The Case for Adaptive Neuromodulation to Treat Severe Intractable Mental Disorders

Mental disorders are a leading cause of disability worldwide, and available treatments have limited efficacy for severe cases unresponsive to conventional therapies. Neurosurgical interventions, such as lesioning procedures, have shown success in treating refractory cases of mental illness, but may have irreversible side effects. Neuromodulation therapies, specifically Deep Brain Stimulation (DBS), may offer similar therapeutic benefits using a reversible (explantable) and adjustable platform. Early DBS trials have been promising, however, pivotal clinical trials have failed to date. These failures may be attributed to targeting, patient selection, or the “open-loop” nature of DBS, where stimulation parameters are chosen ad hoc during infrequent visits to the clinician’s office that take place weeks to months apart. Further, the tonic continuous stimulation fails to address the dynamic nature of mental illness; symptoms often fluctuate over minutes to days. Additionally, stimulation-based interventions can cause undesirable effects if applied when not needed. A responsive, adaptive DBS (aDBS) system may improve efficacy by titrating stimulation parameters in response to neural signatures (i.e., biomarkers) related to symptoms and side effects. Here, we present rationale for the development of a responsive DBS system for treatment of refractory mental illness, detail a strategic approach for identification of electrophysiological and behavioral biomarkers of mental illness, and discuss opportunities for future technological developments that may harness aDBS to deliver improved therapy

Wireless Neurosensor for Full-Spectrum Electrophysiology Recordings during Free Behavior

SummaryBrain recordings in large animal models and humans typically rely on a tethered connection, which has restricted the spectrum of accessible experimental and clinical applications. To overcome this limitation, we have engineered a compact, lightweight, high data rate wireless neurosensor capable of recording the full spectrum of electrophysiological signals from the cortex of mobile subjects. The wireless communication system exploits a spatially distributed network of synchronized receivers that is scalable to hundreds of channels and vast environments. To demonstrate the versatility of our wireless neurosensor, we monitored cortical neuron populations in freely behaving nonhuman primates during natural locomotion and sleep-wake transitions in ecologically equivalent settings. The interface is electrically safe and compatible with the majority of existing neural probes, which may support previously inaccessible experimental and clinical research

Sulfide Generation by Dominant Halanaerobium Microorganisms in Hydraulically Fractured Shales

Hydraulic fracturing of black shale formations has greatly increased United States oil and natural gas recovery. However, the accumulation of biomass in subsurface reservoirs and pipelines is detrimental because of possible well souring, microbially induced corrosion, and pore clogging. Temporal sampling of produced fluids from a well in the Utica Shale revealed the dominance of Halanaerobium strains within the in situ microbial community and the potential for these microorganisms to catalyze thiosulfate-dependent sulfidogenesis. From these field data, we investigated biogenic sulfide production catalyzed by a Halanaerobium strain isolated from the produced fluids using proteogenomics and laboratory growth experiments. Analysis of Halanaerobium isolate genomes and reconstructed genomes from metagenomic data sets revealed the conserved presence of rhodanese-like proteins and anaerobic sulfite reductase complexes capable of converting thiosulfate to sulfide. Shotgun proteomics measurements using a Halanaerobium isolate verified that these proteins were more abundant when thiosulfate was present in the growth medium, and culture-based assays identified thiosulfate-dependent sulfide production by the same isolate. Increased production of sulfide and organic acids during the stationary growth phase suggests that fermentative Halanaerobium uses thiosulfate to remove excess reductant. These findings emphasize the potential detrimental effects that could arise from thiosulfate-reducing microorganisms in hydraulically fractured shales, which are undetected by current industry-wide corrosion diagnostics. IMPORTANCE Although thousands of wells in deep shale formations across the United States have been hydraulically fractured for oil and gas recovery, the impact of microbial metabolism within these environments is poorly understood. Our research demonstrates that dominant microbial populations in these subsurface ecosystems contain the conserved capacity for the reduction of thiosulfate to sulfide and that this process is likely occurring in the environment. Sulfide generation (also known as “souring”) is considered deleterious in the oil and gas industry because of both toxicity issues and impacts on corrosion of the subsurface infrastructure. Critically, the capacity for sulfide generation via reduction of sulfate was not detected in our data sets. Given that current industry wellhead tests for sulfidogenesis target canonical sulfate-reducing microorganisms, these data suggest that new approaches to the detection of sulfide-producing microorganisms may be necessary

Clades of huge phages from across Earth's ecosystems.

