Search

BackgroundTo improve knowledge and to encourage active involvement of young adults with juvenile idiopathic arthritis (JIA), an informative website with written and video information and an online portal with access to the personal medical record, self-monitoring, and e-consult functionalities were developed. Before implementing these applications in daily practice, it is important to gain insight into their feasibility in terms of ease of use, perceived usefulness and intention to use. ObjectiveThe aim of this study was to evaluate and to examine the feasibility of the website and the online portal for young adults with JIA. MethodsA qualitative, feasibility study was conducted among the first users: 13 young adults with JIA. After provided access to the website and online portal, patients were interviewed on perceived usefulness, ease of use, and intention to (re)use the applications. ResultsParticipants in the study considered the website and online portal as useful and easy-to-use. New medical information and feedback would motivate them to revisit the applications again. On the website, videos showing other young adults, telling how they handle their condition, were found as the most useful. On the portal, access to their medical records was most appreciated: it made the young JIA patients feel in control and it helped them monitor symptoms and disease activity. e-consults were thought to facilitate communication with physicians. ConclusionsThe young adults considered both the website and the online portal as feasible, but they also had valuable suggestions to improve accessibility and use. Based on these findings, a news and event section was added on the website and a direct link was made to a discussion board and social media. To provide and support health information, the website is actively used in daily care. Considering the online portal, the use of self-monitoring tools and e-consult can be stimulated if there is direct linkage to treatment and feedback from the multidisciplinary team. Feasibility testing, before implementing the website and online portal in daily practice, has proven to be a valuable step. Results led to improvements in terms of integration into standard care and topics for further research.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation . Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS., Competing Interests: HM received consulting and IP licensing fees from Abbott Labs. WG received consulting fees from Biohaven and royalties from Nview, LLC and OCDscales, and LLC. EP had received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda, personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda, and Vertos, and holds stock options from SynerFuse and Neuro42. JV had received consulting fees and grant support by Medtronic and Boston Scientific both manufacturers of DBS systems, consulting fees by Newronika and CereGate and honoraria for lecturing by Abbott. JH was a consultant for Neuralink and serves on the Medical Advisory Board of Enspire DBS. SS was a consultant for Boston Scientific, Zimmer Biomet, NeuroPace, Koh Young, and is a co-founder of Motif Neurotech. RSR was employed by Medtronic Inc. MM was employed by Boston Scientific Neuromodulation Corporation. DG was employed by NeuroPace, Inc. LK, MA, LR, SMa, and AP were employed by Newronika. RG was employed by Rune Labs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wong, Mayberg, Wang, Richardson, Halpern, Krinke, Arlotti, Rossi, Priori, Marceglia, Gilron, Cavanagh, Judy, Miocinovic, Devergnas, Sillitoe, Cernera, Oehrn, Gunduz, Goodman, Petersen, Bronte-Stewart, Raike, Malekmohammadi, Greene, Heiden, Tan, Volkmann, Voon, Li, Sah, Coyne, Silburn, Kubu, Wexler, Chandler, Provenza, Heilbronner, Luciano, Rozell, Fox, de Hemptinne, Henderson, Sheth and Okun.)

Objective . Although neural-enabled prostheses have been used to restore some lost functionality in clinical trials, they have faced difficulty in achieving high degree of freedom, natural use compared to healthy limbs. This study investigated the in vivo functionality of a flexible and scalable regenerative peripheral-nerve interface suspended within a microchannel-embedded, tissue-engineered hydrogel (the magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI)) as a potential approach to improving current issues in peripheral nerve interfaces. Approach . Assembled MARTEENI devices were implanted in the gaps of severed sciatic nerves in Lewis rats. Both acute and chronic electrophysiology were recorded, and channel-isolated activity was examined. In terminal experiments, evoked activity during paw compression and stimulus response curves generated from proximal nerve stimulation were examined. Electrochemical impedance spectroscopy was performed to assess the complex impedance of recording sites during chronic data collection. Features of the foreign-body response (FBR) in non-functional implants were examined using immunohistological methods. Main results . Channel-isolated activity was observed in acute, chronic, and terminal experiments and showed a typically biphasic morphology with peak-to-peak amplitudes varying between 50 and 500 µ V. For chronic experiments, electrophysiology was observed for 77 days post-implant. Within the templated hydrogel, regenerating axons formed minifascicles that varied in both size and axon count and were also found to surround device threads. No axons were found to penetrate the FBR. Together these results suggest the MARTEENI is a promising approach for interfacing with peripheral nerves. Significance . Findings demonstrate a high likelihood that observed electrophysiological activity recorded from implanted MARTEENIs originated from neural tissue. The variation in minifascicle size seen histologically suggests that amplitude distributions observed in functional MARTEENIs may be due to a combination of individual axon and mini-compound action potentials. This study provided an assessment of a functional MARTEENI in an in vivo animal model for the first time., (© 2022 IOP Publishing Ltd.)

