Functionalized helical fibre bundles of carbon nanotubes as electrochemical sensors for long-term in vivo monitoring of multiple disease biomarkers

Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures. Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca2+ imaging offers more coverage but lacks the temporal resolution needed to distinguish individual spikes reliably and does not measure local field potentials. Until now, no technology compatible with use in unrestrained animals has combined high spatiotemporal resolution with large volume coverage. Here we design, fabricate and test a new silicon probe known as Neuropixels to meet this need. Each probe has 384 recording channels that can programmably address 960 complementary metal–oxide–semiconductor (CMOS) processing-compatible low-impedance TiN sites that tile a single 10-mm long, 70 × 20-μm cross-section shank. The 6 × 9-mm probe base is fabricated with the shank on a single chip. Voltage signals are filtered, amplified, multiplexed and digitized on the base, allowing the direct transmission of noise-free digital data from the probe. The combination of dense recording sites and high channel count yielded well-isolated spiking activity from hundreds of neurons per probe implanted in mice and rats. Using two probes, more than 700 well-isolated single neurons were recorded simultaneously from five brain structures in an awake mouse. The fully integrated functionality and small size of Neuropixels probes allowed large populations of neurons from several brain structures to be recorded in freely moving animals. This combination of high-performance electrode technology and scalable chip fabrication methods opens a path towards recording of brain-wide neural activity during behaviour.

The mechanical mismatch between soft neural tissues and stiff neural implants hinders the long-term performance of implantable neuroprostheses. Here, we designed and fabricated soft neural implants with the shape and elasticity of dura mater, the protective membrane of the brain and spinal cord. The electronic dura mater, which we call e-dura, embeds interconnects, electrodes, and chemotrodes that sustain millions of mechanical stretch cycles, electrical stimulation pulses, and chemical injections. These integrated modalities enable multiple neuroprosthetic applications. The soft implants extracted cortical states in freely behaving animals for brain-machine interface and delivered electrochemical spinal neuromodulation that restored locomotion after paralyzing spinal cord injury.

Brain function depends on simultaneous electrical, chemical and mechanical signaling at the cellular level. This multiplicity has confounded efforts to simultaneously measure or modulate these diverse signals in vivo. Here we present fiber probes that allow for simultaneous optical stimulation, neural recording and drug delivery in behaving mice with high resolution. These fibers are fabricated from polymers by means of a thermal drawing process that allows for the integration of multiple materials and interrogation modalities into neural probes. Mechanical, electrical, optical and microfluidic measurements revealed high flexibility and functionality of the probes under bending deformation. Long-term in vivo recordings, optogenetic stimulation, drug perturbation and analysis of tissue response confirmed that our probes can form stable brain-machine interfaces for at least 2 months. We expect that our multifunctional fibers will permit more detailed manipulation and analysis of neural circuits deep in the brain of behaving animals than achievable before.