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Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution in animal models. In humans, however, current approaches restrict recordings to a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here we describe a new probe variant and set of techniques that enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single-unit classes, with differing firing rates, locations along the length of the electrode array, waveform spatial spread and modulation by LFP events such as inter-ictal discharges and burst suppression. Although some challenges remain in creating a turnkey recording system, high-density silicon arrays provide a path for studying human-specific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution. Neuropixels probes were used to simultaneously record from more than 200 cortical neurons in human participants during neurosurgical procedures. The approach could reveal insights underlying human cognition and pathology.

Neural recording electrode technologies have contributed considerably to neuroscience by enabling the extracellular detection of low-frequency local field potential oscillations and high-frequency action potentials of single units. Nevertheless, several long-standing limitations exist, including low multiplexity, deleterious chronic immune responses and long-term recording instability. Driven by initiatives encouraging the generation of novel neurotechnologies and the maturation of technologies to fabricate high-density electronics, novel electrode technologies are emerging. Here, we provide an overview of recently developed neural recording electrode technologies with high spatial integration, long-term stability and multiple functionalities. We describe how these emergent neurotechnologies can approach the ultimate goal of illuminating chronic brain activity with minimal disruption of the neural environment, thereby providing unprecedented opportunities for neuroscience research in the future.Here, Hong and Lieber review recent developments in electrode technologies for the recording of single-unit spiking activity. They focus on advances in electrodes with high spatial integration, long-term stability and multifunctional capacities.

Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiology of neuronal circuits within organoids remains under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we captured spontaneous extracellular activity from brain organoids derived from human induced pluripotent stem cells. We inferred functional connectivity from spike timing, revealing a large number of weak connections within a skeleton of significantly fewer strong connections. A benzodiazepine increased the uniformity of firing patterns and decreased the relative fraction of weakly connected edges. Our analysis of the local field potential demonstrate that brain organoids contain neuronal assemblies of sufficient size and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug action, and the effects of external stimuli upon neuronal networks. Brain organoids replicate cellular organization found in the developing human brain. Here, the authors utilize microelectronics to map activity in brain organoids and assemble functional circuits that mirror complexity found in brain networks in vivo.

New silicon probes known as Neuropixels are shown to record from hundreds of neurons simultaneously in awake and freely moving rodents. High-density neural activity probe Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions. Existing technologies reliably measure activity from a relatively small number of neurons with high spatial and temporal resolution, or from a large volume of neurons with low resolution. Timothy Harris and colleagues describe the design, fabrication and performance of Neuropixels, a silicon probe that can measure well-isolated neural activity from hundreds of neurons. They integrated these probes into a lightweight system that could record activity simultaneously and with high fidelity from hundreds of neurons in awake and freely moving rodents. Sensory, motor and cognitive operations involve the coordinated action of large neuronal populations across multiple brain regions in both superficial and deep structures 1 , 2 . Existing extracellular probes record neural activity with excellent spatial and temporal (sub-millisecond) resolution, but from only a few dozen neurons per shank. Optical Ca 2+ imaging 3 , 4 , 5 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 6 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.

Stably recording the electrical activity of the same neurons over the adult life of an animal is important to neuroscience research and biomedical applications. Current implantable devices cannot provide stable recording on this timescale. Here, we introduce a method to precisely implant electronics with an open, unfolded mesh structure across multiple brain regions in the mouse. The open mesh structure forms a stable interwoven structure with the neural network, preventing probe drifting and showing no immune response and neuron loss during the year-long implantation. Rigorous statistical analysis, visual stimulus-dependent measurement and unbiased, machine-learning-based analysis demonstrated that single-unit action potentials have been recorded from the same neurons of behaving mice in a very long-term stable manner. Leveraging this stable structure, we demonstrated that the same neurons can be recorded over the entire adult life of the mouse, revealing the aging-associated evolution of single-neuron activities. The authors developed flexible, unfolded mesh electronics for implantation in multiple brain regions of mice. The probes show minimal immune response and electrode drift, enabling stable recording of single-unit action potentials from the same neurons during the adult life of animals.

Investigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models. Currently technologies for monitoring and controlling neural activities in 3D models are lacking. Here the authors report a 3D high-density multielectrode array, with optical stimulation and drug delivery, to investigate neural circuit dynamics in engineered 3D neural tissues.