Demands for implantable bioelectronic devices to increase the number of channels for greater functional capacity and resolution, shrink implant size to minimize tissue response and patient burden, and support battery changes and electronics upgrades for long-term operational viability, cannot be met with existing implant-connector technology. In this paper we describe our novel approach to develop a rematable high-channel-density implant-connector technology, with a focus on the design, fabrication, and characterization of its microgasket. The microgaskets made of polydimethylsiloxane elastomer (PDMSe) have achieved much better electrical isolation for neural stimulation (~5 MΩ at 10 kHz) compared with conventional implant connectors (50 kΩ at 10 kHz), despite a 200-fold increase in channel density (conventional: ~0.0644 ch/mm 2 , microgasket: ~12.8 ch/mm 2 ). The microgaskets also achieved high electrical isolation for neural recording (i.e., ~35 MΩ at 1 kHz) at the same high channel density. When mechanically compressed the microscale vias in the PDMSe microgaskets deform laterally, which could damage or enhance gasket-traversing conductive spring elements in each microscale via depending on their design. We have demonstrated that by lowering the height-to-width aspect ratio of the gasket vias, they can maintain their shape under clamping pressures high enough to achieve high isolation.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury., Competing Interests: RR was employed by Medtronic, Inc. HBo was employed by Boston Scientific Neuromodulation Corporation. DG was employed by the NeuroPace, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wong, Deuschl, Wolke, Bergman, Muthuraman, Groppa, Sheth, Bronte-Stewart, Wilkins, Petrucci, Lambert, Kehnemouyi, Starr, Little, Anso, Gilron, Poree, Kalamangalam, Worrell, Miller, Schiff, Butson, Henderson, Judy, Ramirez-Zamora, Foote, Silburn, Li, Oyama, Kamo, Sekimoto, Hattori, Giordano, DiEuliis, Shook, Doughtery, Widge, Mayberg, Cha, Choi, Heisig, Obatusin, Opri, Kaufman, Shirvalkar, Rozell, Alagapan, Raike, Bokil, Green and Okun.)

Peripheral nerve injuries can be debilitating to motor and sensory function, with severe cases often resulting in complete limb amputation. Over the past two decades, prosthetic limb technology has rapidly advanced to provide users with crude motor control of up to 20° of freedom; however, the nerve-interfacing technology required to provide high movement selectivity has not progressed at the same rate. The work presented here focuses on the development of a magnetically aligned regenerative tissue-engineered electronic nerve interface (MARTEENI) that combines polyimide "threads" encapsulated within a magnetically aligned hydrogel scaffold. The technology exploits tissue-engineered strategies to address concerns over traditional peripheral nerve interfaces including poor axonal sampling through the nerve and rigid substrates. A magnetically templated hydrogel is used to physically support the polyimide threads while also promoting regeneration in close proximity to the electrode sites on the polyimide. This work demonstrates the utility of magnetic templating for use in tuning the mechanical properties of hydrogel scaffolds to match the stiffness of native nerve tissue while providing an aligned substrate for Schwann cell migration in vitro. MARTEENI devices were fabricated and implanted within a 5-mm-long rat sciatic-nerve transection model to assess regeneration at 6 and 12 weeks. MARTEENI devices do not disrupt tissue remodeling and show axon densities equivalent to fresh tissue controls around the polyimide substrates. Devices are observed to have attenuated foreign-body responses around the polyimide threads. It is expected that future studies with functional MARTEENI devices will be able to record and stimulate single axons with high selectivity and low stimulation regimes., (Copyright © 2021. Published by Elsevier Ltd.)

Thin-film polyimide-metal neuroelectronic interfaces hold the potential to alleviate many neurological disorders. However, their long-term reliability is challenged by an aggressive implant environment that causes delamination and degradation of critical materials, resulting in a degradation or complete loss of implant function. Herein, a rigorous and in-depth analysis is presented on the fabrication and modification of critical materials in these thin-film neural interfaces. Special attention is given to improving the interfacial adhesion between thin films and processing modifications to maximize device reliability. Fundamental material analyses are performed on the polyimide substrate and adhesion-promotion candidates, including amorphous silicon carbide (a-SiC:H), amorphous carbon, and silane coupling agents. Basic fabrication rules are identified to markedly improve polyimide self-adhesion, including optimizing the polyimide-cure profile and maximizing high-energy surface activation. In general, oxide-forming materials are identified as poor adhesive aids to polyimide without targeted modifications. Methods are identified to incorporate effective a-SiC:H interfacial layers to improve metal adherence to polyimide, in addition to examples of alloying between adjacent material layers that can impact the trace resistivity and long-term reliability of the thin-film interfaces. The provided rationale and consequences of key decisions made should promote more reproducible science using robust and reliable neuroelectronic technology., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Background : Freezing of gait (FOG) is a common symptom in Parkinson's disease (PD) and can be difficult to treat with dopaminergic medications or with deep brain stimulation (DBS). Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation (BCDBS) delivers current in various frequencies of bursts (e.g., 4, 10, or 15 Hz), while maintaining an intra-burst frequency identical to conventional DBS. Objective : To evaluate the safety and tolerability of BCDBS in PD patients with FOG. Methods : Ten PD subjects with STN or GPi DBS and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state. Results : There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS. Conclusions : BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy., Competing Interests: RR was employed by the company Medtronic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wong, Hu, Barmore, Lopes, Moore, Legacy, Tahafchi, Jackson, Judy, Raike, Wang, Tsuboi, Okun and Almeida.)

