking as well as light-induced spiking at physiological frequencies. Optically induced excitatory and inhibitory postsynaptic currents could be elicited in either ChR2+ or ChR2− neurons in vitro and in acute brain slices taken from transplanted severe combined immunodeficient (SCID) mice. Furthermore, we created a clonal hESC line that expresses ChR2-mCherry under the control of the synapsin-1 promoter. On neuronal differentiation, ChR2-mCherry expression was restricted to neurons and was stably expressed for at least 6 months, providing more predictable light-induced currents than transient infections. This pluripotent cell line will allow both in vitro and in vivo analysis of functional development as well as the integration capacity of neuronal populations for cell-replacement strategies.

Detection and tracking of stem cell state are difficult due to insufficient means for rapidly screening cell state in a noninvasive manner. This challenge is compounded when stem cells are cultured in aggregates or three-dimensional (3D) constructs because living cells in this form are difficult to analyze without disrupting cellular contacts. Multiphoton laser scanning microscopy is uniquely suited to analyze 3D structures due to the broad tunability of excitation sources, deep sectioning capacity, and minimal phototoxicity but is throughput limited. A novel multiphoton fluorescence excitation flow cytometry (MPFC) instrument could be used to accurately probe cells in the interior of multicell aggregates or tissue constructs in an enhanced-throughput manner and measure corresponding fluorescent properties. By exciting endogenous fluorophores as intrinsic biomarkers or exciting extrinsic reporter molecules, the properties of cells in aggregates can be understood while the viable cellular aggregates are maintained. Here we introduce a first generation MPFC system and show appropriate speed and accuracy of image capture and measured fluorescence intensity, including intrinsic fluorescence intensity. Thus, this novel instrument enables rapid characterization of stem cells and corresponding aggregates in a noninvasive manner and could dramatically transform how stem cells are studied in the laboratory and utilized in the clinic.

Brain-computer interface (BCI) systems must process neural signals with consistent timing in order to support adequate system performance. Thus, it is important to have the capability to determine whether a particular BCI configuration (i.e., hardware and software) provides adequate timing performance for a particular experiment. This report presents a method of measuring and quantifying different aspects of system timing in several typical BCI experiments across a range of settings, and presents comprehensive measures of expected overall system latency for each experimental configuration.

Surface tension driven passive pumping is a microfluidic technology that uses the surface tension present in small droplets to generate flow. To enhance the potential of this type of passive pumping, a new 'micro passive pumping' technique has been developed that allows for high throughput fluidic delivery by combining passive pumping with a small droplet-based fluidic ejection system. Flow rates of up to four milliliters per minute (mL/min) were achieved that are solely limited by the channel geometry and droplet size. Fluid exchange rates can be performed within tens of milliseconds (ms) by delivering fluids from multiple nozzles. The technique can be extended to a multitude of platforms, as channels are not pressurized and therefore do not require bonding to a substrate. This technique provides a novel flow control for high-speed and packeted flow applications without requiring external tubing connections or substrate bonding.

Functional mapping of eloquent cortex is often necessary prior to invasive brain surgery, but current techniques that derive this mapping have important limitations. In this article, we demonstrate the first comprehensive evaluation of a rapid, robust, and practical mapping system that uses passive recordings of electrocorticographic signals. This mapping procedure is based on the BCI2000 and SIGFRIED technologies that we have been developing over the past several years. In our study, we evaluated 10 patients with epilepsy from four different institutions and compared the results of our procedure with the results derived using electrical cortical stimulation (ECS) mapping. The results show that our procedure derives a functional motor cortical map in only a few minutes. They also show a substantial concurrence with the results derived using ECS mapping. Specifically, compared with ECS maps, a next-neighbor evaluation showed no false negatives, and only 0.46 and 1.10% false positives for hand and tongue maps, respectively. In summary, we demonstrate the first comprehensive evaluation of a practical and robust mapping procedure that could become a new tool for planning of invasive brain surgeries.

This article formulates and tests set covering and related models with spatial characteristics for selecting sites that provide habitat for species that are identified as “critical” (e.g., typically threatened, endangered, or rare), thereby enhancing their persistence. The first two models presented require the creation of a core area for each critical species and a buffer zone surrounding the core, with and without being constrained to include at least one representation of each and every common (i.e., noncritical) species. The final model aims at minimizing costs of protecting predetermined numbers of common species while all critical species remain covered and buffered. These models are implemented for occurrence data of terrestrial mammals in Oregon. They enable, among other things, a comparison between the budgetary impacts of reserve networks with and without buffering rings for critical species, and a determination of the marginal cost of common species protection.

