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      Reactive Amine Functionalized Microelectrode Arrays Provide Short-Term Benefit but Long-Term Detriment to In Vivo Recording Performance

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          Abstract

          Intracortical microelectrode arrays (MEAs) are used for recording neural signals. However, indwelling devices result in chronic neuroinflammation, which leads to decreased recording performance through degradation of the device and surrounding tissue. Coating the MEAs with bioactive molecules is being explored to mitigate neuroinflammation. Such approaches often require an intermediate functionalization step such as (3-aminopropyl)triethoxysilane (APTES), which serves as a linker. However, the standalone effect of this intermediate step has not been previously characterized. Here, we investigated the effect of coating MEAs with APTES by comparing APTES-coated to uncoated controls in vivo and ex vivo. First, we measured water contact angles between silicon uncoated and APTES-coated substrates to verify the hydrophilic characteristics of the APTES coating. Next, we implanted MEAs in the motor cortex (M1) of Sprague–Dawley rats with uncoated or APTES-coated devices. We assessed changes in the electrochemical impedance and neural recording performance over a chronic implantation period of 16 weeks. Additionally, histology and bulk gene expression were analyzed to understand further the reactive tissue changes arising from the coating. Results showed that APTES increased the hydrophilicity of the devices and decreased electrochemical impedance at 1 kHz. APTES coatings proved detrimental to the recording performance, as shown by a constant decay up to 16 weeks postimplantation. Bulk gene analysis showed differential changes in gene expression between groups that were inconclusive with regard to the long-term effect on neuronal tissue. Together, these results suggest that APTES coatings are ultimately detrimental to chronic neural recordings. Furthermore, interpretations of studies using APTES as a functionalization step should consider the potential consequences if the final functionalization step is incomplete.

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          BDNF: A Key Factor with Multipotent Impact on Brain Signaling and Synaptic Plasticity

          Brain-derived neurotrophic factor (BDNF) is one of the most widely distributed and extensively studied neurotrophins in the mammalian brain. Among its prominent functions, one can mention control of neuronal and glial development, neuroprotection, and modulation of both short- and long-lasting synaptic interactions, which are critical for cognition and memory. A wide spectrum of processes are controlled by BDNF, and the sometimes contradictory effects of its action can be explained based on its specific pattern of synthesis, comprising several intermediate biologically active isoforms that bind to different types of receptor, triggering several signaling pathways. The functions of BDNF must be discussed in close relation to the stage of brain development, the different cellular components of nervous tissue, as well as the molecular mechanisms of signal transduction activated under physiological and pathological conditions. In this review, we briefly summarize the current state of knowledge regarding the impact of BDNF on regulation of neurophysiological processes. The importance of BDNF for future studies aimed at disclosing mechanisms of activation of signaling pathways, neuro- and gliogenesis, as well as synaptic plasticity is highlighted.
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            Detecting outliers when fitting data with nonlinear regression – a new method based on robust nonlinear regression and the false discovery rate

            Background Nonlinear regression, like linear regression, assumes that the scatter of data around the ideal curve follows a Gaussian or normal distribution. This assumption leads to the familiar goal of regression: to minimize the sum of the squares of the vertical or Y-value distances between the points and the curve. Outliers can dominate the sum-of-the-squares calculation, and lead to misleading results. However, we know of no practical method for routinely identifying outliers when fitting curves with nonlinear regression. Results We describe a new method for identifying outliers when fitting data with nonlinear regression. We first fit the data using a robust form of nonlinear regression, based on the assumption that scatter follows a Lorentzian distribution. We devised a new adaptive method that gradually becomes more robust as the method proceeds. To define outliers, we adapted the false discovery rate approach to handling multiple comparisons. We then remove the outliers, and analyze the data using ordinary least-squares regression. Because the method combines robust regression and outlier removal, we call it the ROUT method. When analyzing simulated data, where all scatter is Gaussian, our method detects (falsely) one or more outlier in only about 1–3% of experiments. When analyzing data contaminated with one or several outliers, the ROUT method performs well at outlier identification, with an average False Discovery Rate less than 1%. Conclusion Our method, which combines a new method of robust nonlinear regression with a new method of outlier identification, identifies outliers from nonlinear curve fits with reasonable power and few false positives.
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              Neural stimulation and recording electrodes.

              Electrical stimulation of nerve tissue and recording of neural electrical activity are the basis of emerging prostheses and treatments for spinal cord injury, stroke, sensory deficits, and neurological disorders. An understanding of the electrochemical mechanisms underlying the behavior of neural stimulation and recording electrodes is important for the development of chronically implanted devices, particularly those employing large numbers of microelectrodes. For stimulation, materials that support charge injection by capacitive and faradaic mechanisms are available. These include titanium nitride, platinum, and iridium oxide, each with certain advantages and limitations. The use of charge-balanced waveforms and maximum electrochemical potential excursions as criteria for reversible charge injection with these electrode materials are described and critiqued. Techniques for characterizing electrochemical properties relevant to stimulation and recording are described with examples of differences in the in vitro and in vivo response of electrodes.
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                Author and article information

                Journal
                ACS Appl Bio Mater
                ACS Appl Bio Mater
                mt
                aabmcb
                ACS Applied Bio Materials
                American Chemical Society
                2576-6422
                30 January 2024
                19 February 2024
                : 7
                : 2
                : 1052-1063
                Affiliations
                []Department of Bioengineering, The University of Texas at Dallas , 800 W. Campbell Road, Richardson, Texas 75080, United States
                []Department of Biomedical Engineering, Case Western Reserve University. 10900 Euclid Ave , Cleveland, Ohio 44106, United States
                [§ ]Advanced Platform Technology Center, Louis Stokes Cleveland Veterans Affairs Medical Center , Cleveland, Ohio 44106, United States
                []School of Behavioral and BrainSciences, The University of Texas at Dallas , 800 W. Campbell Road, Richardson, Texas 75080, United States
                Author notes
                Author information
                https://orcid.org/0000-0002-8161-9723
                https://orcid.org/0009-0000-4467-3803
                https://orcid.org/0000-0001-8030-6947
                Article
                10.1021/acsabm.3c01014
                10880090
                38290529
                de4df098-dc9d-44d0-9705-81a32b909999
                © 2024 The Authors. Published by American Chemical Society

                Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 28 October 2023
                : 10 January 2024
                : 08 January 2024
                Funding
                Funded by: National Institute of Neurological Disorders and Stroke, doi 10.13039/100000065;
                Award ID: 12635723
                Funded by: Rehabilitation Research and Development Service, doi 10.13039/100006380;
                Award ID: 12635707
                Funded by: Rehabilitation Research and Development Service, doi 10.13039/100006380;
                Award ID: 12418820
                Funded by: National Institute of Biomedical Imaging and Bioengineering, doi 10.13039/100000070;
                Award ID: T32EB004314
                Funded by: National Institute of Neurological Disorders and Stroke, doi 10.13039/100000065;
                Award ID: R01NS110823
                Categories
                Article
                Custom metadata
                mt3c01014
                mt3c01014

                coating,microelectrode arrays,motor cortex,neuroinflammation,surface modification

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