The chronic reliability of bioelectronic neural interfaces has been challenged by foreign body reactions (FBRs) resulting in fibrotic encapsulation and poor integration with neural tissue. Engineered microtopographies could alleviate these challenges by manipulating cellular responses to the implanted device. Parallel microchannels have been shown to modulate neuronal cell alignment and axonal growth, and Sharklet™ microtopographies of targeted feature sizes can modulate bio-adhesion of an array of bacteria, marine organisms, and epithelial cells due to their unique geometry. We hypothesized that a Sharklet™ micropattern could be identified that inhibited fibroblasts partially responsible for FBR while promoting Schwann cell proliferation and alignment. in vitro cell assays were used to screen the effect of Sharklet™ and channel micropatterns of varying dimensions from 2 to 20 μm on fibroblast and Schwann cell metrics (e.g., morphology/alignment, nuclei count, metabolic activity), and a hierarchical analysis of variance was used to compare treatments. In general, Schwann cells were found to be more metabolically active and aligned than fibroblasts when compared between the same pattern. 20 μm wide channels spaced 2 μm apart were found to promote Schwann cell attachment and alignment while simultaneously inhibiting fibroblasts and warrant further in vivo study on neural interface devices. No statistically significant trends between cellular responses and geometrical parameters were identified because mammalian cells can change their morphology dependent on their environment in a manner dissimilar to bacteria. Our results showed although surface patterning is a strong physical tool for modulating cell behavior, responses to micropatterns are highly dependent on the cell type., (© 2020 Wiley Periodicals LLC.)

Background: Biomimetic hydrogels used in tissue engineering can improve tissue regeneration and enable targeted cellular behavior; there is growing interest in combining hydrogels with microelectronics to create new neural interface platforms to help patient populations. However, effective processes must be developed to integrate flexible but relatively stiff (e.g., 1-10 GPa) microelectronic arrays within soft (e.g., 1-10 kPa) hydrogels., New Method: Here, a novel method for integrating polyimide microelectrode arrays within a biomimetic hydrogel scaffold is demonstrated for use as a tissue-engineered electronic nerve interface (TEENI). Tygon tubing and a series of 3D printed molds were used to facilitate hydrogel fabrication and device assembly., Comparison With Existing Methods: Other comparable regenerative peripheral nerve interface technologies do not utilize the flexible microelectrode array design nor the hydrogel scaffold described here. These methods typically use stiff electrode arrays that are affixed to a similarly stiff implantable tube serving as the nerve guidance conduit., Results: Our results indicate that there is a substantial mechanical mismatch between the flexible microelectronic arrays and the soft hydrogel. However, using the methods described here, there is consistent fabrication of these regenerative peripheral nerve interfaces suitable for implantation., Conclusions: The assembly process that was developed resulted in repeatable and consistent integration of microelectrode arrays within a soft tissue-engineered hydrogel. As reported elsewhere, these devices have been successfully implanted in a rat sciatic nerve model and yielded neural recordings. This process can be adapted for other applications and hydrogels in which flexible electronic materials are combined with soft regenerative scaffolds., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

High-channel-count neural interfaces are typically packaged by being permanently bonded to their packaged electronics followed by encapsulation. Such interfaces are often intimately integrated into neural tissue, their removal to replace the battery or upgrade electronics is not undesirable. Gaskets are widely used to provide liquid/electrical isolation and to seal the connection between two or more mating parts. Pressure-driven microgaskets are well established in the field of microfluidics. Although rematable microgaskets for fluidic interconnects exist, the use of microgaskets for electrical isolation have not been demonstrated. Our approach is to electrically isolate 2-D arrays of contact pads using a compressible silicone microgasket. Electrochemical impedance spectroscopy (EIS) was used to quantify the electrical isolation of the microgasket on contact pads, which were formed in a polyimide flex circuit, as a function of frequency after being soaked in saline. Experiments have shown that the compressed sub-millimeter PDMSe microgasket can provide excellent isolation (i.e., >30 MΩ at 1 KHz) that is comparable to the other more conventional packaging methods, such as encapsulation in polydimethylsiloxane elastomer (PDMSe) or parylene-C. Our microgasket-based approach should be scalable to high channel counts and high channel densities enabling much smaller and higher-performance neural implants.

The burgeoning field of nanotechnology aims to create and deploy nanoscale structures, devices, and systems with novel, size-dependent properties and functions. The nanotechnology revolution has sparked radically new technologies and strategies across all scientific disciplines, with nanotechnology now applied to virtually every area of research and development in the US and globally. NanoFlorida was founded to create a forum for scientific exchange, promote networking among nanoscientists, encourage collaborative research efforts across institutions, forge strong industry-academia partnerships in nanoscience, and showcase the contributions of students and trainees in nanotechnology fields. The 2019 NanoFlorida International Conference expanded this vision to emphasize national and international participation, with a focus on advances made in translating nanotechnology. This review highlights notable research in the areas of engineering especially in optics, photonics and plasmonics and electronics; biomedical devices, nano-biotechnology, nanotherapeutics including both experimental nanotherapies and nanovaccines; nano-diagnostics and -theranostics; nano-enabled drug discovery platforms; tissue engineering, bioprinting, and environmental nanotechnology, as well as challenges and directions for future research., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Freezing of Gait (FoG) is an episodic motor disturbance in Parkinson disease (PD) that causes patients to be unable to initiate or maintain their locomotion. Prior work that used simple and easy-to-learn algorithms based on a singular feature and rule-based classifiers are not sufficient to learn variations in patient walking styles and freezing patterns. Efforts to use machine-learning algorithms suffer from challenges caused by imbalanced datasets. Here, we propose a new approach for FoG detection using a wide set of online calculable features and an instance-based and non-parametric Possibilistic K-Nearest-Neighbor (KNN) classifier. The issue of imbalanced datasets is addressed using the Self-Organizing-Map (SOM) algorithm.

