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Penetrating flexible electrode arrays can simultaneously record thousands of individual neurons in the brains of live animals. However, it has been challenging to spatially map and longitudinally monitor the dynamics of large three-dimensional neural networks. Here we show that optimized ultraflexible electrode arrays distributed across multiple cortical regions in head-fixed mice and in freely moving rats allow for months-long stable electrophysiological recording of several thousand neurons at densities of about 1,000 neural units per cubic millimetre. The chronic recordings enhanced decoding accuracy during optogenetic stimulation and enabled the detection of strongly coupled neuron pairs at the million-pair and millisecond scales, and thus the inference of patterns of directional information flow. Longitudinal and volumetric measurements of neural couplings may facilitate the study of large-scale neural circuits.

ObjectiveBroca's aphasia is a syndrome of impaired fluency with retained comprehension. The authors used an unbiased algorithm to examine which neuroanatomical areas are most likely to result in Broca's aphasia following surgical lesions.MethodsPatients were prospectively evaluated with standardized language batteries before and after surgery. Broca's area was defined anatomically as the pars opercularis and triangularis of the inferior frontal gyrus. Broca's aphasia was defined by the Western Aphasia Battery language assessment. Resections were outlined from MRI scans to construct 3D volumes of interest. These were aligned using a nonlinear transformation to Montreal Neurological Institute brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm was used to test for areas statistically associated with Broca's aphasia when incorporated into a resection, as well as areas associated with deficits in fluency independent of Western Aphasia Battery classification. Postoperative MRI scans were reviewed in blinded fashion to estimate the percentage resection of Broca's area compared to areas identified using the VLSM algorithm.ResultsA total of 289 patients had early language evaluations, of whom 19 had postoperative Broca's aphasia. VLSM analysis revealed an area that was highly correlated (p < 0.001) with Broca's aphasia, spanning ventral sensorimotor cortex and supramarginal gyri, as well as extending into subcortical white matter tracts. Reduced fluency scores were significantly associated with an overlapping region of interest. The fluency score was negatively correlated with fraction of resected precentral, postcentral, and supramarginal components of the VLSM area.ConclusionsBroca's aphasia does not typically arise from neurosurgical resections in Broca's area. When Broca's aphasia does occur after surgery, it is typically in the early postoperative period, improves by 1 month, and is associated with resections of ventral sensorimotor cortex and supramarginal gyri.

ObjectivesSpine surgery is associated with early impairment of gastrointestinal motility, with postoperative ileus rates of 5-12%. A standardized postoperative medication regimen aimed at early restoration of bowel function can reduce morbidity and cost, and its study should be prioritized.MethodsA standardized postoperative bowel medication protocol was implemented for all elective spine surgeries performed by a single neurosurgeon from March 1, 2022 to June 30, 2022 at a metropolitan Veterans Affairs medical center. Daily bowel function was tracked and medications were advanced using the protocol. Clinical, surgical, and length of stay data are reported.ResultsAcross 20 consecutive surgeries in 19 patients, mean age was 68.9 years [standard deviation (SD) = 10; range 40-84]. Seventy-four percent reported preoperative constipation. Surgeries consisted of 45% fusion and 55% decompression; lumbar retroperitoneal approaches constituted 30% (10% anterior, 20% lateral). Two patients were discharged in good condition prior to bowel movement after meeting institutional discharge criteria; the other 18 cases all had return of bowel function by postoperative day (POD) 3 (mean = 1.8-days, SD = 0.7). There were no inpatient or 30-day complications. Mean discharge occurred 3.3-days post-surgery (SD = 1.5; range 1-6; home 95%, skilled nursing facility 5%). Estimated cumulative cost of the bowel regimen was $17 on POD 3.ConclusionsCareful monitoring of return of bowel function after elective spine surgery is important for preventing ileus, reducing healthcare cost, and ensuring quality. Our standardized postoperative bowel regimen was associated with return of bowel function within 3 days and low costs. These findings can be utilized in quality-of-care pathways.

Measuring electrical potentials in the extracellular space of the brain is a popular technique because it can detect action potentials from putative individual neurons. Electrophysiology is undergoing a transformation where the number of recording channels, and thus number of neurons detected, is growing at a dramatic rate. This rapid scaling is paving the way for both new discoveries and commercial applications; however, as the number of channels increases there will be an increasing need to make these systems more power efficient. One area ripe for optimization are the signal acquisition specifications needed to detect and sort action potentials (i.e., "spikes") to putative single neuron sources. In this work, we take existing recordings collected using Intan hardware and modify them in a way that corresponds to reduced recording performance. The accuracy of these degraded recordings to spike sort using MountainSort4 is evaluated by comparing against expert labels. We show that despite reducing signal specifications by a factor of 2 or more, spike sorting accuracy does not change substantially. Specifically, reducing both sample rate and bit depth from 30 kHz and 16 bits to 12 kHz and 12 bits resulted in a 3% drop in spike sorting accuracy. Our results suggest that current neural acquisition systems are over-specified. These results may inform the design of next generation neural acquisition systems enabling higher channel count systems.