Neural optogenetic applications over the past decade have steadily increased; however the effects of commonly used blue light paradigms on surrounding, non-optogenetic protein-expressing CNS cells are rarely considered, despite their simultaneous exposure. Here we report that blue light (450 nm) repetitively delivered in both long-duration boluses and rapid optogenetic bursts gene-specifically altered basal expression of inflammatory and neurotrophic genes in immortalized and primary murine wild type microglial cultures. In addition, blue light reduced pro-inflammatory gene expression in microglia activated with lipopolysaccharide. These results demonstrate previously unreported, off-target effects of blue light in cells not expressing optogenetic constructs. The unexpected gene modulatory effects of blue light on wild type CNS resident immune cells have novel and important implications for the neuro-optogenetic field. Further studies are needed to elucidate the molecular mechanisms and potential therapeutic utility of blue light modulation of the wild type CNS.

Introduction: A better understanding of brain changes underlying functional gains with brain-computer interface (BCI) use in stroke rehabilitation is needed. Hypothesis: BCI therapy will produce observable neuroplastic changes, and behavioral gains will relate to changes in diffusion tensor imaging (DTI) metrics of the corticospinal tracts (CSTs). Methods: We obtained DTI and behavioral data from 16 stroke patients with upper extremity motor impairment before, during, and after BCI therapy. Additional DTI and behavior data were obtained from 9 control subjects at similar time intervals before receiving any BCI therapy. Behavioral measures included Stroke Impact Scale (SIS), Action Research Arm Test (ARAT), 9-Hole Peg Test (9HPT), and grip strength. We performed deterministic tractography of the ipsilesional CST (iCST) and contralesional CST (cCST) and extracted DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, trace) from each. DTI and behavioral metrics were analyzed for changes from baseline between therapy and control groups. Individual changes in DTI metrics were analyzed for correlation with behavior changes during the therapy period. Results: Group by time interactions were identified in DTI metrics of the iCST, with multiple metrics increasing with therapy. Changes in individual SIS Activities of Daily Living and 9HPT scores correlated with individual changes in both the iCST and cCST. Similarly, changes in SIS Hand Function correlated with cCST changes, and changes in grip strength correlated with iCST changes. Correlations between changes in ARAT scores and cCST changes trended to significance. Correlations significant at p Conclusions: BCI therapy can induce structural neuroplastic changes during stroke recovery. These changes may be used to track both subjective and objective behavioral gains.

A series of animal experiments was conducted to characterize changes in the complex impedance of chronically implanted electrodes in neural tissue. Consistent trends in impedance changes were observed across all animals, characterized as a general increase in the measured impedance magnitude at 1 kHz. Impedance changes reach a peak approximately 7 days post-implant. Reactive responses around individual electrodes were described using immuno- and histo-chemistry and confocal microscopy. These observations were compared to measured impedance changes. Several features of impedance changes were able to differentiate between confined and extensive histological reactions. In general, impedance magnitude at 1 kHz was significantly increased in extensive reactions, starting about 4 days post-implant. Electrodes with extensive reactions also displayed impedance spectra with a characteristic change at high frequencies. This change was manifested in the formation of a semi-circular arc in the Nyquist space, suggestive of increased cellular density in close proximity to the electrode site. These results suggest that changes in impedance spectra are directly influenced by cellular distributions around implanted electrodes over time and that impedance measurements may provide an online assessment of cellular reactions to implanted devices.

One limitation to the use of neuroprosthestic devices for chronic application, in the treatment of disease, is the reactive cell responses that occur surrounding the device after insertion. These cell and tissue responses result in increases in device impedance and failure of the device to interact with target populations of neurons. However, few tools are available to assess which components of the reactive response contribute most to changes in tissue impedance. An in vitro culture system has been developed that is capable of assessing individual components of the reactive response. The system utilizes alginate cell encapsulation to construct three-dimensional architectures that approach the cell densities found in rat cortex. The system was constructed around neuroNexus acute probes with on-board circuitry capable of monitoring the electrical properties of the surrounding tissue. This study demonstrates the utility of the system by demonstrating that differences in cell density within the three-dimensional alginate constructs result in differences in resistance and capacitance as measured by electrochemical impedance spectroscopy. We propose that this system can be used to model components of the reactive responses in brain tissue, and that the measurements recorded in vitro are comparable to measurements recorded in vivo.