Bacteriophages typically have small genomes1 and depend on their bacterial hosts for replication2. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of more than 200 kilobases (kb), including a genome of 735 kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems

Developing collaborative platforms to advance neurotechnology and its translation

Neurotechnological devices are failing to deliver on their therapeutic promise because of the time it takes to translate them from bench to clinic. In this Perspective, we reflect on lessons learned from medical device successes and failures and consider how such lessons might shape a strategic vision for translating neurotechnologies in the future. We articulate how the intentional design and deployment of “scientific platforms,” from the technology stack of hardware and software through the supporting ecosystem, could catalyze a new wave of innovation, discovery, and therapy. We also identify specific actions that could promote future neurotechnology roadmaps and industrial-academic-government collaborative activities. We believe that community-supported neurotechnology platforms will prove to be transformational in accelerating ideas from bench to bedside, maximizing scientific discovery and improving patient care

A 100-Channel Hermetically Sealed Implantable Device for Chronic Wireless Neurosensing Applications

A 100-channel fully implantable wireless broadband neural recording system was developed. It features 100 parallel broadband (0.1 Hz-7.8 kHz) neural recording channels, a medical grade 200 mAh Li-ion battery recharged inductively at 150 kHz, and data telemetry using 3.2 GHz to 3.8 GHz FSK modulated wireless link for 48 Mbps Manchester encoded data. All active electronics are hermetically sealed in a titanium enclosure with a sapphire window for electromagnetic transparency. A custom, high-density configuration of 100 individual hermetic feedthrough pins enable connection to an intracortical neural recording microelectrode array. A 100 MHz bandwidth custom receiver was built to remotely receive the FSK signal and achieved -77.7 dBm sensitivity with 10(-8) BER at 48 Mbps data rate. ESD testing on all the electronic inputs and outputs has proven that the implantable device satisfies the HBM Class-1B ESD Standard. In addition, the evaluation of the worst-case charge density delivered to the tissue from each I/O pin verifies the patient safety of the device in the event of failure. Finally, the functionality and reliability of the complete device has been tested on-bench and further validated chronically in ongoing freely moving swine and monkey animal trials for more than one year to date

An Implantable Neural Sensing Microsystem with Fiber-Optic Data Transmission and Power Delivery

sensor

2014 Annual Agricultural Outlook

This paper is a 2014 agricultural outlook covering multiple agricultural commodities and issues

Genome-resolved metagenomics extends the environmental distribution of the Verrucomicrobia phylum to the deep terrestrial subsurface

ABSTRACT Bacteria of the phylum Verrucomicrobia are prevalent and are particularly common in soil and freshwater environments. Their cosmopolitan distribution and reported capacity for polysaccharide degradation suggests members of Verrucomicrobia are important contributors to carbon cycling across Earth’s ecosystems. Despite their prevalence, the Verrucomicrobia are underrepresented in isolate collections and genome databases; consequently, their ecophysiological roles may not be fully realized. Here, we expand genomic sampling of the Verrucomicrobia phylum by describing a novel genus, “Candidatus Marcellius,” belonging to the order Opitutales. “Ca. Marcellius” was recovered from a shale-derived produced fluid metagenome collected 313 days after hydraulic fracturing, the deepest environment from which a member of the Verrucomicrobia has been recovered to date. We uncover genomic attributes that may explain the capacity of this organism to inhabit a shale gas well, including the potential for utilization of organic polymers common in hydraulic fracturing fluids, nitrogen fixation, adaptation to high salinities, and adaptive immunity via CRISPR-Cas. To illuminate the phylogenetic and environmental distribution of these metabolic and adaptive traits across the Verrucomicrobia phylum, we performed a comparative genomic analysis of 31 publicly available, nearly complete Verrucomicrobia genomes. Our genomic findings extend the environmental distribution of the Verrucomicrobia 2.3 kilometers into the terrestrial subsurface. Moreover, we reveal traits widely encoded across members of the Verrucomicrobia, including the capacity to degrade hemicellulose and to adapt to physical and biological environmental perturbations, thereby contributing to the expansive habitat range reported for this phylum. IMPORTANCE The Verrucomicrobia phylum of bacteria is widespread in many different ecosystems; however, its role in microbial communities remains poorly understood. Verrucomicrobia are often low-abundance community members, yet previous research suggests they play a major role in organic carbon degradation. While Verrucomicrobia remain poorly represented in culture collections, numerous genomes have been reconstructed from metagenomic data sets in recent years. The study of genomes from across the phylum allows for an extensive assessment of their potential ecosystem roles. The significance of this work is (i) the recovery of a novel genus of Verrucomicrobia from 2.3 km in the subsurface with the ability to withstand the extreme conditions that characterize this environment, and (ii) the most extensive assessment of ecophysiological traits encoded by Verrucomicrobia genomes to date. We show that members of this phylum are specialist organic polymer degraders that can withstand a wider range of environmental conditions than previously thought