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We present a high electrode density and high channel count CMOS (complementary metal-oxide-semiconductor) active neural probe containing 1344 neuron sized recording pixels (20 µm × 20 µm) and 12 reference pixels (20 µm × 80 µm), densely packed on a 50 µm thick, 100 µm wide, and 8 mm long shank. The active electrodes or pixels consist of dedicated in-situ circuits for signal source amplification, which are directly located under each electrode. The probe supports the simultaneous recording of all 1356 electrodes with sufficient signal to noise ratio for typical neuroscience applications. For enhanced performance, further noise reduction can be achieved while using half of the electrodes (678). Both of these numbers considerably surpass the state-of-the art active neural probes in both electrode count and number of recording channels. The measured input referred noise in the action potential band is 12.4 µVrms, while using 678 electrodes, with just 3 µW power dissipation per pixel and 45 µW per read-out channel (including data transmission).

Silicon neuroprobes hold great potential for studies of large-scale neural activity and brain computer interfaces, but data on brain response in chronic implants is limited. Here we explored with in vivo  cellular imaging the response to multisite silicon probes for neural recordings. We tested a chronic implant for mice consisting of a CMOS-compatible silicon probe rigidly implanted in the cortex under a cranial imaging window. Multiunit recordings of cortical neurons with the implant showed no degradation of electrophysiological signals weeks after implantation (mean spike and noise amplitudes of 186 ± 42 µV pp and 16 ± 3.2 µV rms , respectively, n = 5 mice). Two-photon imaging through the cranial window allowed longitudinal monitoring of fluorescently-labeled astrocytes from the second week post implantation for 8 weeks (n = 3 mice). The imaging showed a local increase in astrocyte-related fluorescence that remained stable from the second to the tenth week post implantation. These results demonstrate that, in a standard electrophysiology protocol in mice, rigidly implanted silicon probes can provide good short to medium term chronic recording performance with a limited astrocyte inflammatory response. The precise factors influencing the response to silicon probe implants remain to be elucidated.

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.

Simultaneous electrical stimulation and recording are used to gain insights into the function of neuronal circuitry. However, artifacts produced by the electrical stimulation pulses prevent the recording of neural responses during, and a short period after, the stimulation duration. In this work, we describe a mixed-signal recording topology with template subtraction for removing the artifact during the stimulation pulse. Emulated artifacts generated from a lumped electrical circuit model and experimental artifacts in cardiac cell cultures are used to evaluate the topology. The simulations show that delays between the emulated artifact and its estimated compensation template represent the largest error source of the analog template subtraction. The quantization error appears like random noise and determines the threshold level for the action potential detection. Simulations show that removal of the artifacts is possible, allowing the detection of action potentials during the stimulation pulsing period, even for high-amplitude saturating artifacts. Measurement results with artifacts elicited in cardiac cell cultures show feasible applications of this topology. The proposed topology therefore promisingly opens up a previously unavailable detection window for improving the analysis of the neuronal activity.

Abstract It is an uninformative truism to state that the brain operates at multiple spatial and temporal scales, each with each own set of emergent phenomena. More worthy of attention is the point that our current understanding of it cannot clearly indicate which of these phenomenological scales are the significant contributors to the brain’s function and primary output (i.e. behaviour). Apart from the sheer complexity of the problem, a major contributing factor to this state of affairs is the lack of instrumentation that can simultaneously address these multiple scales without causing function altering damages to the underlying tissue. One important facet of this problem is that standard neural recording devices normally require one output connection per electrode. This limits the number of electrodes that can fit along the thin shafts of implantable probes generating a limiting balance between density and spread. Sharing a single output connection between multiple electrodes relaxes this constraint and permits designs of ultra-high density probes. Here we report the design and in-vivo validation of such a device, a complementary metal-oxide-semiconductor (CMOS) scanning probe with 1344 electrodes; the outcome of the European research project NeuroSeeker. We show that this design targets both local and global spatial scales by allowing the simultaneous recording of more than 1000 neurons spanning 7 functional regions with a single shaft. The neurons show similar recording longevity and signal to noise ratio to passive probes of comparable size and no adverse effects in awake or anesthetized animals. Addressing the data management of this device we also present novel visualization and monitoring methods. Using the probe with freely moving animals we show how accessing a number of cortical and subcortical brain regions offers a novel perspective on how the brain operates around salient behavioural events. Finally, we compare this probe with lower density, non CMOS designs (which have to adhere to the one electrode per output line rule). We show that an increase in density results in capturing neural firing patterns, undetectable by lower density devices, which correlate to self-similar structures inherent in complex naturalistic behaviour. To help design electrode configurations for future, even higher density, CMOS probes, recordings from many different brain regions were obtained with an ultra-dense passive probe. Footnotes * Added more animals results for the analysis presented

Cross-validating new methods for recording neural activity is necessary to accurately interpret and compare the signals they measure. Here we describe a procedure for precisely aligning two probes for in vivo paired-recordings such that the spiking activity of a single neuron is monitored with both a dense extracellular silicon polytrode and a juxtacellular micro-pipette. Our new method allows for efficient, reliable, and automated guidance of both probes to the same neural structure with micron resolution. We also describe a new dataset of paired-recordings, which is available online. We propose that our novel targeting system, and ever expanding cross-validation dataset, will be vital to the development of new algorithms for automatically detecting/sorting single-units, characterizing new electrode materials/designs, and resolving nagging questions regarding the origin and nature of extracellular neural signals.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of myeloid blasts in the bone marrow. Despite the availability of potential curative treatments, patients frequently experience unfavorable outcomes. One crucial aspect contributing to relapse is the plasticity of leukemic clones, which enables them to switch between active proliferation and dormancy. The adaptability of AML underscores the need for novel therapies targeting AML-specific proteins. To address this, genome-wide CRISPR screens can be utilized to identify cancer entity-specific vulnerabilities. Leveraging publicly available functional genomics datasets and comparing AML with non-AML cancer cell lines, we identified a significant dependency on the cell cycle-regulating gene MYBL2 in AML. We describe MYBL2 as a key driver of AML cell growth and proliferation, highlighting its established role as a cell cycle regulator. Also, our findings uncover its previously unrecognized function as an inhibitor of cellular senescence. A knockdown of MYBL2 induces cell cycle arrest in the G2/M phase with subsequent induction of apoptosis in vitro, and reduces leukemic burden in a patient-derived xenograft (PDX) model in vivo. Interestingly, some AML cells evade apoptosis and enter a senescent-like phenotype upon MYBL2 -knockdown, which is reversible upon re-expression of MYBL2 . Finally, analyses of clinical data from two publicly available patient cohorts demonstrate a lower probability of survival in patients with higher MYBL2 expression, further hinting at the potential relevance of MYBL2 in AML. In conclusion, our findings demonstrate the essential role of MYBL2 in AML, governing the balance between cell proliferation, cell survival and senescence, ultimately influencing the fate of AML cells.