Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter that is essential for normal brain function. It is involved in multiple neuronal activities, including plasticity, information processing, and network synchronization. Abnormal GABA levels result in severe brain disorders and therefore GABA has been the target of a wide range of drug therapeutics. GABA being non-electroactive is challenging to detect in real-time. To date, GABA is detected mainly via microdialysis with a high-performance liquid chromatography (HPLC) system that employs electrochemical (EC) and spectroscopic methodology. However, these systems are bulky and unsuitable for real-time continuous monitoring. As opposed to microdialysis, biosensors are easy to miniaturize and are highly suitable for in vivo studies; they selectively oxidize GABA into a secondary electroactive product (usually hydrogen peroxide, H2O2) in the presence of enzymes, which is then detected by amperometry. Unfortunately, this method requires a rather cumbersome process with prereactors and relies on externally applied reagents. Here, we report the design and implementation of a GABA microarray probe that operates on a newly conceived principle. It consists of two microbiosensors, one for glutamate (Glu) and one for GABA detection, modified with glutamate oxidase and GABASE enzymes, respectively. By simultaneously measuring and subtracting the H2O2 oxidation currents generated from these microbiosensors, GABA and Glu can be detected continuously in real-time in vitro and ex vivo and without the addition of any externally applied reagents. The detection of GABA by this probe is based upon the in-situ generation of α-ketoglutarate from the Glu oxidation that takes place at the Glu microbiosensor. A GABA sensitivity of 36 ± 2.5 pA μM-1cm-2, which is 26-fold higher than reported in the literature, and a limit of detection of 2 ± 0.12 μM were achieved in an in vitro setting. The GABA probe was successfully tested in an adult rat brain slice preparation. These results demonstrate that the developed GABA probe constitutes a novel and powerful neuroscientific tool that could be employed in the future for in vivo longitudinal studies of the combined role of GABA and Glu (a major excitatory neurotransmitter) signaling in brain disorders, such as epilepsy and traumatic brain injury, as well as in preclinical trials of potential therapeutic agents for the treatment of these disorders.

Electrical microstimulation has enabled partial restoration of vision, hearing, movement, somatosensation, as well as improving organ functions by electrically modulating neural activities. However, chronic microstimulation is faced with numerous challenges. The implantation of an electrode array into the neural tissue triggers an inflammatory response, which can be exacerbated by the delivery of electrical currents. Meanwhile, prolonged stimulation may lead to electrode material degradation., which can be accelerated by the hostile inflammatory environment. Both material degradation and adverse tissue reactions can compromise stimulation performance over time. For stable chronic electrical stimulation, an ideal microelectrode must present 1) high charge injection limit, to efficiently deliver charge without exceeding safety limits for both tissue and electrodes, 2) small size, to gain high spatial selectivity, 3) excellent biocompatibility that ensures tissue health immediately next to the device, and 4) stable in vivo electrochemical properties over the application period. In this review, the challenges in chronic microstimulation are described in detail. To aid material scientists interested in neural stimulation research, the in vitro and in vivo testing methods are introduced for assessing stimulation functionality and longevity and a detailed overview of recent advances in electrode material research and device fabrication for improving chronic microstimulation performance is provided.

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The brain is a complex network that accounts for only 5% of human mass but consumes 20% of our energy. Uncovering the mysteries of the brain’s functions in motion, memory, learning, behavior, and mental health remains a hot but challenging topic. Neurochemicals in the brain, such as neurotransmitters, neuromodulators, gliotransmitters, hormones, and metabolism substrates and products, play vital roles in mediating and modulating normal brain function, and their abnormal release or imbalanced concentrations can cause various diseases, such as epilepsy, Alzheimer’s disease, and Parkinson’s disease. A wide range of techniques have been used to probe the concentrations of neurochemicals under normal, stimulated, diseased, and drug-induced conditions in order to understand the neurochemistry of drug mechanisms and develop diagnostic tools or therapies. Recent advancements in detection methods, device fabrication, and new materials have resulted in the development of neurochemical sensors with improved performance. However, direct in vivo measurements require a robust sensor that is highly sensitive and selective with minimal fouling and reduced inflammatory foreign body responses. Here, we review recent advances in neurochemical sensor development for in vivo studies, with a focus on electrochemical and optical probes. Other alternative methods are also compared. We discuss in detail the in vivo challenges for these methods and provide an outlook for future directions.

Abnormal neurochemical signaling is often the underlying cause of brain disorders. Electrochemical microsensors are widely used to monitor neurochemicals with high spatialtemporal resolution. However, they rely on carbon fiber microelectrodes that often limit their sensing performance. In this study, we demonstrate the potential of a hybrid multiwall carbon nanotube (MWCNT) film modified boron-doped ultrananocrystalline diamond (UNCD) microelectrode (250 μm diameter) microsensor for improved detection of dopamine (DA) in the presence of common interferents. A series of modified microelectrodes with varying film thicknesses were microfabricated by electrophoretic deposition (EPD) and characterized by scanning electron microscopy, x-ray photoelectron spectroscopy, electrochemical impedance spectroscopy (EIS) and silver deposition imaging. Using cyclic voltammetry, the 100-nm "thin" film microelectrode produced the most favorable combination of DA sensitivity value of 36 ±2% μA/μM/cm 2 with a linear range of 33 nM to 1 μM and a limit of detection (LOD) of 9.5 ± 1.2% nM. The EIS spectra of these microelectrodes revealed three regions with inhomogeneous pore geometry and differing impedance values and electrochemical activity, which was found to be film thickness dependent. Using differential pulse voltammetry, the modified microelectrode showed excellent selectivity by exhibiting three distinct peaks for the DA, serotonin and excess ascorbic acid in a ternary mixture. These results provide two key benefits: first, remarkable improvements in DA sensitivity (>125-fold), selectivity (>2000-fold) and LOD (>180-fold), second, these MWCNTs can be selectively coated with a simple, scalable and low cost EPD process for highly multiplexed microsensor technologies. These advances offer considerable promise for further progress in chemical neurosciences.