Memory enables access to past experiences to guide future behavior. Humans can determine which memories to trust (high confidence) and which to doubt (low confidence). How memory retrieval, memory confidence, and memory-guided decisions are related, however, is not understood. In particular, how confidence in memories is used in decision making is unknown. We developed a spatial memory task in which rats were incentivized to gamble their time: betting more following a correct choice yielded greater reward. Rat behavior reflected memory confidence, with higher temporal bets following correct choices. We applied machine learning to identify a memory decision variable and built a generative model of memories evolving over time that accurately predicted both choices and confidence reports. Our results reveal in rats an ability thought to exist exclusively in primates and introduce a unified model of memory dynamics, retrieval, choice, and confidence.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain 'replay' of spatial trajectories at ∼20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here, we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

The hippocampus is diversely interconnected with other brain systems along its axis. Cycles of theta-frequency activity are believed to propagate from the septal to temporal pole, yet it is unclear how this one-way route supports the flexible cognitive capacities of this structure. We leveraged novel thin-film microgrid arrays conformed to the human hippocampal surface to track neural activity two-dimensionally in vivo. All oscillation frequencies identified between 1-15 Hz propagated across the tissue. Moreover, they dynamically shifted between two roughly opposite directions oblique to the long axis. This predominant propagation axis was mirrored across participants, hemispheres, and consciousness states. Directionality was modulated in a participant who performed a behavioral task, and it could be predicted by wave amplitude topography over the hippocampal surface. Our results show that propagation directions may thus represent distinct meso-scale network computations, operating along versatile spatiotemporal processing routes across the hippocampal body.

Cognitive faculties such as imagination, planning, and decision-making entail the ability to represent hypothetical experience. Crucially, animal behavior in natural settings implies that the brain can represent hypothetical future experience not only quickly but also constantly over time, as external events continually unfold. To determine how this is possible, we recorded neural activity in the hippocampus of rats navigating a maze with multiple spatial paths. We found neural activity encoding two possible future scenarios (two upcoming maze paths) in constant alternation at 8 Hz: one scenario per ∼125-ms cycle. Further, we found that the underlying dynamics of cycling (both inter- and intra-cycle dynamics) generalized across qualitatively different representational correlates (location and direction). Notably, cycling occurred across moving behaviors, including during running. These findings identify a general dynamic process capable of quickly and continually representing hypothetical experience, including that of multiple possible futures.

Representations related to past experiences play a critical role in memory and decision-making processes. The rat hippocampus expresses these types of representations during sharp-wave ripple (SWR) events, and previous work identified a minority of SWRs that contain “replay” of spatial trajectories at ~20x the movement speed of the animal. Efforts to understand replay typically make multiple assumptions about which events to examine and what sorts of representations constitute replay. We therefore lack a clear understanding of both the prevalence and the range of representational dynamics associated with replay. Here we develop a state space model that uses a combination of movement dynamics of different speeds to capture the spatial content and time evolution of replay during SWRs. Using this model, we find that the large majority of replay events contain spatially coherent, interpretable content. Furthermore, many events progress at real-world, rather than accelerated, movement speeds, consistent with actual experiences.

ObjectiveElectrode arrays for chronic implantation in the brain are a critical technology in both neuroscience and medicine. Recently, flexible, thin-film polymer electrode arrays have shown promise in facilitating stable, single-unit recordings spanning months in rats. While array flexibility enhances integration with neural tissue, it also requires removal of the dura mater, the tough membrane surrounding the brain, and temporary bracing to penetrate the brain parenchyma. Durotomy increases brain swelling, vascular damage, and surgical time. Insertion using a bracing shuttle results in additional vascular damage and brain compression, which increase with device diameter; while a higher-diameter shuttle will have a higher critical load and more likely penetrate dura, it will damage more brain parenchyma and vasculature. One way to penetrate the intact dura and limit tissue compression without increasing shuttle diameter is to reduce the force required for insertion by sharpening the shuttle tip.ApproachWe describe a novel design and fabrication process to create silicon insertion shuttles that are sharp in three dimensions and can penetrate rat dura, for faster, easier, and less damaging implantation of polymer arrays. Sharpened profiles are obtained by reflowing patterned photoresist, then transferring its sloped profile to silicon with dry etches.Main resultsWe demonstrate that sharpened shuttles can reliably implant polymer probes through dura to yield high quality single unit and local field potential recordings for at least 95 days. On insertion directly through dura, tissue compression is minimal.SignificanceThis is the first demonstration of a rat dural-penetrating array for chronic recording. This device obviates the need for a durotomy, reducing surgical time and risk of damage to the blood-brain barrier. This is an improvement to state-of-the-art flexible polymer electrode arrays that facilitates their implantation, particularly in multi-site recording experiments. This sharpening process can also be integrated into silicon electrode array fabrication.