We examine the irreplaceability of sites in the context of the species set covering problem and the maximal covering species problem. We show that a succession of 0-1 programming problems can be solved to quickly determine the set of irreplaceable sites. For the widely available Oregon data set, we find a general lack of trend in the number of irreplaceable sites with the number of sites available for selection used. Moreover, we observe that irreplaceability at one level of resource may not be a predictor of irreplaceability at a higher or a lower level of resource. Finally, we investigate the economic value of irreplaceable sites by trial removals of those sites.

Most prior decision models for nature reserve-site selection have considered just two options for candidate sites: protected or not protected. In many reserve planning contexts this is an artificial and unrealistic limitation, as multiple categories of protection may be possible and desirable, especially if certain conservation elements such as rare species require special protection or management. In this paper we consider the implications of different levels of protection for species conservation and for the selection of reserve sites. New integer programming models are formulated for this problem of optimal site selection, and are presented in the context of a five-step procedure for identifying tradeoffs in the number of sites selected for each of multiple categories of protection. Results of a case study using data from Oregon are presented and compared to results from a previous study by Csuti et al.

Designing electrodes for neural interfacing applications requires deep consideration of a multitude of materials factors. These factors include, but are not limited to, the stiffness, biocompatibility, biostability, dielectric, and conductivity properties of the materials involved. The combination of materials properties chosen not only determines the ability of the device to perform its intended function, but also the extent to which the body reacts to the presence of the device after implantation. Advances in the field of materials science continue to yield new and improved materials with properties well-suited for neural applications. Although many of these materials have been well-established for non-biological applications, their use in medical devices is still relatively novel. The intention of this review is to outline new material advances for neural electrode arrays, in particular those that interface with the surface of the nervous tissue, as well as to propose future directions for neural surface electrode development.

The ability to record from and stimulate neurons is key to our further understanding of the nervous system. Not only is it vital to many areas of research, but many clinical techniques rely on the ability to stimulate and record in the long term. Many medical devices rely upon this technology (e.g., cochlear implants that restore hearing, anti-epilepsy “pacemakers,” and artificial limbs). However, precise recording inside the brain is difficult. Most current devices penetrate the brain’s protective layers and cease to function within a month due to the scar tissue that encapsulates the implant and the death of neurons near the implant. Most human implants compensate by being very large, recording from large numbers of neurons at a time.

Brain–computer interfaces (BCIs) are an emerging novel technology for stroke rehabilitation. Little is known about how dose-response relationships for BCI therapies affect brain and behavior changes. We report preliminary results on stroke patients (n = 16, 11 M) with persistent upper extremity motor impairment who received therapy using a BCI system with functional electrical stimulation of the hand and tongue stimulation. We collected MRI scans and behavioral data using the Action Research Arm Test (ARAT), 9-Hole Peg Test (9-HPT), and Stroke Impact Scale (SIS) before, during, and after the therapy period. Using anatomical and functional MRI, we computed Laterality Index (LI) for brain activity in the motor network during impaired hand finger tapping. Changes from baseline LI and behavioral scores were assessed for relationships with dose, intensity, and frequency of BCI therapy. We found that gains in SIS Strength were directly responsive to BCI therapy: therapy dose and intensity correlated positively with increased SIS Strength (p ≤ 0.05), although no direct relationships were identified with ARAT or 9-HPT scores. We found behavioral measures that were not directly sensitive to differences in BCI therapy administration but were associated with concurrent brain changes correlated with BCI therapy administration parameters: therapy dose and intensity showed significant (p ≤ 0.05) or trending (0.05 < p < 0.1) negative correlations with LI changes, while therapy frequency did not affect LI. Reductions in LI were then correlated (p ≤ 0.05) with increased SIS Activities of Daily Living scores and improved 9-HPT performance. Therefore, some behavioral changes may be reflected by brain changes sensitive to differences in BCI therapy administration, while others such as SIS Strength may be directly responsive to BCI therapy administration. Data preliminarily suggest that when using BCI in stroke rehabilitation, therapy frequency may be less important than dose and intensity.