Bioelectronic neural interfaces can fail in vivo due to water penetration and corrosion of the packaging technology used to protect sensitive portions of the device. Although anisotropic conductive adhesive (ACA) is gaining popularity in the neural interface community to connect fabricated electrode arrays with back-end packages, the durability of ACA in chronic implants is largely unknown. We have designed a platform that uses an aggressive reactive-accelerated aging (RAA) environment to rapidly assess the ability of ACA and silicone-rubber encapsulation to maintain electrical integrity in vitro. All RAA experiments were performed at 77°C, for 24 days, and with 10 to 20 mM H 2 O 2 , which approximates a 1 year implantation. Results from these experiments showed that ACA rapidly fails (i.e., 2 to 4 days RAA) due to water absorption through the silicone encapsulant. Electrical impedance spectroscopy (EIS) confirmed water penetration through the package and the resulting corrosion of the sensitive metallic components.

Here we report on the development of polyimide-based flexible magnetic actuators for actively combating biofouling that occurs in many chronically implanted devices. The thin-film flexible devices are microfabricated and integrated into a single-pore silicone catheter to demonstrate a proof-of-concept for a self-clearing smart catheter. The static and dynamic mechanical responses of the thin-film magnetic microdevices were quantitatively measured and compared to theoretical values. The mechanical fatigue properties of these polyimide-based microdevices were also characterized up to 300 million cycles. Finally, the biofouling removal capabilities of magnetically powered microdevices were demonstrated using bovine serum albumin and bioconjugated microbeads. Our results indicate that these thin-film microdevices are capable of significantly reducing the amount of biofouling. At the same time, we demonstrated that these microdevices are mechanically robust enough to withstand a large number of actuation cycles during its chronic implantation.

A reactive-accelerated-aging (RAA) soak-test has been employed to challenge microfabricated neural interface devices against an aggressive environment that mimics worstcase chronic physiological inflammation. The RAA tests were able to determine the ability of different materials to increase the adhesive strength of the polyimide and platinum-goldplatinum metallization thin-film interface. It was found that a 3-day RAA soak-test at 87 °C in phosphate buffered saline with 10 to 20 mM hydrogen peroxide resulted in adhesive failure of the metal-polyimide interface when titanium was used as the primary adhesion promotor. The addition of hydrogenated amorphous silicon carbide was able to eliminate the onset of adhesive failure of the metal-polyimide interface during 7-day RAA soak tests. However, sporadic cracking of the silicon carbide layer resulted in a minority of broken metal interconnects that resulted in failed electrodes. These tests have demonstrated the ability of RAA soak tests to provide rapid in vitro assessment of microfabricated neural interfaces and thereby reduce the time needed to develop synthetic methods to fabricate chronically reliable devices.

Research on neural interfaces has historically concentrated on development of systems for the brain; however, there is increasing interest in peripheral nerve interfaces (PNIs) that could provide benefit when peripheral nerve function is compromised, such as for amputees. Efforts focus on designing scalable and high-performance sensory and motor peripheral nervous system interfaces. Current PNIs face several design challenges such as undersampling of signals from the thousands of axons, nerve-fiber selectivity, and device-tissue integration. To improve PNIs, several researchers have turned to tissue engineering. Peripheral nerve tissue engineering has focused on designing regeneration scaffolds that mimic normal nerve extracellular matrix composition, provide advanced microarchitecture to stimulate cell migration, and have mechanical properties like the native nerve. By combining PNIs with tissue engineering, the goal is to promote natural axon regeneration into the devices to facilitate close contact with electrodes; in contrast, traditional PNIs rely on insertion or placement of electrodes into or around existing nerves, or do not utilize materials to actively facilitate axon regeneration. This review presents the state-of-the-art of PNIs and nerve tissue engineering, highlights recent approaches to combine neural-interface technology and tissue engineering, and addresses the remaining challenges with foreign-body response., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

Freezing-of-Gait (FoG) is a syndrome of Parkinson's disease defined by episodes when patients show a complete inability to take a step or continue with their locomotion. In order to develop closed-loop therapeutic strategies, including deep brain stimulation, a reliable means of detecting freezing episodes is required. By using wearable accelerometers, freezing episodes can be detected with energy-based algorithms when the ratio of the energy in the freeze band (3 to 8 Hz) to that of the locomotion band (0.5 to 3 Hz) is above a patient-specific threshold. However, due to the great variability in patient activity type, walking style, and freezing pattern, this detection method often does not work. Here we describe a new FoG-detection method that captures temporal, spatial, and physiological features and uses a support-vector-machine to classify freezing episodes. Since our method uses more diverse features, it is able to more robustly detect FoG events. We have shown that when the energy-based method fails (e.g., area under the receiver operator curve is ~0.5), our new method performs well (e.g., area under ROC curve is 0.96).

This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.

High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.

The Defense Advanced Research Projects Agency (DARPA) has funded innovative scientific research and technology developments in the field of brain-computer interfaces (BCI) since the 1970s. This review highlights some of DARPA's major advances in the field of BCI, particularly those made in recent years. Two broad categories of DARPA programs are presented with respect to the ultimate goals of supporting the nation's warfighters: (1) BCI efforts aimed at restoring neural and/or behavioral function, and (2) BCI efforts aimed at improving human training and performance. The programs discussed are synergistic and complementary to one another, and, moreover, promote interdisciplinary collaborations among researchers, engineers, and clinicians. Finally, this review includes a summary of some of the remaining challenges for the field of BCI, as well as the goals of new DARPA efforts in this domain., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

The proceedings of the 2nd Annual Deep Brain Stimulation Think Tank summarize the most contemporary clinical, electrophysiological, and computational work on DBS for the treatment of neurological and neuropsychiatric disease and represent the insights of a unique multidisciplinary ensemble of expert neurologists, neurosurgeons, neuropsychologists, psychiatrists, scientists, engineers and members of industry. Presentations and discussions covered a broad range of topics, including advocacy for DBS, improving clinical outcomes, innovations in computational models of DBS, understanding of the neurophysiology of Parkinson's disease (PD) and Tourette syndrome (TS) and evolving sensor and device technologies.

