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47 Publications

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    02/01/24 | Brain-wide neural activity underlying memory-guided movement.
    Chen S, Liu Y, Wang ZA, Colonell J, Liu LD, Hou H, Tien N, Wang T, Harris T, Druckmann S, Li N, Svoboda K
    Cell. 2024 Feb 01;187(3):676-691.e16. doi: 10.1016/j.cell.2023.12.035

    Behavior relies on activity in structured neural circuits that are distributed across the brain, but most experiments probe neurons in a single area at a time. Using multiple Neuropixels probes, we recorded from multi-regional loops connected to the anterior lateral motor cortex (ALM), a circuit node mediating memory-guided directional licking. Neurons encoding sensory stimuli, choices, and actions were distributed across the brain. However, choice coding was concentrated in the ALM and subcortical areas receiving input from the ALM in an ALM-dependent manner. Diverse orofacial movements were encoded in the hindbrain; midbrain; and, to a lesser extent, forebrain. Choice signals were first detected in the ALM and the midbrain, followed by the thalamus and other brain areas. At movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.

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    11/03/23 | Volitional activation of remote place representations with a hippocampal brain-machine interface.
    Lai C, Tanaka S, Harris TD, Lee AK
    Science. 2023 Nov 03;382(6670):566-573. doi: 10.1126/science.adh5206

    The hippocampus is critical for recollecting and imagining experiences. This is believed to involve voluntarily drawing from hippocampal memory representations of people, events, and places, including maplike representations of familiar environments. However, whether representations in such "cognitive maps" can be volitionally accessed is unknown. We developed a brain-machine interface to test whether rats can do so by controlling their hippocampal activity in a flexible, goal-directed, and model-based manner. We found that rats can efficiently navigate or direct objects to arbitrary goal locations within a virtual reality arena solely by activating and sustaining appropriate hippocampal representations of remote places. This provides insight into the mechanisms underlying episodic memory recall, mental simulation and planning, and imagination and opens up possibilities for high-level neural prosthetics that use hippocampal representations.

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    09/15/23 | Low-latency extracellular spike assignment for high-density electrodes at single-neuron resolution
    Chongxi Lai , Dohoung Kim , Brian Lustig , Shinsuke Tanaka , Brian Barbarits , Lakshmi Narayan , Jennifer Colonell , Ole Paulsen , Albert K. Lee , Timothy D. Harris
    bioRxiv. 2023 Sep 15:. doi: 10.1101/2023.09.14.557854

    Real-time neural signal processing is essential for brain-machine interfaces and closed-loop neuronal perturbations. However, most existing applications sacrifice cell-specific identity and temporal spiking information for speed. We developed a hybrid hardware-software system that utilizes a Field Programmable Gate Array (FPGA) chip to acquire and process data in parallel, enabling individual spikes from many simultaneously recorded neurons to be assigned single-neuron identities with 1-millisecond latency. The FPGA assigns labels, validated with ground-truth data, by comparing multichannel spike waveforms from tetrode or silicon probe recordings to a spike-sorted model generated offline in software. This platform allowed us to rapidly inactivate a region in vivo based on spikes from an upstream neuron before these spikes could excite the downstream region. Furthermore, we could decode animal location within 3 ms using data from a population of individual hippocampal neurons. These results demonstrate our system’s suitability for a broad spectrum of research and clinical applications.

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    08/25/23 | Ultra-high density electrodes improve detection, yield, and cell type specificity of brain recordings.
    Ye Z, Shelton AM, Shaker JR, Boussard J, Colonell J, Manavi S, Chen S, Windolf C, Hurwitz C, Namima T, Pedraja F, Weiss S, Raducanu B, Ness TV, Einevoll GT, Laurent G, Sawtell NB, Bair W, Pasupathy A, Mora Lopez C, Dutta B, Paninski L, Siegle JH, Koch C, Olsen SR, Harris TD, Steinmetz NA
    bioRxiv. 2023 Aug 25:. doi: 10.1101/2023.08.23.554527