An outstanding challenge for humanity is to continue to understand how our brain works and invent technology to restore neural circuit functionalities. Many neural interfaces used for neuron cell cultures are flat, open, rigid, and opaque, posing challenges to reflecting the native microenvironment of the brain and precise engagement with neurons. Here we present a novel neural interface consisting of silicon nitride microtube arrays formed by a new nanotechnology platform that simply relies on strain-induced self-rolled-up membrane (S-RUM) mechanism [1]. We have found that these microtubes provide robust physical confinement and unprecedented guidance effect towards outgrowth of primary cortical neurons [2]. What is more surprising is that a dramatic increase (20x) of the growth rate inside the microtube compared to regions outside the microtubes has been observed [2]. The outgrowth of hippocampal neurons is also explored using identical platforms with the intent of integrating both networks on the same chip. The unique characteristics of these S-RUM microtubes that enabled the cell guidance and acceleration will be discussed in detail: (1) True 3D geometrical confinement: the perfect cylindrical geometry of the S-RUM microtubes with tunable diameters and ultra-thin walls, the same type of small and confined spaces neurons grow in vivo, provides conformal 3D adhesion tailored to different kinds of cells. (2) Electrostatic adhesion: the deposited SiN x thin films are found to have a high density of trapped positive charges that naturally attract the axon towards the microtube opening. The ability of the microtube array to control the speed and direction of axonal extension provides a key element in arranging patterned neural networks that have both short and long range connections. (3) Optically transparent: having the ability to see through both the tube and the underlying substrate enabled direct observation of how cells transition from the flat regions to different parts of the tube.

Tracking and predicting motor outcomes is important in determining effective stroke rehabilitation strategies. Diffusion tensor imaging (DTI) allows for evaluation of the underlying structural integrity of brain white matter tracts and may serve as a potential biomarker for tracking and predicting motor recovery. In this study, we examined the longitudinal relationship between DTI measures of the posterior limb of the internal capsule (PLIC) and upper-limb motor outcomes in 13 stroke patients (median 20-month post-stroke) who completed up to 15 sessions of intervention using brain-computer interface (BCI) technology. Patients’ upper-limb motor outcomes and PLIC DTI measures including fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) were assessed longitudinally at four time points: pre-, mid-, immediately post- and one-month-post intervention. DTI measures and ratios of each DTI measure comparing the ipsilesional and contralesional PLIC were correlated with patients’ motor outcomes to examine the relationship between structural integrity of the PLIC and patients’ motor recovery. We found that lower diffusivity and higher FA values of the ipsilesional PLIC were significantly correlated with better upper-limb motor function. Baseline DTI ratios were significantly correlated with motor outcomes measured immediately post and one-month-post BCI interventions. A few patients achieved improvements in motor recovery meeting the minimum clinically important difference (MCID). These findings suggest that upper-limb motor recovery in stroke patients receiving BCI interventions relates to the microstructural status of the PLIC. Lower diffusivity and higher FA measures of the ipsilesional PLIC contribute towards better motor recovery in the stroke-affected upper-limb. DTI-derived measures may be a clinically useful biomarker in tracking and predicting motor recovery in stroke patients receiving BCI interventions.

The prevalence of fluorescent assisted studies and assays together with the advent of optogenetics have led to a dramatic increase in the use of blue light on living tissues both in vitro and in vi...

The myelin sheath enables saltatory conduction by demarcating the axon into a narrow nodal region for excitation and an extended, insulated internodal region for efficient spread of passive current. This anatomical demarcation produces a dramatic heterogeneity in ionic fluxes during excitation, a classical example being the restriction of Na influx at the node. Recent studies have revealed that action potentials also induce calcium influx into myelinated axons of mammalian optic nerves. Does calcium influx in myelinated axons show spatial heterogeneity during nerve excitation? To address this, we analyzed spatial profiles of axonal calcium transients during action potentials by selectively staining axons with calcium indicators and subjected the data to theoretical analysis with parameters for axial calcium diffusion empirically determined using photolysis of caged compounds. The results show surprisingly that during action potentials, calcium influx occurs uniformly along an axon of a fully myelinated mouse optic nerve.

Methods are presented to incorporate polymer-based bioactive matrices into micro-fabricated implantable microelectrode arrays. Using simple techniques, hydrogels infused with bioactive molecules are deposited within wells in the substrate of the device. This method allows local drug delivery without increasing the footprint of the device. In addition, each well can be loaded individually, allowing spatial and temporal control over diffusion gradients in the microenvironment of the implanted neural interface probe. In vivo testing verified the following: diffusion of the bioactive molecules, integration of the bioactive molecules with the intended neural target and concurrent extracellular recording using nearby electrodes. These results support the feasibility of using polymer gels to deliver bioactive molecules to the region close to microelectrode shanks. This technique for microdrug delivery may serve as a means to intervene with the initial phases of the neuroinflammatory tissue response to permanently implanted microelectrode arrays.