Here, we report on the development and evaluation of novel unobstructing magnetic microactuators for maintaining the patency of implantable ventricular catheters used in hydrocephalus application. The treatment of hydrocephalus requires chronic implantation of a shunt system to divert excess cerebrospinal fluid from the brain. These shunt systems suffer from a high failure rate (>40%) within the first year of implantation, often due to biological accumulation. Previously, we have shown that magnetic microactuators can be used to remove biological blockage. The new cantilever-based magnetic microactuator presented in this paper improves upon the previous torsional design using a bimorph to induce a postrelease out-of-plane deflection that will prevent the device from occluding the pore at rest. The mechanical evaluations (i.e., postrelease deflection, static and dynamic responses) of fabricated devices are reported and compared with theoretical values.

The mechanical robustness of microfabricated torsional magnetic actuators in withstanding the strong static fields (7 T) and time-varying field gradients (17 T/m) produced by an MR system was studied in this investigation. The static and dynamic mechanical characteristics of 30 devices were quantitatively measured before and after exposure to both strong uniform and non-uniform magnetic fields. The results showed no statistically significant change in both the static and dynamic mechanical performance, which mitigate concerns about the mechanical stability of these devices in association with MR systems under the conditions used for this assessment. The MR-induced heating was also measured in a 3-T/128-MHz MR system. The results showed a minimal increase (1.6 °C) in temperature due to the presence of the magnetic microactuator array. Finally, the size of the MR-image artifacts created by the magnetic microdevices were quantified. The signal loss caused by the devices was approximately four times greater than the size of the device.

There is a push in electrophysiology experiments to record simultaneously from many channels (upwards of 64) over long time periods (many hours). Given the relatively high sampling rates (10-40 kHz) and resolutions (12-24 bits per sample), these experiments accumulate exorbitantly large amounts of data (e.g., 100 GB per experiment), which can be very time-consuming to process. Here, we present an FPGA-based spike-sorting platform that can increase the speed of offline spike sorting by at least 25 times, effectively reducing the time required to sort data from long experiments from several hours to just a few minutes. We attempted to preserve the flexibility of software by implementing several different algorithms in the design, and by providing user control over parameters such as spike detection thresholds. The results of sorting a published benchmark dataset using this hardware tool are shown to be comparable to those using similar software tools., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We report a technique for generating controllable, time-varying and localizable forces on arrays of cells in a massively parallel fashion. To achieve this, we grow magnetic nanoparticle-dosed cells in defined patterns on micromagnetic substrates. By manipulating and coalescing nanoparticles within cells, we apply localized nanoparticle-mediated forces approaching cellular yield tensions on the cortex of HeLa cells. We observed highly coordinated responses in cellular behavior, including the p21-activated kinase-dependent generation of active, leading edge-type filopodia and biasing of the metaphase plate during mitosis. The large sample size and rapid sample generation inherent to this approach allow the analysis of cells at an unprecedented rate: in a single experiment, potentially tens of thousands of cells can be stimulated for high statistical accuracy in measurements. This technique shows promise as a tool for both cell analysis and control.

Miniature solenoids routinely enhance small volume nuclear magnetic resonance imaging and spectroscopy; however, no such techniques exist for patients. We present an implantable microcoil for diverse clinical applications, with a microliter coil volume. The design is loosely based on implantable depth electrodes, in which a flexible tube serves as the substrate, and a metal stylet is inserted into the tube during implantation. The goal is to provide enhanced signal-to-noise ratio (SNR) of structures that are not easily accessed by surface coils. The first-generation prototype was designed for implantation up to 2 cm, and provided initial proof-of-concept for microscopy. Subsequently, we optimized the design to minimize the influence of lead inductances, and to thereby double the length of the implantable depth (4 cm). The second-generation design represents an estimated SNR improvement of over 30% as compared to the original design when extended to 4 cm. Impedance measurements indicate that the device is stable for up to 24 h in body temperature saline. We evaluated the SNR and MR-related heating of the device at 3T. The implantable microcoil can differentiate fat and water peaks, and resolve submillimeter features.

Background: Malaria is a global health priority with a heavy burden of fatality and morbidity. Improvements in field diagnostics are needed to support the agenda for malaria elimination. Saliva has shown significant potential for use in non-invasive diagnostics, but the development of off-the-shelf saliva diagnostic kits requires best practices for sample preparation and quantitative insight on the availability of biomarkers and the dynamics of immunoassay in saliva. This pilot study measured the levels of the PfHRP2 in patient saliva to inform the development of salivary diagnostic tests for malaria., Methods: Matched samples of blood and saliva were collected between January and May, 2011 from eight patients at Palawan Baptist Hospital in Roxas, Palawan, Philippines. Parasite density was determined from thick-film blood smears. Concentrations of PfHRP2 in saliva of malaria-positive patients were measured using a custom chemiluminescent ELISA in microtitre plates. Sixteen negative-control patients were enrolled at UCLA. A substantive difference between this protocol and previous related studies was that saliva samples were stabilized with protease inhibitors., Results: Of the eight patients with microscopically confirmed P. falciparum malaria, seven tested positive for PfHRP2 in the blood using rapid diagnostic test kits, and all tested positive for PfHRP2 in saliva. All negative-control samples tested negative for salivary PfHRP2. On a binary-decision basis, the ELISA agreed with microscopy with 100 % sensitivity and 100 % specificity. Salivary levels of PfHRP2 ranged from 17 to 1,167 pg/mL in the malaria-positive group., Conclusion: Saliva is a promising diagnostic fluid for malaria when protein degradation and matrix effects are mitigated. Systematic quantitation of other malaria biomarkers in saliva would identify those with the best clinical relevance and suitability for off-the-shelf diagnostic kits.

