High frequency, real-time neurochemical and neuropharmacological measurements in situ in the living body.

The beautiful and complex brain machinery is perfectly synchronized, and our bodies have evolved to protect it against a myriad of potential threats. Shielded physically by the skull and chemically by the blood brain barrier, the brain processes internal and external information so that we can efficiently relate to the world that surrounds us while simultaneously and unconsciously controlling our vital functions. When coupled with the brittle nature of its internal chemical and electric signals, the brain's "armor" render accessing it a challenging and delicate endeavor that has historically limited our understanding of its structural and neurochemical intricacies. In this review, we briefly summarize the advancements made over the past 10 years to decode the brain's neurochemistry and neuropharmacology in situ, at the site of interest in the brain, with special focus on what we consider game-changing emerging technologies (eg, genetically encoded indicators and electrochemical aptamer-based sensors) and the challenges these must overcome before chronic, in situ chemosensing measurements become routine.

Multichannel Silicon Probes for Awake Hippocampal Recordings in Large Animals.

Decoding laminar information across deep brain structures and cortical regions is necessary in order to understand the neuronal ensembles that represent cognition and memory. Large animal models are essential for translational research due to their gyrencephalic neuroanatomy and significant white matter composition. A lack of long-length probes with appropriate stiffness allowing penetration to deeper structures with minimal damage to the neural interface is one of the major technical limitations to applying the approaches currently utilized in lower order animals to large animals. We therefore tested the performance of multichannel silicon probes of various solutions and designs that were developed specifically for large animal electrophysiology. Neurophysiological signals from dorsal hippocampus were recorded in chronically implanted awake behaving Yucatan pigs. Single units and local field potentials were analyzed to evaluate performance of given silicon probes over time. EDGE-style probes had the highest yields during intra-hippocampal recordings in pigs, making them the most suitable for chronic implantations and awake behavioral experimentation. In addition, the cross-sectional area of silicon probes was found to be a crucial determinant of silicon probe performance over time, potentially due to reduction of damage to the neural interface. Novel 64-channel EDGE-style probes tested acutely produced an optimal single unit separation and a denser sampling of the laminar structure, identifying these research silicon probes as potential candidates for chronic implantations. This study provides an analysis of multichannel silicon probes designed for large animal electrophysiology of deep laminar brain structures, and suggests that current designs are reaching the physical thresholds necessary for long-term (∼1 month) recordings with single-unit resolution.

Aptamer-functionalized neural recording electrodes for the direct measurement of cocaine in vivo.

Cocaine is a highly addictive psychostimulant that acts through competitive inhibition of the dopamine transporter. In order to fully understand the region specific neuropathology of cocaine abuse and addiction, it is unequivocally necessary to develop cocaine sensing technology capable of directly measuring real-time cocaine transient events local to different brain regions throughout the pharmacokinetic time course of exposure. We have developed an electrochemical aptamer-based in vivo cocaine sensor on a silicon based neural recording probe platform capable of directly measuring cocaine from discrete brain locations using square wave voltammetry (SWV). The sensitivity of the sensor for cocaine follows a modified exponential Langmuir model relationship and complete aptamer-target binding occurs in < 2 sec and unbinding in < 4 sec. The resulting temporal resolution is a 75X increase from traditional microdialysis sampling methods. When implanted in the rat dorsal striatum, the cocaine sensor exhibits stable SWV signal drift (modeled using a logarithmic exponential equation) and is capable of measuring real-time in vivo response to repeated local cocaine infusion as well as systemic IV cocaine injection. The in vivo sensor is capable of obtaining reproducible measurements over a period approaching 3 hours, after which signal amplitude significantly decreases likely due to tissue encapsulation. Finally, aptamer functionalized neural recording probes successfully detect spontaneous and evoked neural activity in the brain. This dual functionality makes the cocaine sensor a powerful tool capable of monitoring both biochemical and electrophysiological signals with high spatial and temporal resolution.

Correction: Aptamer-functionalized neural recording electrodes for the direct measurement of cocaine in vivo.