A variety of decision models have been formulated for the optimal selection of nature reserve sites to represent a diversity of species or other conservation features. Unfortunately, many of these models tend to select scattered sites and do not take into account important spatial attributes such as reserve shape and connectivity. These attributes are likely to affect not only the persistence of species but also the general ecological functioning of reserves and the ability to effectively manage them. In response, researchers have begun formulating reserve design models that improve spatial coherence by controlling spatial attributes. We review the spatial attributes that are thought to be important in reserve design and also review reserve design models that incorporate one or more of these attributes. Spatial modeling issues, computational issues, and the trade-offs among competing optimization objectives are discussed. Directions for future research are identified. Ultimately, an argument is made for the development of models that capture the dynamic interdependencies among sites and species populations and thus incorporate the reasons why spatial attributes are important.

Landscape fragmentation and habitat loss are significant threats to the conservation of biological diversity. Creating and restoring corridors between isolated habitat patches can help mitigate or reverse the impacts of fragmentation. It is important that restoration and protection efforts be undertaken in the most efficient and effective way possible because conservation budgets are often severely limited. We address the question of where restoration should take place to efficiently reconnect habitat with a landscape-spanning corridor. Building upon findings in percolation theory, we develop a shortest-path optimization methodology for assessing the minimum amount of restoration needed to establish such corridors. This methodology is applied to large numbers of simulated fragmented landscapes to generate mean and variance statistics for the amount of restoration needed. The results provide new information about the expected level of resources needed to realize different corridor configurations under different degrees of fragmentation and different characterizations of habitat connectivity (“neighbor rules”). These results are expected to be of interest to conservation planners and managers in the allocation of conservation resources to restoration projects.

The political redistricting problem can be viewed as one of dividing an area into relatively equally populated districts which are compact and contiguous, while preserving existing political and community ties, and providing proportional representation for minorities. Several disciplines have contributed to the literature of political redistricting theory and practice. This paper reviews that subset of the literature which deals with methods for creating districting plans. Emphasis is placed on the demographic, geographic and political criteria used in districting, and on the methodological features of computer districting algorithms.

An important aspect of the development of cortical prostheses is the enhancement of suitable implantable microelectrode arrays for chronic neural recording. The objective of this study was to investigate the recording performance of silicon-substrate micromachined probes in terms of reliability and signal quality. These probes were found to consistently and reliably provide high-quality spike recordings over extended periods of time lasting up to 127 days. In a consecutive series of ten rodents involving 14 implanted probes, 13/14 (93%) of the devices remained functional throughout the assessment period. More than 90% of the probe sites consistently recorded spike activity with signal-to-noise ratios sufficient for amplitudes and waveform-based discrimination. Histological analysis of the tissue surrounding the probes generally indicated the development of a stable interface sufficient for sustained electrical contact. The results of this study demonstrate that these planar silicon probes are suitable for long-term recording in the cerebral cortex and provide an effective platform technology foundation for microscale intracortical neural interfaces for use in humans.

Designing an optimal nature reserve for the protection of biological diversity has been a long-standing challenge in conservation biology. A fundamental question has always been, which areas of land should be set aside. During the past two decades, quantitative methods from the field of operations research have been applied to the problem of selecting reserve sites. Here, we trace the development of decision models for systematic reserve design, from the iterative methods developed in the 1980s to the sophisticated spatial models being formulated today. Collaborations among ecologists, conservation biologists, and operations researchers have been key to the progress made thus far. We expect that mathematical reserve design models will become more widely used, in response to a growing need to identify effective alternatives for complex conservation problems worldwide.

A decision model is developed for identifying alternative configurations of new protected habitat areas to augment and enhance major global flyways of migratory birds. New habitat areas are selected to fill in the spatial gaps between existing protected stopovers such as wildlife refuges. The methodology is applied to the US portion of the Atlantic flyway in order to develop alternative networks of habitat stepping stones extending from Maine to Florida. The model is formulated as a zero-one program and solutions are derived using a greedy adding heuristic procedure. Two ecological-economic objectives drive the model: maximizing the geographic coverage of the protected stopovers, and maximizing average stopover quality, as represented by an index based on wetland prevalence and land cost. Thirty-five alternative solutions were generated, indicating the tradeoffs between the objectives. These results are expected to be useful to natural resource agencies and conservation organizations in the development of habitat conservation, preservation, and restoration policies and programs.

