Engineering strategies towards overcoming bleeding and glial scar formation around neural probes

Neural probes are sophisticated electrophysiological tools used for intra-cortical recording and stimulation. These microelectrode arrays, designed to penetrate and interface the brain from within, contribute at the forefront of basic and clinical neuroscience. However, one of the challenges and currently most significant limitations is their ‘seamless’ long-term integration into the surrounding brain tissue. Following implantation, which is typically accompanied by bleeding, the tissue responds with a scarring process, resulting in a gliotic region closest to the probe. This glial scarring is often associated with neuroinflammation, neurodegeneration, and a leaky blood–brain interface (BBI). The engineering progress on minimizing this reaction in the form of improved materials, microfabrication, and surgical techniques is summarized in this review. As research over the past decade has progressed towards a more detailed understanding of the nature of this biological response, it is time to pose the question: Are penetrating probes completely free from glial scarring at all possible?

ProbeInterface: a unified framework for probe handling in extracellular electrophysiology

Recording neuronal activity with penetrating extracellular multi-channel electrode arrays, more commonly known as neural probes, is one of the most widespread approaches to probe neuronal activity. Despite a plethora of available extracellular probe designs, the time-consuming process of mapping of electrode channel order and relative geometries, as required by spike-sorting software is invariably left to the end-user. Consequently, this manual process is prone to mis-mapping mistakes, which in turn lead to undesirable spike-sorting errors and inefficiencies.Here we introduce ProbeInterface, an open-source project that aims to unify neural probe metadata descriptions by removing the manual step of probe mapping prior to spike-sorting for the analysis of extracellular neural recordings. ProbeInterface is first of all a Python API, which enables users to create and visualize probes and probe groups at any required complexity level. Second, ProbeInterface facilitates the generation of comprehensive wiring description ina reproducible fashion for any specific data-acquisition setup, which usually involves the use of a recording probe, a headstage, adapters, and an acquisition system. Third, we collaborate with probe manufacturers to compile an open library of available probes, which can be downloaded at run time using our Python API. Finally, with ProbeInterface we define a file format for probe handling which includes all necessary information for a FAIR probe description and is compatiblewith and complementary to other open standards in neuroscience.

Flexible Neural Probes with Electrochemical Modified Microelectrodes for Artifact-Free Optogenetic Applications

With the rapid increase in the use of optogenetics to investigate nervous systems, there is high demand for neural interfaces that can simultaneously perform optical stimulation and electrophysiological recording. However, high-magnitude stimulation artifacts have prevented experiments from being conducted at a desirably high temporal resolution. Here, a flexible polyimide-based neural probe with polyethylene glycol (PEG) packaged optical fiber and Pt-Black/PEDOT-GO (graphene oxide doped poly(3,4-ethylene-dioxythiophene)) modified microelectrodes was developed to reduce the stimulation artifacts that are induced by photoelectrochemical (PEC) and photovoltaic (PV) effects. The advantages of this design include quick and accurate implantation and high-resolution recording capacities. Firstly, electrochemical performance of the modified microelectrodes is significantly improved due to the large specific surface area of the GO layer. Secondly, good mechanical and electrochemical stability of the modified microelectrodes is obtained by using Pt-Black as bonding layer. Lastly, bench noise recordings revealed that PEC noise amplitude of the modified neural probes could be reduced to less than 50 µV and no PV noise was detected when compared to silicon-based neural probes. The results indicate that this device is a promising optogenetic tool for studying local neural circuits.

Minimally-invasive insertion strategy and in vivo evaluation of multi-shank flexible intracortical probes

Chronically implanted neural probes are powerful tools to decode brain activity however, recording population and spiking activity over long periods remains a major challenge. Here, we designed and fabricated flexible intracortical Michigan-style arrays with a shank cross-section per electrode of 250 μm$$^2$$ 2 utilizing the polymer paryleneC with the goal to improve the immune acceptance. As flexible neural probes are unable to penetrate the brain due to the low buckling force threshold, a tissue-friendly insertion system was developed by reducing the effective shank length. The insertion strategy enabled the implantation of the four, bare, flexible shanks up to 2 mm into the mouse brain without increasing the implantation footprint and therefore, minimizing the acute trauma. In acute recordings from the mouse somatosensory cortex and the olfactory bulb, we demonstrated that the flexible probes were able to simultaneously detect local field potentials as well as single and multi-unit activity. Additionally, the flexible arrays outperformed stiff probes with respect to yield of single unit activity. Following the successful in vivo validation, we further improved the microfabrication towards a double-metal-layer process, and were able to double the number of electrodes per shank by keeping the shank width resulting in a cross-section per electrode of 118 μm$$^2$$ 2 .

Full bandwidth electrophysiology of seizures and epileptiform activity enabled by flexible graphene micro-transistor depth neural probes

ABSTRACTMapping the entire frequency bandwidth of neuronal oscillations in the brain is of paramount importance for understanding physiological and pathological states. The ability to record simultaneously infraslow activity (<0.1 Hz) and higher frequencies (0.1-600 Hz) using the same recording electrode would particularly benefit epilepsy research. However, commonly used metal microelectrode technology is not well suited for recording infraslow activity. Here we use flexible graphene depth neural probes (gDNP), consisting of a linear array of graphene microtransistors, to concurrently record infraslow and high frequency neuronal activity in awake rodents. We show that gDNPs can reliably record and map with high spatial resolution seizures, post-ictal spreading depolarisation, and high frequency epileptic activity through cortical laminae to the CA1 layer of the hippocampus in a mouse model of chemically-induced seizures. We demonstrate functionality of chronically implanted devices over 10 weeks by recording with high fidelity spontaneous spike-wave discharges and associated infraslow activity in a rat model of absence epilepsy. Altogether, our work highlights the suitability of this technology for in vivo electrophysiology research, in particular, to examine the contributions of infraslow activity to seizure initiation and termination.