Ultra-Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks

Intracellular access with high spatiotemporal resolution can enhance our understanding of how neurons or cardiomyocytes regulate and orchestrate network activity, and how this activity can be affected with pharmacology or other interventional modalities. Nanoscale devices often employ electroporation to transiently permeate the cell membrane and record intracellular potentials, which tend to decrease rapidly to extracellular potential amplitudes with time. Here, we report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. We report large action potential amplitudes that are indicative of intracellular access from 3D tissue-like networks of neurons and cardiomyocytes across recording days and that do not decrease to extracellular amplitudes for the duration of the recording of several minutes. Our findings are validated with cross-sectional microscopy, pharmacology, and electrical interventions. Our experiments and simulations demonstrate that individual electrical addressability of nanowires is necessary for high-fidelity intracellular electrophysiological recordings. This study advances our understanding of and control over high-quality multi-channel intracellular recordings, and paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms.Comment: Main manuscript: 33 pages, 4 figures, Supporting information: 43 pages, 27 figures, Submitted to Advanced Material

Community mental healthcare providers' attitudes and practices related to smoking cessation interventions for people living with severe mental illness

Objective: This study aimed to describe mental healthcare providers’ attitudes about tobacco use, their personal smoking status, their confidence in offering smoking cessation support to clients living with severe mental illness, and the extent to which they incorporated smoking cessation interventions into their practice. The study also aimed to determine whether the providers’ attitudes, smoking status, and confidence were associated with offering smoking cessation support to clients. Methods: Self-administered questionnaires were distributed within community-based mental health agencies to those who provide care and support to adults living with severe mental illness. Outcomes measured included respondents’ smoking status, attitudes related to the provision of smoking cessation support, confidence in providing smoking cessation intervention, and smoking cessation practices. We conducted multivariate analyses using logistic regression analyses to examine the factors associated with the providers’ tobacco-related practices. Results: In total 282 of 871 care providers responded to the survey, 22% of whom were current smokers. The providers who held sympathetic attitudes about their role and their clients’ role in smoking cessation, who were never or former smokers, who were healthcare professionals rather than paraprofessionals, who had relatively more confidence, and who had more experience working in the mental health field were more likely to engage their clients in tobacco-related interventions. Conclusions: In this study the healthcare providers working in community-based mental health have a smoking prevalence rate that exceeds that of the region's general population and did not provide optimal smoking cessation support to their clients. Practice implications: Interventions that bolster the confidence of providers to engage is smoking cessation activities and that support a shift in attitudes about the role of tobacco use in mental health are required

Freestanding van der Waals Heterostructures of Graphene and Transition Metal Dichalcogenides

Vertical stacking of two-dimensional (2D) crystals has recently attracted substantial interest due to unique properties and potential applications they can introduce. However, little is known about their microstructure because fabrication of the 2D heterostructures on a rigid substrate limits one’s ability to directly study their atomic and chemical structures using electron microscopy. This study demonstrates a unique approach to create atomically thin freestanding van der Waals heterostructuresWSe₂/graphene and MoS₂/grapheneas ideal model systems to investigate the nucleation and growth mechanisms in heterostructures. In this study, we use transmission electron microscopy (TEM) imaging and diffraction to show epitaxial growth of the freestanding WSe₂/graphene heterostructure, while no epitaxy is maintained in the MoS₂/graphene heterostructure. Ultra-high-resolution aberration-corrected scanning transmission electron microscopy (STEM) shows growth of monolayer WSe₂ and MoS₂ triangles on graphene membranes and reveals their edge morphology and crystallinity. Photoluminescence measurements indicate a significant quenching of the photoluminescence response for the transition metal dichalcogenides on freestanding graphene, compared to those on a rigid substrate, such as sapphire and epitaxial graphene. Using a combination of (S)TEM imaging and electron diffraction analysis, this study also reveals the significant role of defects on the heterostructure growth. The direct growth technique applied here enables us to investigate the heterostructure nucleation and growth mechanisms at the atomic level without sample handling and transfer. Importantly, this approach can be utilized to study a wide spectrum of van der Waals heterostructures

Scalable Thousand Channel Penetrating Microneedle Arrays on Flex for Multimodal and Large Area Coverage BrainMachine Interfaces

The Utah array powers cutting-edge projects for restoration of neurological function, such as BrainGate, but the underlying electrode technology has itself advanced little in the last three decades. Here, advanced dual-side lithographic microfabrication processes is exploited to demonstrate a 1024-channel penetrating silicon microneedle array (SiMNA) that is scalable in its recording capabilities and cortical coverage and is suitable for clinical translation. The SiMNA is the first penetrating microneedle array with a flexible backing that affords compliancy to brain movements. In addition, the SiMNA is optically transparent permitting simultaneous optical and electrophysiological interrogation of neuronal activity. The SiMNA is used to demonstrate reliable recordings of spontaneous and evoked field potentials and of single unit activity in chronically implanted mice for up to 196 days in response to optogenetic and to whisker air-puff stimuli. Significantly, the 1024-channel SiMNA establishes detailed spatiotemporal mapping of broadband brain activity in rats. This novel scalable and biocompatible SiMNA with its multimodal capability and sensitivity to broadband brain activity will accelerate the progress in fundamental neurophysiological investigations and establishes a new milestone for penetrating and large area coverage microelectrode arrays for brain-machine interfaces

Ultra‐Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks

We report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. Stable amplitudes of intracellular potentials from 3D tissue-like networks of neurons and cardiomyocytes are obtained. Individual electrical addressability is necessary for high-fidelity intracellular electrophysiological recordings. This study paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms

Selective Formation of Porous Pt Nanorods for Highly Electrochemically Efficient Neural Electrode Interfaces

The enhanced electrochemical activity of nanostructured materials is readily exploited in energy devices, but their utility in scalable and human-compatible implantable neural interfaces can significantly advance the performance of clinical and research electrodes. We utilize low-temperature selective dealloying to develop scalable and biocompatible one-dimensional platinum nanorod (PtNR) arrays that exhibit superb electrochemical properties at various length scales, stability, and biocompatibility for high performance neurotechnologies. PtNR arrays record brain activity with cellular resolution from the cortical surfaces in birds and nonhuman primates. Significantly, strong modulation of surface recorded single unit activity by auditory stimuli is demonstrated in European Starling birds as well as the modulation of local field potentials in the visual cortex by light stimuli in a nonhuman primate and responses to electrical stimulation in mice. PtNRs record behaviorally and physiologically relevant neuronal dynamics from the surface of the brain with high spatiotemporal resolution, which paves the way for less invasive brain–machine interfaces

Highly Scalable, Atomically Thin WSe₂ Grown <i>via</i> Metal–Organic Chemical Vapor Deposition

Tungsten diselenide (WSe₂) is a two-dimensional material that is of interest for next-generation electronic and optoelectronic devices due to its direct bandgap of 1.65 eV in the monolayer form and excellent transport properties. However, technologies based on this 2D material cannot be realized without a scalable synthesis process. Here, we demonstrate the first scalable synthesis of large-area, mono and few-layer WSe₂ <i>via</i> metal–organic chemical vapor deposition using tungsten hexacarbonyl (W(CO)₆) and dimethylselenium ((CH₃)₂Se). In addition to being intrinsically scalable, this technique allows for the precise control of the vapor-phase chemistry, which is unobtainable using more traditional oxide vaporization routes. We show that temperature, pressure, Se:W ratio, and substrate choice have a strong impact on the ensuing atomic layer structure, with optimized conditions yielding >8 μm size domains. Raman spectroscopy, atomic force microscopy (AFM), and cross-sectional transmission electron microscopy (TEM) confirm crystalline monoto-multilayer WSe₂ is achievable. Finally, TEM and vertical current/voltage transport provide evidence that a pristine van der Waals gap exists in WSe₂/graphene heterostructures

Effects on kidney disease, fertility and development in mice inheriting a protein-truncating Denys-Drash syndrome allele (Wt1(tmT396))

Denys-Drash syndrome (DDS) is caused by heterozygous mutations of the Wilms' tumour suppressor gene, WT1, characterised by early-onset diffuse mesangial sclerosis often associated with male pseudohermaphroditism and/or Wilms' tumourigenesis. Previously, we reported that the Wt1tmT396 allele induces DDS kidney disease in mice. In the present study heterozygotes (Wt1tmT396/+) were generated on inbred (129/Ola), crossbred (B6/129) and MF1 second backcross (MF1-N2) backgrounds. Whereas male heterozygotes on each background were fertile, inbred heterozygous females were infertile. Kidney disease (proteinuria and sclerosis) was not congenital and developed significantly earlier in inbred mice, although with variable onset. Disease onset in MF1-N2 stocks occurred later in Wt1tmT396/+ mice than reported previously for Wt1R394W/+ mice, and while no kidney disease has been reported in B6/129 Wt1+/- mice, B6/129 Wt1tmT396/+ mice were affected. Offspring of both male and female B6/129 and MF1-N2 Wt1tmT396/+ mice developed kidney disease, but its incidence was significantly higher in offspring of female heterozygotes. Wt1tmT396/tmT396 embryos exhibited identical developmental abnormalities to those reported for Wt1-/- embryos. The results indicate that the Wt1 (tmT396) allele does not predispose to Wilms' tumourigenesis or male pseudohermaphroditism, its effect on kidney disease and female fertility depends on genetic background, stochastic factors may affect disease onset, and disease transmission is subject to a partial parent-of-origin effect. Since the Wt1tmT396 allele has no detectable intrinsic functional activity in vivo, and kidney disease progression is affected by the type of Wt1 mutation, the data support the view that DDS nephropathy results from a dominant-negative action rather than WT1 haploinsufficiency or gain-of-function

Microscale Physiological Events on the Human Cortical Surface

Despite ongoing advances in our understanding of local single-cellular and network-level activity of neuronal populations in the human brain, extraordinarily little is known about their &quot;intermediate&quot; microscale local circuit dynamics. Here, we utilized ultra-high-density microelectrode arrays and a rare opportunity to perform intracranial recordings across multiple cortical areas in human participants to discover three distinct classes of cortical activity that are not locked to ongoing natural brain rhythmic activity. The first included fast waveforms similar to extracellular single-unit activity. The other two types were discrete events with slower waveform dynamics and were found preferentially in upper cortical layers. These second and third types were also observed in rodents, nonhuman primates, and semi-chronic recordings from humans via laminar and Utah array microelectrodes. The rates of all three events were selectively modulated by auditory and electrical stimuli, pharmacological manipulation, and cold saline application and had small causal co-occurrences. These results suggest that the proper combination of high-resolution microelectrodes and analytic techniques can capture neuronal dynamics that lay between somatic action potentials and aggregate population activity. Understanding intermediate microscale dynamics in relation to single-cell and network dynamics may reveal important details about activity in the full cortical circuit