This study investigated the use of planar, silicon-substrate microelectrodes for chronic unit recording in the cerebral cortex. The 16-channel microelectrodes consisted of four penetrating shanks with four recording sites on each shank. The chronic electrode assembly included an integrated silicon ribbon cable and percutaneous connector. In a consecutive series of six rats, 5/6 (83%) of the implanted microelectrodes recorded neuronal spike activity for more than six weeks, with four of the implants (66%) remaining functional for more than 28 weeks. In each animal, more than 80% of the electrode sites recorded spike activity over sequential recording sessions during the postoperative time period. These results provide a performance baseline to support further electrode system development for intracortical neural implant systems for medical applications.

The land-acquisition problem involves selecting multiple discrete parcels to be acquired for a particular land use. In previous models, typical selection criteria have been land cost, land area, and spatial attributes such as contiguity and compactness. Here I introduce a new spatial attribute, convexity. I develop a way to approximate convex shapes in continuous space with ‘cellularly convex’ shapes composed of grid cells. A zero-one programming model is formulated for finding minimum-cost cellularly convex regions of specified area. Computational experience with 144-cell and 1024-cell demonstration problems is reported, and results and extensions are discussed.

The maximal covering subtree problem has applications in transportation network design and extensive facility location. A subtree of a network is a tree that is not a full spanning tree. Finding an optimal subtree may involve the two objectives, minimizing the total arc cost or distance of the subtree, and maximizing the subtree's coverage of population or demand at nodes. Coverage may be defined as direct or indirect: indirect coverage requires that a node be within a distance threshold s>0 of the subtree, and direct coverage requires that a node be connected to the subtree (s=0). Previous approaches to this problem have sought to identify optimal subtrees of a “parent” network that is itself a tree (e.g., a minimum spanning tree). In this paper four new bi-objective zero–one programming models are presented. The first two are models for the problem of finding optimal subtrees on a single spanning tree parent under conditions of (1) direct and (2) indirect coverage. These problems have been addressed previously in the literature. In the third and fourth models, the subtree can be selected from among multiple candidate parent spanning trees simultaneously. The latter models address a new generalization of the first problem and offer both increased flexibility and the potential for a more diverse array of solutions. The models have “integer-friendly” solution properties and are relatively small in terms of the number of decision variables and constraints. Computational experience is reported for a demonstration problem and results are compared to the results of previous models.

Introduction: Brain-computer interface (BCI) is an emerging technology for stroke rehabilitation, but little is known about how the administration of these therapies affects brain and behavior. We examine relationships between BCI therapy dose, intensity, and frequency with changes in laterality index (LI), Action Research Arm Test (ARAT), and Stroke Impact Scale (SIS). Methods: We collected ARAT and SIS scores as well as anatomical and functional MRI of 16 stroke patients with upper extremity motor impairment before, during, and after therapy using a BCI system with tongue and functional electrical stimulation. We acquired fMRI during finger tapping of each hand and computed LI with 3 mask sets at 2 thresholds. Changes from baseline LI and behavioral scores were assessed for correlation with cumulative therapy sessions, cumulative BCI runs, and overall runs/session using Spearman analysis and generalized estimating equations (GEE). Changes from baseline were also compared between subjects with different therapy frequencies. Results: Increased sessions correlated with changes in impaired finger tapping LI in 2 of 6 mask-threshold combinations (p Conclusions: Patterns of brain activation shift toward contralesional hemisphere with additional therapy sessions and additional BCI runs. Increased BCI therapy intensity also correlates with increased self-reported strength. When using BCI in stroke rehabilitation, therapy frequency may be less important than dose and intensity, and neuroimaging and self-report measures may be more sensitive to differences in therapy administration.

Advancements in neural interfaces capable of neural stimulation have shown that neural implants may potentially target the central nervous system to treat neurological disorders. Unfortunately, many of the current technologies used to stimulate and record from the brain do not suffice for this purpose; those that provide a sufficient channel density, which is required for interfacing and chronic functionality in vivo, fail quickly, while others that last for an extended period of time in vivo are limited in recording and stimulation capabilities. Of the current methodologies available, electrocorticography (ECoG) based implants show promise for providing both high channel density interfaces as well as chronic functionality after implantation. This study evaluates the performance of a μECoG for the purpose of chronic stimulation.