Large-scale neural population recordings with single-cell resolution across the primate brain remain challenging. Here we introduce the Neuroscroll probe that isolates single neuronal activities simultaneously from 1,024 densely spaced channels that are flexibly distributed across the shank of the probe. The Neuroscroll probe length is easily tunable for individual probes from 10 mm to 90 mm, covering the brain size of non-human primates and humans, and the probes remain intact and functional after repeated bending deformations. The Neuroscroll probes provided reliable recordings from large neural populations with high chronic stability up to 105 weeks in rats. Recording with each Neuroscroll probe yielded hundreds of well-isolated single units simultaneously from multiple brain regions distributed across the entire depth of the rhesus macaque brain. With the thousand simultaneously recorded channels, unprecedented probe length, excellent mechanical stability and flexible recording site distribution, the Neuroscroll probes enable a wide range of new experimental paradigms in system neuroscience studies with great versatility. A probe incorporating 1,024 simultaneously recorded channels with shank length up to 90 mm exhibits high chronic recording stability and enables brain-wide large-scale neural population recordings with single-cell resolution in non-human primates.

Large-scale brain activity mapping is important for understanding the neural basis of behaviour. Electrocorticograms (ECoGs) have high spatiotemporal resolution, bandwidth, and signal quality. However, the invasiveness and surgical risks of electrode array implantation limit its application scope. We developed an ultrathin, flexible shape-changing electrode array (SCEA) for large-scale ECoG mapping with minimal invasiveness. SCEAs were inserted into cortical surfaces in compressed states through small openings in the skull or dura and fully expanded to cover large cortical areas. MRI and histological studies on rats proved the minimal invasiveness of the implantation process and the high chronic biocompatibility of the SCEAs. High-quality micro-ECoG activities mapped with SCEAs from male rodent brains during seizures and canine brains during the emergence period revealed the spatiotemporal organization of different brain states with resolution and bandwidth that cannot be achieved using existing noninvasive techniques. The biocompatibility and ability to map large-scale physiological and pathological cortical activities with high spatiotemporal resolution, bandwidth, and signal quality in a minimally invasive manner offer SCEAs as a superior tool for applications ranging from fundamental brain research to brain-machine interfaces. The invasiveness of extensive craniotomy hinders large-scale cortex mapping. Here, the authors developed a flexible, shape-changing electrode array which enables minimally invasive implantation and achieves high spatiotemporal resolution brain mapping.

The authors use fiber-based fabrication to create flexible biocompatible probes with integrated optical, electrical and microfluidic capabilities. Functionality is demonstrated by characterizing the temporal dynamics of opsin expression following viral delivery, long-term tracking of individual neuron action potentials and modulation of neural circuits in the context of mouse behavior. Optogenetic interrogation of neural pathways relies on delivery of light-sensitive opsins into tissue and subsequent optical illumination and electrical recording from the regions of interest. Despite the recent development of multifunctional neural probes, integration of these modalities in a single biocompatible platform remains a challenge. We developed a device composed of an optical waveguide, six electrodes and two microfluidic channels produced via fiber drawing. Our probes facilitated injections of viral vectors carrying opsin genes while providing collocated neural recording and optical stimulation. The miniature (<200 μm) footprint and modest weight (<0.5 g) of these probes allowed for multiple implantations into the mouse brain, which enabled opto-electrophysiological investigation of projections from the basolateral amygdala to the medial prefrontal cortex and ventral hippocampus during behavioral experiments. Fabricated solely from polymers and polymer composites, these flexible probes minimized tissue response to achieve chronic multimodal interrogation of brain circuits with high fidelity.

Advances in technologies that can record and stimulate deep brain activity in humans have led to impactful discoveries within the field of neuroscience and contributed to the development of novel therapies for neurological and psychiatric disorders. Further progress, however, has been hindered by device limitations in that recording of single-neuron activity during freely moving behaviors in humans has not been possible. Additionally, implantable neurostimulation devices, currently approved for human use, have limited stimulation programmability and restricted full-duplex bidirectional capability. In this study, we developed a wearable bidirectional closed-loop neuromodulation system (Neuro-stack) and used it to record single-neuron and local field potential activity during stationary and ambulatory behavior in humans. Together with a highly flexible and customizable stimulation capability, the Neuro-stack provides an opportunity to investigate the neurophysiological basis of disease, develop improved responsive neuromodulation therapies, explore brain function during naturalistic behaviors in humans and, consequently, bridge decades of neuroscientific findings across species. The Neuro-stack is a wearable platform for recording from single neurons in freely moving humans. It also allows for personalized stimulation during real-time decoding of neural activity.