Chronic large-scale neural recording
Keywords: Materials Science and Engineering.

There are more connections between neurons in the human brain than there are stars in our galaxy. Although such complexity is likely requisite for the ability to internalize, integrate, and respond to the continuous streams of information that the brain must process, it also makes the effective treatment of neurological disorders, such as Parkinson's and Alzheimer's disease, especially challenging. In recent years, the development of new implantable-device technologies to read-out and write-in electrical and chemical signals to and from the brain have created unprecedented opportunities to understand normal brain function and to ameliorate dysfunction resulting from disease or injury. Despite remarkable results in clinical studies and increasing market approvals, the mechanisms underlying the therapeutic effects of neuroprosthetics, as well as their debilitating side effects and reasons for their failure, remain poorly understood. Here, we report a new strategy to take advantage of the scalability and electronic processing power of CMOS-based devices combined with a three-dimensional neural interface. This architecture allows for each wire to be independently addressable for recording and stimulation purposes, ameliorating issues of scalability. The core concept consists of a bundle of insulated microwires perpendicularly mated to a large-scale CMOS amplifier array, such as a pixel array found in commercial camera or display chips. While microwires have low insertion damage and excellent electrical recording performance, they have been difficult to scale because they require individual mounting and connectorization. By arranging them into bundles, we control the spatial arrangement and three-dimensional structure of the distal (neuronal) end, with a robust parallel contact plane on the proximal side mated to a planar pixel array. The modular nature of the design allows a wide array of microwire types and size to be mated to different CMOS chips. The density of the microwires for the proximal (chip) end and the distal (brain) end can be modulated independently, allowing the wire-to-wire spacing to be tailored as desired. We thus link the rapid progress and power of commercial CMOS multiplexing, digitization and data acquisition hardware together with a bio-compatible, flexible and sensitive neural interface array. In our preliminary experiments, it became clear that the critical limitation of our technology is the insertion of arrays of microwires without damaging the surrounding tissue. This is challenging because the innermost meninge (pia), a relatively stiff membrane on the surface of the brain, has interwoven vasculature that makes it difficult to remove without causing severe trauma. While the insertion of a single microwire < 20 µm in diameter causes little to no observable damage, the insertion of many creates additional dimpling of the brain surface, more so than the compression caused by any individual wire. This led us to realize that a firm understanding of the underlying mechanics of insertion into brain tissue was needed to inform the optimal design for high-density penetrating arrays. To that end, we developed a high-performance mechanical measurement system using a modified nanoindentation head as a force transducer. This instrument resolves the poor performance of typical load cells for sensitive measurements, providing 3 nN force resolution and < 0.02 nm extension resolution, by far the most sensitive instrument ever applied to penetration in the brain. This technique has allowed us to investigate the dependence of size and tip geometry on the brain penetration process, as well as the mechanical scaling of diameter. Surprisingly, real-time microscopy revealed that at small enough length scales (< 25 µm), blood vessel rupture and bleeding during implantation could be entirely avoided. These measurements provided us a conceptual framework for guidance of probe design. Finally, we report on the viability of chronically implanted large-scale microwire arrays. While most new probe technologies or designs are able to demonstrate proof of concept functionality in acute preparations, very few show the ability to record chronic unit activity. To demonstrate the ability of chronically implanted microwire bundles to resolve network events spanning multiple regions, we recorded the neural activity from animals implanted with the ~400 wires daily for 4-6 months. This work provides a method for the millisecond-timescale sampling of hundreds of cells from large cortical regions. This allows detailed single-trial dynamics to be resolved in multiple regions simultaneously. We demonstrated this capability by showing that we can record ~1000 neurons simultaneously for several months in a large-scale study in 10 mice