Background:. Clinical outcomes after nerve injury and repair remain suboptimal. Patients may be plagued by poor functional recovery and painful neuroma at the repair site, characterized by disorganized collagen and sprouting axons. Collagen deposition during wound healing can be intrinsically imaged using second harmonic generation (SHG) microscopy. The purpose of this study was to develop a protocol for SHG imaging of nerves and to assess whether collagen alignment can be quantified after nerve repair. Methods:. Sciatic nerve transection and epineural repair was performed in male rats. The contralateral nerves were used as intra-animal controls. Ten-millimeter nerve segments were harvested and fixed onto slides. SHG images were collected using a 20× objective on a multiphoton microscope. Collagen fiber alignment was calculated using CurveAlign software. Alignment was calculated on a scale from 0 to 1, where 1 represents perfect alignment. Statistical analysis was performed using a linear mixed-effects model. Results:. Eight male rats underwent right sciatic nerve repair using 9-0 Nylon suture. There were gross variations in collagen fiber organization in the repaired nerves compared with the controls. Quantitatively, collagen fibers were more aligned in the control nerves (mean alignment 0.754, SE 0.055) than in the repairs (mean alignment 0.413, SE 0.047; P < 0.001). Conclusions:. SHG microscopy can be used to quantitate collagen after nerve repair via fiber alignment. Given that the development of neuroma likely reflects aberrant wound healing, ex vivo and/or in vivo SHG imaging may be useful for further investigation of the variables predisposing to neuroma.

In this article, spectral domain optical coherence tomography is used to measure the hemodynamic response induced by optogenetic stimulation in the somatosensory cortex of transgenic mice. By analyzing the 3-D angiograms and Doppler measurements produced by coherence tomography, we observed significant increase in blood flow as a result of increased vessel diameter and blood velocity following optical stimulation of cortical neurons. Such distinct responses were not observed in control experiments where the brain of wild-type mice were exposed to the same light pulses.

Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from ultraviolet to infrared could allow for simultaneous electrophysiology and optical imaging, as well as optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mechanical flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high-resolution neurophysiological recording. We characterize optical transparency of the device at >90% transmission over the ultraviolet to infrared spectrum and demonstrate its utility through optical interface experiments that use this broad spectrum transparency. These include optogenetic activation of focal cortical areas directly beneath electrodes, in vivo imaging of the cortical vasculature via fluorescence microscopy and 3D optical coherence tomography. This study demonstrates an array of interfacing abilities of the CLEAR device and its utility for neural applications., Monitoring neuronal activity in the rodent in vivo brain is commonly done using micro-electrode arrays but these devices are not normally compatible with optical technologies. Here the authors design a transparent and flexible electrode array based on graphene that allows them to combine electrophysiological recordings with optogenetic and imaging experiments.

Micro-electrocorticography (μECoG) displays advantages over traditional invasive methods. The μECoG electrode can record neural activity with high spatial-temporal resolution and it can reduce implantation side effects (e.g. vascular and local-neuronal damage, tissue encapsulation, infection). In this study, we propose a printable transparent μECoG electrode for optogenetic applications by using ultrasonic microfluid printing technique. The device is based on poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) (PEDOT: PSS) as a conductive polymer, polydimethylsiloxane (PDMS) as an insulating polymer and poly(chloro-para-xylylene) (Parylene-C) as the device substrate. We focus on ultrasonic microfluid printing due to its low production cost, excellent material handling capability, and its customizable film thickness (down to 5-20 microns). The ultrasonic fluid-printed μECoG displays high spatial resolution and records simulated signal (0-200 Hz sine wave) effectively with low electrode impedance (50-200 kOhms@1kHz). The μECoG also shows good biocompatibility suitable for customizable chronic implants. This new neural interfacing device could be combined with optogenetics and Brain-Computer Interface (BCI) applications for a possible future use in neurological disease diagnosis and rehabilitations.