    To study the neural basis of behavior, we require methods to sensitively and accurately measure neural activity at single neuron and single spike resolution. Extracellular electrophysiology is a principal method for achieving this, but it has biases in the neurons it detects and it imperfectly resolves their action potentials. To overcome these limitations, we developed a silicon probe with significantly smaller and denser recording sites than previous designs, called Neuropixels Ultra (NP Ultra). This device measures neuronal activity at ultra-high densities (>1300 sites per mm, 10 times higher than previous probes), with 6 µm center-to-center spacing and low noise. This device effectively comprises an implantable voltage-sensing camera that captures a planar image of a neuron's electrical field. We introduce a new spike sorting algorithm optimized for these probes and use it to find that the yield of visually-responsive neurons in recordings from mouse visual cortex improves ∼3-fold. Recordings across multiple brain regions and four species revealed a subset of unexpectedly small extracellular action potentials not previously reported. Further experiments determined that, in visual cortex, these do not correspond to major subclasses of interneurons and instead likely reflect recordings from axons. Finally, using ground-truth identification of cortical inhibitory cell types with optotagging, we found that cell type was discriminable with approximately 75% success among three types, a significant improvement over lower-resolution recordings. NP Ultra improves spike sorting performance, sampling bias, and cell type classification.

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    08/06/23 | Multi-day Neuron Tracking in High Density Electrophysiology Recordings using EMD
    Augustine Xiaoran Yuan , Jennifer Colonell , Anna Lebedeva , Adam Charles , Timothy Harris
    bioRxiv. 2023 Aug 06:. doi: 10.1101/2023.08.03.551724

    Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. New advances in high density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here we propose a neuron tracking method that can identify the same cells independent of firing statistics, which are used by most existing methods. Our method is based on between-day non-rigid alignment of spike sorted clusters. We verified the same cell identify using measured visual receptive fields. This method succeeds on datasets separated from one to 47 days, with an 86% average recovery rate.

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    04/10/23 | Mental navigation and telekinesis with a hippocampal map-based brain-machine interface
    Chongxi Lai , Shinsuke Tanaka , Timothy D. Harris , Albert K. Lee
    bioRxiv. 2023 Apr 10:. doi: 10.1101/2023.04.07.536077

    The hippocampus is critical for recollecting and imagining experiences. This is believed to involve voluntarily drawing from hippocampal memory representations of people, events, and places, including the hippocampus’ map-like representations of familiar environments. However, whether the representations in such “cognitive maps” can be volitionally and selectively accessed is unknown. We developed a brain-machine interface to test if rats could control their hippocampal activity in a flexible, goal-directed, model-based manner. We show that rats can efficiently navigate or direct objects to arbitrary goal locations within a virtual reality arena solely by activating and sustaining appropriate hippocampal representations of remote places. This should provide insight into the mechanisms underlying episodic memory recall, mental simulation/planning, and imagination, and open up possibilities for high-level neural prosthetics utilizing hippocampal representations.

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    03/02/23 | Brain-wide neural activity underlying memory-guided movement
    Susu Chen , Yi Liu , Ziyue Wang , Jennifer Colonell , Liu D. Liu , Han Hou , Nai-Wen Tien , Tim Wang , Timothy Harris , Shaul Druckmann , Nuo Li , Karel Svoboda
    bioRxiv. 2023 Mar 02:. doi: 10.1101/2023.03.01.530520

    Behavior requires neural activity across the brain, but most experiments probe neurons in a single area at a time. Here we used multiple Neuropixels probes to record neural activity simultaneously in brain-wide circuits, in mice performing a memory-guided directional licking task. We targeted brain areas that form multi-regional loops with anterior lateral motor cortex (ALM), a key circuit node mediating the behavior. Neurons encoding sensory stimuli, choice, and actions were distributed across the brain. However, in addition to ALM, coding of choice was concentrated in subcortical areas receiving input from ALM, in an ALM-dependent manner. Choice signals were first detected in ALM and the midbrain, followed by the thalamus, and other brain areas. At the time of movement initiation, choice-selective activity collapsed across the brain, followed by new activity patterns driving specific actions. Our experiments provide the foundation for neural circuit models of decision-making and movement initiation.

