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39 Janelia Publications

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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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    04/16/21 | Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings.
    Steinmetz NA, Aydın Ç, Lebedeva A, Okun M, Pachitariu M, Bauza M, Beau M, Bhagat J, Böhm C, Broux M, Chen S, Colonell J, Gardner RJ, Karsh B, Kloosterman F, Kostadinov D, Mora-Lopez C, O'Callaghan J, Park J, Putzeys J, Sauerbrei B, van Daal RJ, Vollan AZ, Wang S, Welkenhuysen M, Ye Z, Dudman JT, Dutta B, Hantman AW, Harris KD, Lee AK, Moser EI, O'Keefe J, Renart A, Svoboda K, Häusser M, Haesler S, Carandini M, Harris TD
    Science. 2021 Apr 16;372(6539):. doi: 10.1126/science.abf4588

    Measuring the dynamics of neural processing across time scales requires following the spiking of thousands of individual neurons over milliseconds and months. To address this need, we introduce the Neuropixels 2.0 probe together with newly designed analysis algorithms. The probe has more than 5000 sites and is miniaturized to facilitate chronic implants in small mammals and recording during unrestrained behavior. High-quality recordings over long time scales were reliably obtained in mice and rats in six laboratories. Improved site density and arrangement combined with newly created data processing methods enable automatic post hoc correction for brain movements, allowing recording from the same neurons for more than 2 months. These probes and algorithms enable stable recordings from thousands of sites during free behavior, even in small animals such as mice.

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    10/16/20 | Robotic Multi-Probe-Single-Actuator Inchworm Neural Microdrive
    Smith R, Kolb I, Tanaka S, Lee A, Harris T, Barbic M
    bioRxiv. 2020 Oct 16:

    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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    02/13/20 | The Neuropixels probe: A CMOS based integrated microsystems platform for neuroscience and brain-computer interfaces.
    Dutta B, Trautmann EM, Welkenhuysen M, Shenoy KV, Andrei A, Harris TD, Lopez CM, O'Callahan J, Putzeys J, Raducanu BC, Severi S, Stavisky SD
    2019 IEEE International Electron Devices Meeting (IEDM). 2020 Feb 13:. doi: 10.1109/IEDM19573.201910.1109/IEDM19573.2019.8993611

    We review recent progress in neural probes for brain recording, with a focus on the Neuropixels platform. Historically the number of neurons’ recorded simultaneously, follows a Moore’s law like behavior, with numbers doubling every 6.7 years. Using traditional techniques of probe fabrication, continuing to scale up electrode densities is very challenging. We describe a custom CMOS process technology that enables electrode counts well beyond 1000 electrodes; with the aim to characterize large neural populations with single neuron spatial precision and millisecond timing resolution. This required integrating analog and digital circuitry with the electrode array, making it a standalone integrated electrophysiology recording system. Input referred noise and power per channel is 7.5µV and <50µW respectively to ensure tissue heating <1°C. This approach enables doubling the number of measured neurons every 12 months.

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    12/01/19 | Neuropixels data-acquisition system: A scalable platform for parallel recording of 10 000+ electrophysiological signals.
    Putzeys J, Musa S, Mora Lopez C, Raducanu BC, Carton A, De Ceulaer J, Karsh B, Siegle JH, Van Helleputte N, Harris TD, Dutta B
    IEEE Transactions on Biomedical Circuits and Systems. 2019 Dec 01;13(6):1635-1644. doi: 10.1109/TBCAS.2019.2943077

    Although CMOS fabrication has enabled a quick evolution in the design of high-density neural probes and neural-recording chips, the scaling and miniaturization of the complete data-acquisition systems has happened at a slower pace. This is mainly due to the complexity and the many requirements that change depending on the specific experimental settings. In essence, the fundamental challenge of a neural-recording system is getting the signals describing the largest possible set of neurons out of the brain and down to data storage for analysis. This requires a complete system optimization that considers the physical, electrical, thermal and signal-processing requirements, while accounting for available technology, manufacturing constraints and budget. Here we present a scalable and open-standards-based open-source data-acquisition system capable of recording from over 10,000 channels of raw neural data simultaneously. The components and their interfaces have been optimized to ensure robustness and minimum invasiveness in small-rodent electrophysiology.

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    09/25/19 | Can one concurrently record electrical spikes from every neuron in a mammalian brain?
    Kleinfeld D, Luan L, Mitra PP, Robinson JT, Sarpeshkar R, Shepard K, Xie C, Harris TD
    Neuron. 2019 Sep 25;103(6):1005. doi: 10.1016/j.neuron.2019.08.011

    The classic approach to measure the spiking response of neurons involves the use of metal electrodes to record extracellular potentials. Starting over 60 years ago with a single recording site, this technology now extends to ever larger numbers and densities of sites. We argue, based on the mechanical and electrical properties of existing materials, estimates of signal-to-noise ratios, assumptions regarding extracellular space in the brain, and estimates of heat generation by the electronic interface, that it should be possible to fabricate rigid electrodes to concurrently record from essentially every neuron in the cortical mantle. This will involve fabrication with existing yet nontraditional materials and procedures. We further emphasize the need to advance materials for improved flexible electrodes as an essential advance to record from neurons in brainstem and spinal cord in moving animals.