Correction for 'Aptamer-functionalized neural recording electrodes for the direct measurement of cocaine in vivo' by I. Mitch Taylor et al., J. Mater. Chem. B, 2017, 5, 2445-2458.

Point-of-Care Technologies for the Advancement of Precision Medicine in Heart, Lung, Blood, and Sleep Disorders.

The commercialization of new point of care technologies holds great potential in facilitating and advancing precision medicine in heart, lung, blood, and sleep (HLBS) disorders. The delivery of individually tailored health care to a patient depends on how well that patient's health condition can be interrogated and monitored. Point of care technologies may enable access to rapid and cost-effective interrogation of a patient's health condition in near real time. Currently, physiological data are largely limited to single-time-point collection at the hospital or clinic, whereas critical information on some conditions must be collected in the home, when symptoms occur, or at regular intervals over time. A variety of HLBS disorders are highly dependent on transient variables, such as patient activity level, environment, time of day, and so on. Consequently, the National Heart Lung and Blood Institute sponsored a request for applications to support the development and commercialization of novel point-of-care technologies through small businesses (RFA-HL-14-011 and RFA-HL-14-017). Three of the supported research projects are described to highlight particular point-of-care needs for HLBS disorders and the breadth of emerging technologies. While significant obstacles remain to the commercialization of such technologies, these advancements will be required to achieve precision medicine.

Predicting and managing heat dissipation from a neural probe.

Light stimulating neural probes are rapidly increasing our understanding of neural pathways. Relocating the externally coupled light source to the probe tip has the potential to dramatically improve the flexibility of the technique. However, this approach would generate heat within the embedded probe where even minor temperature excursions could easily damage tissues under study. A COMSOL model was used to study the thermal effects of these heated probes in the brain including blood perfusion and metabolic heating, and to investigate the effect of passive methods for improving heat dissipation. The probe temperature initially decreases with insertion depth, and then becomes steady. Extending the probe beyond the heated region has a similar effect, while increasing the size of the heated region steadily decreases the probe temperature. Increasing the thermal conductivity of the probe promotes spreading, decreasing the probe temperature. The effects of insertion depth and probe power dissipation were experimentally tested with a microfabricated, heated mock neural probe. The heated probe was tested in 0.65 % agarose gel at room temperature and in ex vivo cow brain at body temperature. The thermal resistance between the probe and the neural tissue or agarose gel was determined at a range of insertion depths and compared to the COMSOL model.

A high aspect ratio microelectrode array for mapping neural activity in vitro.

A novel high-aspect-ratio penetrating microelectrode array was designed and fabricated for the purpose of recording neural activity. The array allows two dimensional recording of 64 sites in vitro with high aspect ratio penetrating electrodes. Traditional surface electrode arrays, although easy to fabricate, do not penetrate to the viable tissue such as central hippocampus slices and thus have a lower signal/noise ratio and lower selectivity than a penetrating array. In the unfolded hippocampus preparation, the CA1-CA3 pyramidal cell layer in the whole unfolded rodent hippocampus preparation is encased by the alveus on one side and the Schaffer tract on the other and requires penetrating electrodes for high signal to noise ratio recording. An array of 64 electrode spikes, each with a target height of 200µm and diameter of 20µm, was fabricated in silicon on a transparent glass substrate. The impedance of the individual electrodes was measured to be approximately 1.5MΩ±497kΩ. The signal to noise ratio was measured and found to be 19.4±3dB compared to 3.9±0.8dB S/N for signals obtained with voltage sensitive dye RH414. A mouse unfolded hippocampus preparation was bathed in solution containing 50 micro-molar 4-amino pyridine and a complex two dimensional wave of activity was recorded using the array. These results indicate that this novel penetrating electrode array is able to obtain data superior to that of voltage sensitive dye techniques for broad field two-dimensional neuronal activity recording. When used with the unfolded hippocampus preparation, the combination forms a uniquely capable tool for imaging hippocampal network activity in the entire hippocampus.