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    02/04/23 | Large-scale brain-wide neural recording in nonhuman primates
    Eric M. Trautmann , Janis K. Hesse , Gabriel M. Stine , Ruobing Xia , Shude Zhu , Daniel J. O’Shea , Bill Karsh , Jennifer Colonell , Frank F. Lanfranchi , Saurabh Vyas , Andrew Zimnik , Natalie A. Steinmann , Daniel A. Wagenaar , Alexandru Andrei , Carolina Mora Lopez , John O’Callaghan , Jan Putzeys , Bogdan C. Raducanu , Marleen Welkenhuysen , Mark Churchland , Tirin Moore , Michael Shadlen , Krishna Shenoy , Doris Tsao , Barundeb Dutta , Timothy Harris
    bioRxiv. 2023 Feb 04:. doi: 10.1101/2023.02.01.526664

    High-density, integrated silicon electrodes have begun to transform systems neuroscience, by enabling large-scale neural population recordings with single cell resolution. Existing technologies, however, have provided limited functionality in nonhuman primate species such as macaques, which offer close models of human cognition and behavior. Here, we report the design, fabrication, and performance of Neuropixels 1.0-NHP, a high channel count linear electrode array designed to enable large-scale simultaneous recording in superficial and deep structures within the macaque or other large animal brain. These devices were fabricated in two versions: 4416 electrodes along a 45 mm shank, and 2496 along a 25 mm shank. For both versions, users can programmably select 384 channels, enabling simultaneous multi-area recording with a single probe. We demonstrate recording from over 3000 single neurons within a session, and simultaneous recordings from over 1000 neurons using multiple probes. This technology represents a significant increase in recording access and scalability relative to existing technologies, and enables new classes of experiments involving fine-grained electrophysiological characterization of brain areas, functional connectivity between cells, and simultaneous brain-wide recording at scale.

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    11/10/22 | Robotic Multi-Probe-Single-Actuator Inchworm Neural Microdrive
    Smith R, Kolb I, Tanaka S, Lee A, Harris T, Barbic M
    eLife. 2022 Nov 10:. doi: 10.7554/eLife.71876

    Electrophysiology is one of the major experimental techniques used in neuroscience. The favorable spatial and temporal resolution as well as the increasingly larger site counts of brain recording electrodes contribute to the popularity and importance of electrophysiology in neuroscience. Such electrodes are typically mechanically placed in the brain to perform acute or chronic freely moving animal measurements. The micro positioners currently used for such tasks employ a single translator per independent probe being placed into the targeted brain region, leading to significant size and weight restrictions. To overcome this limitation, we have developed a miniature robotic multi-probe neural microdrive that utilizes novel phase-change-material-filled resistive heater micro-grippers. The microscopic dimensions, gentle gripping action, independent electronic actuation control, and high packing density of the grippers allow for micrometer-precision independent positioning of multiple arbitrarily shaped parallel neural electrodes with only a single piezo actuator in an inchworm motor configuration. This multi-probe-single-actuator design allows for significant size and weight reduction, as well as remote control and potential automation of the microdrive. We demonstrate accurate placement of multiple independent recording electrodes into the CA1 region of the rat hippocampus in vivo in acute and chronic settings. Thus, our robotic neural microdrive technology is applicable towards basic neuroscience and clinical studies, as well as other multi-probe or multi-sensor micro-positioning applications.

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    09/02/21 | Electrode pooling can boost the yield of extracellular recordings with switchable silicon probes.
    Lee KH, Ni Y, Colonell J, Karsh B, Putzeys J, Pachitariu M, Harris TD, Meister M
    Nature Communications. 2021 Sep 02;12(1):5245. doi: 10.1038/s41467-021-25443-4

    State-of-the-art silicon probes for electrical recording from neurons have thousands of recording sites. However, due to volume limitations there are typically many fewer wires carrying signals off the probe, which restricts the number of channels that can be recorded simultaneously. To overcome this fundamental constraint, we propose a method called electrode pooling that uses a single wire to serve many recording sites through a set of controllable switches. Here we present the framework behind this method and an experimental strategy to support it. We then demonstrate its feasibility by implementing electrode pooling on the Neuropixels 1.0 electrode array and characterizing its effect on signal and noise. Finally we use simulations to explore the conditions under which electrode pooling saves wires without compromising the content of the recordings. We make recommendations on the design of future devices to take advantage of this strategy.

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