Building on a long history of innovation in neural-recording interfaces, the Defense Advanced Research Projects Agency (DARPA) has launched a program to address the key challenges related to transitioning advanced neuroprosthesis technology to clinical use for amputated service members. The goal of the Reliable Neural Technology (RE-NET) Program is to develop new technology to extract information from the nervous system at a scale and rate needed to reliably control modern robotic prostheses over the lifetime of the amputee. The RE-NET program currently encompasses three separate efforts: histology for interface stability over time (HIST), reliable peripheral interfaces (RPIs), and reliable central nervous system (CNS) interfaces (RCIs).

Here we report on the development of torsional magnetic microactuators for displacing biological materials in implantable catheters. Static and dynamic behaviors of the devices were characterized in air and in fluid using optical experimental methods. The devices were capable of achieving large deflections (>60°) and had resonant frequencies that ranged from 70 Hz to 1.5 kHz in fluid. The effect of long-term actuation (>2.5 · 10(8) cycles) was quantified using resonant shift as the metric (Δf < 2%). Cell-clearing capabilities of the devices were evaluated by examining the effect of actuation on a layer of aggressively growing adherent cells. On average, actuated microdevices removed 37.4% of the adherent cell layer grown over the actuator surface. The effect of actuation time, deflection angle, and beam geometry were evaluated. The experimental results indicate that physical removal of adherent cells at the microscale is feasible using magnetic microactuation.

Arrays of carbon nanotube (CNT) microelectrodes (nominal geometric surface areas 20-200 μm(2)) were fabricated by photolithography with chemical vapor deposition of randomly oriented CNTs. Raman spectroscopy showed strong peak intensities in both G and D bands (G/D = 0.86), indicative of significant disorder in the graphitic layers of the randomly oriented CNTs. The impedance spectra of gold and CNT microelectrodes were compared using equivalent circuit models. Compared to planar gold surfaces, pristine nanotubes lowered the overall electrode impedance at 1 kHz by 75%, while nanotubes treated in O(2) plasma reduced the impedance by 95%. Cyclic voltammetry in potassium ferricyanide showed potential peak separations of 133 and 198 mV for gold and carbon nanotube electrodes, respectively. The interaction of cultured cardiac myocytes with randomly oriented and vertically aligned CNTs was investigated by the sectioning of myocytes using focused-ion-beam milling. Vertically aligned nanotubes deposited by plasma-enhanced chemical vapor deposition (PECVD) were observed to penetrate the membrane of neonatal-rat ventricular myocytes, while randomly oriented CNTs remained external to the cells. These results demonstrated that CNT electrodes can be leveraged to reduce impedance and enhance biological interfaces for microelectrodes of subcellular size.

Applications such as brain-machine interfaces require hardware spike sorting in order to 1) obtain single-unit activity and 2) perform data reduction for wireless data transmission. Such systems must be low-power, low-area, high-accuracy, automatic, and able to operate in real time. Several detection, feature-extraction, and dimensionality-reduction algorithms for spike sorting are described and evaluated in terms of accuracy versus complexity. The nonlinear energy operator is chosen as the optimal spike-detection algorithm, being most robust over noise and relatively simple. Discrete derivatives is chosen as the optimal feature-extraction method, maintaining high accuracy across signal-to-noise ratios with a complexity orders of magnitude less than that of traditional methods such as principal-component analysis. We introduce the maximum-difference algorithm, which is shown to be the best dimensionality-reduction method for hardware spike sorting.

Artificial sensations can be produced by direct brain stimulation of sensory areas through implanted microelectrodes, but the perceptual psychophysics of such artificial sensations are not well understood. Based on prior work in cortical stimulation, we hypothesized that perceived intensity of electrical stimulation may be explained by the population response of the neurons affected by the stimulus train. To explore this hypothesis, we modeled perceived intensity of a stimulation pulse train with a leaky neural integrator. We then conducted a series of two-alternative forced choice behavioral experiments in which we systematically tested the ability of rats to discriminate frequency, amplitude, and duration of electrical pulse trains delivered to the whisker barrel somatosensory cortex. We found that the model was able to predict the performance of the animals, supporting the notion that perceived intensity can be largely accounted for by spatiotemporal integration of the action potentials evoked by the stimulus train.

To create a wireless neural recording system that can benefit from the continuous advancements being made in embedded microcontroller and communications technologies, an embedded-system-based architecture for wireless neural recording has been designed, fabricated, and tested. The system consists of commercial-off-the-shelf wireless-enabled processor modules (motes) for communicating the neural signals, and a back-end database server and client application for archiving and browsing the neural signals. A neural-signal-acquisition application has been developed to enable the mote to either acquire neural signals at a rate of 4000 12-bit samples per second, or detect and transmit spike heights and widths sampled at a rate of 16670 12-bit samples per second on a single channel. The motes acquire neural signals via a custom low-noise neural-signal amplifier with adjustable gain and high-pass corner frequency that has been designed, and fabricated in a 1.5-microm CMOS process. In addition to browsing acquired neural data, the client application enables the user to remotely toggle modes of operation (real-time or spike-only), as well as amplifier gain and high-pass corner frequency.