Chronic imaging of the peripheral nervous system with contemporary techniques requires repetitive surgical procedures to reopen an area of interest in order to see underlying biological processes over time. The recurrence of surgical openings on an animal increases trauma, stress, and risk of infection. Such effects can greatly lessen the physiological relevance of any data recorded in this manner. In order to bypass repetitive surgery, a Peripheral Nerve Window (PNW) device has been created for chronic in vivo imaging purposes. Intravital imaging window devices have been used previously to image parts of the rodent model such as the brain, spinal cord, and mammary tissue, but currently have not been used in the peripheral nervous system because of lack of bone anchoring and access to deep nerve tissue. We demonstrate a novel surgical technique in a rat which transposes the sciatic nerve above the surrounding muscle tissue allowing the PNW access to an 8mm section of the nerve. Subsequent days of observation revealed increased vasculature development primarily around the nerve, showing that this preparation can be used to image nerve tissue and surrounding vasculature for up to one week post-implantation.

The relationship of the structural integrity of white matter tracts and cortical activity to motor functional outcomes in stroke patients is of particular interest in understanding mechanisms of brain structural and functional changes while recovering from stroke. This study aims to probe these underlying mechanisms using diffusion tensor imaging (DTI) and fMRI measures. We examined the structural integrity of the posterior limb of the internal capsule (PLIC) using DTI and corticomotor activity using motor-task fMRI in stroke patients who completed up to 15 sessions of rehabilitation therapy using Brain-Computer Interface (BCI) technology. We hypothesized that (1) the structural integrity of PLIC and corticomotor activity are affected by stroke; (2) changes in structural integrity and corticomotor activity following BCI intervention are related to motor recovery; (3) there is a potential relationship between structural integrity and corticomotor activity. We found that (1) the ipsilesional PLIC showed significantly decreased fractional anisotropy (FA) values when compared to the contralesional PLIC; (2) lower ipsilesional PLIC-FA values were significantly associated with worse motor outcomes (i.e., ipsilesional PLIC-FA and motor outcomes were positively correlated.); (3) lower ipsilesional PLIC-FA values were significantly associated with greater ipsilesional corticomotor activity during impaired-finger-tapping-task fMRI (i.e., ipsilesional PLIC-FA and ipsilesional corticomotor activity were negatively correlated), with an overall bilateral pattern of corticomotor activity observed; and (4) baseline FA values predicted motor recovery assessed after BCI intervention. These findings suggest that (1) greater vs. lesser microstructural integrity of the ipsilesional PLIC may contribute toward better vs. poor motor recovery respectively in the stroke-affected limb and demand lesser vs. greater cortical activity respectively from the ipsilesional motor cortex; and that (2) PLIC-FA is a promising biomarker in tracking and predicting motor functional recovery in stroke patients receiving BCI intervention.

It has been known that stroke constitutes a major source of acquired disability, with nearly 800,000 new strokes each year in the USA alone. While advances in public and preventative health have helped reduce stroke incidence in high-income countries in recent decades, growth of the aging population, increasing stroke rates in low- to middle-income countries and medical advances that have reduced stroke mortality are all contributing to an increase in stroke survivors worldwide. Large numbers of stroke survivors have residual motor deficits. This editorial will provide an introduction to a class of new therapies being investigated with the aim of improving motor outcomes in stroke patients that uses what is known as brain–computer interface technology.

This study aims to examine the changes in task-related brain activity induced by rehabilitative therapy using brain-computer interface (BCI) technologies and whether these changes are relevant to functional gains achieved through the use of these therapies. Stroke patients with persistent upper-extremity motor deficits received interventional rehabilitation therapy using a closed-loop neurofeedback BCI device (n = 8) or no therapy (n = 6). Behavioral assessments using the Stroke Impact Scale, the Action Research Arm Test (ARAT), and the Nine-Hole Peg Test (9-HPT) as well as task-based fMRI scans were conducted before, during, after, and 1 month after therapy administration or at analogous intervals in the absence of therapy. Laterality Index (LI) values during finger tapping of each hand were calculated for each time point and assessed for correlation with behavioral outcomes. Brain activity during finger tapping of each hand shifted over the course of BCI therapy, but not in the absence of therapy, to greater involvement of the non-lesioned hemisphere (and lesser involvement of the stroke-lesioned hemisphere) as measured by LI. Moreover, changes from baseline LI values during finger tapping of the impaired hand were correlated with gains in both objective and subjective behavioral measures. These findings suggest that the administration of interventional BCI therapy can induce differential changes in brain activity patterns between the lesioned and non-lesioned hemispheres and that these brain changes are associated with changes in specific motor functions.