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    04/01/19 | Multimodal in vivo brain electrophysiology with integrated glass microelectrodes.
    Hunt DL, Lai C, Smith RD, Lee AK, Harris TD, Barbic M
    Nature Biomedical Engineering. 2019 Apr 01;3(9):741-53. doi: 10.1038/s41551-019-0373-8

    Electrophysiology is the most used approach for the collection of functional data in basic and translational neuroscience, but it is typically limited to either intracellular or extracellular recordings. The integration of multiple physiological modalities for the routine acquisition of multimodal data with microelectrodes could be useful for biomedical applications, yet this has been challenging owing to incompatibilities of fabrication methods. Here, we present a suite of glass pipettes with integrated microelectrodes for the simultaneous acquisition of multimodal intracellular and extracellular information in vivo, electrochemistry assessments, and optogenetic perturbations of neural activity. We used the integrated devices to acquire multimodal signals from the CA1 region of the hippocampus in mice and rats, and show that these data can serve as ground-truth validation for the performance of spike-sorting algorithms. The microdevices are applicable for basic and translational neurobiology, and for the development of next-generation brain-machine interfaces.

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    01/18/19 | Cortical column and whole-brain imaging with molecular contrast and nanoscale resolution.
    Gao R, Asano SM, Upadhyayula S, Pisarev I, Milkie DE, Liu T, Singh V, Graves AR, Huynh GH, Zhao Y, Bogovic JA, Colonell J, Ott CM, Zugates CT, Tappan S, Rodriguez A, Mosaliganti KR, Sheu S, Pasolli HA, et al
    Science (New York, N.Y.). 2019 Jan 18;363(6424):eaau8302. doi: 10.1126/science.aau8302

    Optical and electron microscopy have made tremendous inroads toward understanding the complexity of the brain. However, optical microscopy offers insufficient resolution to reveal subcellular details, and electron microscopy lacks the throughput and molecular contrast to visualize specific molecular constituents over millimeter-scale or larger dimensions. We combined expansion microscopy and lattice light-sheet microscopy to image the nanoscale spatial relationships between proteins across the thickness of the mouse cortex or the entire Drosophila brain. These included synaptic proteins at dendritic spines, myelination along axons, and presynaptic densities at dopaminergic neurons in every fly brain region. The technology should enable statistically rich, large-scale studies of neural development, sexual dimorphism, degree of stereotypy, and structural correlations to behavior or neural activity, all with molecular contrast.

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    11/25/18 | Magnetocaloric materials as switchable high contrast ratio MRI labels.
    Barbic M, Dodd SJ, Morris HD, Dilley N, Marcheschi B, Huston A, Harris TD, Koretsky AP
    Magnetic Resonance in Medicine. 2018 Nov 25;81(4):2238-46. doi: 10.1002/mrm.27615

    PURPOSE: To develop switchable and tunable labels with high contrast ratio for MRI using magnetocaloric materials that have sharp first-order magnetic phase transitions at physiological temperatures and typical MRI magnetic field strengths.

    METHODS: A prototypical magnetocaloric material iron-rhodium (FeRh) was prepared by melt mixing, high-temperature annealing, and ice-water quenching. Temperature- and magnetic field-dependent magnetization measurements of wire-cut FeRh samples were performed on a vibrating sample magnetometer. Temperature-dependent MRI of FeRh samples was performed on a 4.7T MRI.

    RESULTS: Temperature-dependent MRI clearly demonstrated image contrast changes due to the sharp magnetic state transition of the FeRh samples in the MRI magnetic field (4.7T) and at a physiologically relevant temperature (~37°C).

    CONCLUSION: A magnetocaloric material, FeRh, was demonstrated to act as a high contrast ratio switchable MRI contrast agent due to its sharp first-order magnetic phase transition in the DC magnetic field of MRI and at physiologically relevant temperatures. A wide range of magnetocaloric materials are available that can be tuned by materials science techniques to optimize their response under MRI-appropriate conditions and be controllably switched in situ with temperature, magnetic field, or a combination of both.

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    07/25/18 | An unbiased template of the Drosophila brain and ventral nerve cord.
    Bogovic JA, Otsuna H, Heinrich L, Ito M, Jeter J, Meissner GW, Nern A, Colonell J, Malkesman O, Saalfeld S
    bioRxiv. 2018 Jul 25:. doi: 10.1101/376384

    The fruit fly Drosophila melanogaster is an important model organism for neuroscience with a wide array of genetic tools that enable the mapping of individuals neurons and neural subtypes. Brain templates are essential for comparative biological studies because they enable analyzing many individuals in a common reference space. Several central brain templates exist for Drosophila, but every one is either biased, uses sub-optimal tissue preparation, is imaged at low resolution, or does not account for artifacts. No publicly available Drosophila ventral nerve cord template currently exists. In this work, we created high-resolution templates of the Drosophila brain and ventral nerve cord using the best-available technologies for imaging, artifact correction, stitching, and template construction using groupwise registration. We evaluated our central brain template against the four most competitive, publicly available brain templates and demonstrate that ours enables more accurate registration with fewer local deformations in shorter time.

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