Here we demonstrate the mechanical robustness of microfabricated torsional magnetic actuators in withstanding the magnetic fields produced by a 7 T MRI magnet. The static and dynamic mechanical characteristics of 30 devices were quantitatively measured before and after exposure to both uniform and non-uniform magnetic fields. The results show no statistically significant change in both the static and dynamic mechanical performance, which mitigates concerns about the mechanical compatibility of our devices with MRI scanners. Additional experiments are required to quantify the potential image-artifact size and radio-frequency-induced heating caused by the magnetic microactuators inside an MRI scanner.

Conjugated magnetic nanoparticles have recently demonstrated potential in activating unique and specific activity within cells. Leveraging microfabrication, we have developed a technique of localizing nanoparticles to specific, subcellular locations by a micropatterned ferromagnetic substrate. Controlled patterns of nanoparticles were assembled and dynamically controlled with submicrometer precision within live cells. We anticipate that the technique will be useful as a compact, simple method of generating localizable, subcellular chemical and mechanical signals, compatible with standard microscopy.

Purpose: To investigate the feasibility of electrically stimulating the lateral rectus muscle to recover its physiologic abduction ability in cases of complete sixth cranial (abducens) nerve palsy., Methods: In the feline lateral rectus muscle model, the effects of a charge-balanced, biphasic, current-controlled stimulus on the movement of the eye were investigated while stimulation frequency, amplitude, and pulse duration was varied. Eye deflection was measured with a force transducer. Denervated conditions were simulated by injection of botulinum toxin A., Results: Three chemically denervated and 4 control lateral rectus muscles were analyzed. In control lateral rectus muscles, the minimum fusion frequency was approximately 170 Hz, and the maximum evoked abduction was 27 degrees. The minimum fusion frequency was unchanged after 4 weeks of chemical denervation. Stimulation of chemically denervated lateral rectus muscle resulted in 17 degrees of abduction. For both innervated and chemically denervated lateral rectus muscle, frequencies greater than 175 Hz yielded very little increase in abduction. Modulating amplitude produced noticeable movement throughout the tested range (0.2 to 9 mA)., Conclusions: Results from the feline lateral rectus muscle showed that electrical stimulation is a feasible approach to evoke a contraction from a denervated lateral rectus muscle. The degree of denervation of the feline lateral rectus muscle was indeterminate. Varying the stimulation amplitude allowed greater eye movement. It is very likely that both frequency and amplitude must be modulated for finer control of static eye position.

We have designed, simulated, and fabricated micro-magnetic substrates for the reversible self-assembly of cell-internalized magnetic fluorescent nanoparticles according to lithographically defined patterns within live cells. Magnetic nanoparticles have recently demonstrated potential in activating highly specific activity within single cells. Using microfabrication, we have developed a technique of localizing both particles and large magnetic fields to highly specific, engineered, sub-cellular locations with various modes of operation. The substrates were simulated in 3 dimensions with ANSYS FEA, and consist of micro-patterned, electroplated permalloy elements planarized with SU-8. Various modes of magnet-orientation dependent patterns of nanoparticles were generated and verified within live cells, with their precise location verified under separate blue and green (absorption and emission wavelengths of the particles) filters using a fluorescent microscope. Results correspond well with modeled positions and response time. We anticipate using the tool as a compact, simple method of generating highly localized, easily distinguishable, sub-cellular chemical and mechanical signals that is compatible with standard biological fluorescence setups.

In this paper we perform a system-level analysis of a wireless biosignal telemetry system. We perform an analysis of each major system component (e.g., analog front end, analog-to-digital converter, digital signal processor, and wireless link), in which we consider physical, algorithmic, and design limitations. Since there are a wide range applications for wireless biosignal telemetry systems, each with their own unique set of requirements for key parameters (e.g., channel count, power dissipation, noise level, number of bits, etc.), our analysis is equally broad. The net result is a set of plots, in which the power dissipation for each component and as the system as a whole, are plotted as a function of the number of channels for different architectural strategies. These results are also compared to existing implementations of complete wireless biosignal telemetry systems.

Here we demonstrate the functional capability of microfabricated magnetic actuators in clearing biological accumulation on a model catheter pore. Cell-clearing performance was quantitatively measured by comparing the effect of actuation on the cell density of aggressively growing adherent murine cells. Devices were actuated at a frequency of 100 Hz and a magnetic field of 17.8 kA/m for 30, 45, or 60 min. On average, microactuators removed 37.4% of the adherent cells. The results also revealed that the cell-clearing capability of the microactuator increased as a function of the actuation duration and angle of deflection.

A fully-differential low-power low-noise preamplifier for biopotential and neural-recording applications is presented. This design, which has been simulated in a standard 90-nm CMOS process, consumes 30 microW from a 3-V power supply. The simulated integrated input-referred noise is 2.3 microV over 0.1 Hz to 20 kHz. The amplifier also provides an output swing of +/- 0.9 V with a THD of less than 0.1%

Applications such as brain-machine interfaces require hardware spike sorting in order to (1) obtain single-unit activity and (2) perform data reduction for wireless transmission of data. Such systems must be low-power, low-area, high-accuracy, automatic, and able to operate in real time. Several detection and feature extraction algorithms for spike sorting are described briefly and evaluated in terms of accuracy versus computational complexity. The nonlinear energy operator method is chosen as the optimal spike detection algorithm, being most robust over noise and relatively simple. The discrete derivatives method [1] is chosen as the optimal feature extraction method, maintaining high accuracy across SNRs with a complexity orders of magnitude less than that of traditional methods such as PCA.

Implantable RF-coils have enabled sub-mm resolution magnetic resonance images (MRI) of deep structures. Scaling down the size of RF coils has similarly provided a gain in signal-to-noise ratio in nuclear-magnetic-resonance spectroscopy. By combining both approaches we designed, fabricated, and imaged with an implantable microcoil catheter. While typical implantable catheters use a transverse magnetization, the axial magnetization of the microcoil provides improved sensitivity and allows visualization of the tissue beyond the distal end of the catheter. The microcoil catheter was designed with a diameter of 1 mm for future integration with intracranial devices, and for intraductal use in breast oncology. We modified the NMR-microcoil design to allow implantation of the RF coil, by winding the microcoil on medical-grade silicone tubing and incorporating leads on the catheter to connect circuit components. In order to achieve proper turn spacing, we coated copper wire with 25 microm of biocompatible polymer (Parylene C). Tuning and matching circuitry insured that the impedance of the RF coil was approximately 50 ohm at the operating frequency for 3-T proton MR applications. A duplexer was used to enable use of the microcoil catheter as a transceiver. Experimental verification of the coil design was achieved through ex vivo imaging of neural tissue. As expected, the microcoil catheter provided microscale images with 20-microm in-plane-resolution and 170-microm-thick slices. While 3-T MRI typically provides 1 to 30 voxels per-cubic-millimeter, in this paper we report that the MRI microcoil can provide hundreds, and even thousands of voxels in the same volume.

Wireless-enabled processor modules intended for communicating low-frequency phenomena (i.e., temperature, humidity, and ambient light) have been enabled to acquire and transmit multiple biological signals in real time, which has been achieved by using computationally efficient data acquisition, filtering, and compression algorithms, and interfacing the modules with biological interface hardware. The sensor modules can acquire and transmit raw biological signals at a rate of 32 kb/s, which is near the hardware limit of the modules. Furthermore, onboard signal processing enables one channel, sampled at a rate of 4000 samples/s at 12-bit resolution, to be compressed via adaptive differential-pulse-code modulation (ADPCM) and transmitted in real time. In addition, the sensors can be configured to filter and transmit individual time-referenced "spike" waveforms, or to transmit the spike height and width for alleviating network traffic and increasing battery life. The system is capable of acquiring eight channels of analog signals as well as data via an asynchronous serial connection. A back-end server archives the biological data received via networked gateway sensors, and hosts them to a client application that enables users to browse recorded data. The system also acquires, filters, and transmits oxygen saturation and pulse rate via a commercial-off-the-shelf interface board. The system architecture can be configured for performing real-time nonobtrusive biological monitoring of humans or rodents. This paper demonstrates that low-power, computational, and bandwidth-constrained wireless-enabled platforms can indeed be leveraged for wireless biosignal monitoring.

An electrochemical system that consists of a silver electrode in 0.01 M sodium hydroxide electrolyte was investigated in an effort to develop a sensitive in situ analytical method for nitrate. Cyclic voltammetry demonstrated that the proposed system has a high normalized sensitivity (2.47 A s(1/2) V(-1/2) M(-1) cm(-2)), compared to more complex electroanalytical schemes. Double-potential-step chronocoulometry was used to maximize the signal-to-noise ratio (SNR), and minimize interference from dissolved oxygen in the electrolyte. The integration period for double-potential-step chronocoulometry was determined by optimizing the extended Cottrell equation. The integrated current is proportional to nitrate up to 10 mM and the average detection limit is approximately 1.7 microM. Dissolved oxygen does not degrade performance. To examine the potential interference of other ions when analyzing nitrate, we measured the electrode response to 1000 microM each of NO(2-), Cl(-), PO(4)(3-), SO(4)(2-), F(-), CO(3)(2-), BO(2-), K(+), Ca(2+), and Sr(2+) with and without 1000 microM nitrate. Interference is negligible for most of the ions when nitrate is absent (i.e. <1% of the response to equimolar nitrate). However, interference is substantial (>20% increase or decrease in the electrode response to nitrate) for PO(4)(3-), Ca(2+), and Sr(2+) when equimolar nitrate is present.

This paper investigates the design of a single-chip, 100-channel wireless neural-signal acquisition, processing, and communications device. Design approaches for realizing front-end neural-signal amplifier, data conversion, microprocessor, and transceiver circuitry have been outlined.

Existing approaches used to develop compact low-power multichannel wireless neural recording systems range from creating custom-integrated circuits to assembling commercial-off-the-shelf (COTS) PC-based components. Custom-integrated-circuit designs yield extremely compact and low-power devices at the expense of high development and upgrade costs and turn-around times, while assembling COTS-PC-technology yields high performance at the expense of large system size and increased power consumption. To achieve a balance between implementing an ultra-compact custom-fabricated neural transceiver and assembling COTS-PC-technology, an overlay of a neural interface upon the TinyOS-based MICA2 platform is described. The system amplifies, digitally encodes, and transmits neural signals real-time at a rate of 9.6 kbps, while consuming less than 66 mW of power. The neural signals are received and forwarded to a client PC over a serial connection. This data rate can be divided for recording on up to 6 channels, with a resolution of 8 bits/sample. This work demonstrates the strengths and limitations of the TinyOS-based sensor technology as a foundation for chronic remote biological monitoring applications and, thus, provides an opportunity to create a system that can leverage from the frequent networking and communications advancements being made by the global TinyOS-development community.