The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.

Simultaneous recordings from large populations of individual neurons across distributed brain regions over months to years will enable new avenues of scientific and clinical development. The use of flexible polymer electrode arrays can support long-lasting recording, but the same mechanical properties that allow for longevity of recording make multiple insertions and integration into a chronic implant a challenge. Here is a methodology by which multiple polymer electrode arrays can be targeted to a relatively spatially unconstrained set of brain areas. The method utilizes thin-film polymer devices, selected for their biocompatibility and capability to achieve long-term and stable electrophysiologic recording interfaces. The resultant implant allows accurate and flexible targeting of anatomically distant regions, physical stability for months, and robustness to electrical noise. The methodology supports up to sixteen serially inserted devices across eight different anatomic targets. As previously demonstrated, the methodology is capable of recording from 1024 channels. Of these, the 512 channels in this demonstration used for single neuron recording yielded 375 single units distributed across six recording sites. Importantly, this method also can record single units for at least 160 days. This implantation strategy, including temporarily bracing each device with a retractable silicon insertion shuttle, involves tethering of devices at their target depths to a skull-adhered plastic base piece that is custom-designed for each set of recording targets, and stabilization/protection of the devices within a silicone-filled, custom-designed plastic case. Also covered is the preparation of devices for implantation, and design principles that should guide adaptation to different combinations of brain areas or array designs.

The brain is a massive neuronal network, organized into anatomically distributed sub-circuits, with functionally relevant activity occurring at timescales ranging from milliseconds to years. Current methods to monitor neural activity, however, lack the necessary conjunction of anatomical spatial coverage, temporal resolution, and long-term stability to measure this distributed activity. Here we introduce a large-scale, multi-site, extracellular recording platform that integrates polymer electrodes with a modular stacking headstage design supporting up to 1,024 recording channels in freely behaving rats. This system can support months-long recordings from hundreds of well-isolated units across multiple brain regions. Moreover, these recordings are stable enough to track large numbers of single units for over a week. This platform enables large-scale electrophysiological interrogation of the fast dynamics and long-timescale evolution of anatomically distributed circuits, and thereby provides a new tool for understanding brain activity.

Understanding the detailed dynamics of neuronal networks will require the simultaneous measurement of spike trains from hundreds of neurons (or more). Currently, approaches to extracting spike times and labels from raw data are time consuming, lack standardization, and involve manual intervention, making it difficult to maintain data provenance and assess the quality of scientific results. Here, we describe an automated clustering approach and associated software package that addresses these problems and provides novel cluster quality metrics. We show that our approach has accuracy comparable to or exceeding that achieved using manual or semi-manual techniques with desktop central processing unit (CPU) runtimes faster than acquisition time for up to hundreds of electrodes. Moreover, a single choice of parameters in the algorithm is effective for a variety of electrode geometries and across multiple brain regions. This algorithm has the potential to enable reproducible and automated spike sorting of larger scale recordings than is currently possible.

While ongoing experience proceeds continuously, memories of past experience are often recalled as episodes with defined beginnings and ends. The neural mechanisms that lead to the formation of discrete episodes from the stream of neural activity patterns representing ongoing experience are unknown. To investigate these mechanisms, we recorded neural activity in the rat hippocampus and prefrontal cortex, structures critical for memory processes. We show that during spatial navigation, hippocampal CA1 place cells maintain a continuous spatial representation across different states of motion (movement and immobility). In contrast, during sharp-wave ripples (SWRs), when representations of experience are transiently reactivated from memory, movement- and immobility-associated activity patterns are most often reactivated separately. Concurrently, distinct hippocampal reactivations of movement- or immobility-associated representations are accompanied by distinct modulation patterns in prefrontal cortex. These findings demonstrate a continuous representation of ongoing experience can be separated into independently reactivated memory representations.

How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion., The hippocampus is essential for memory and spatial navigation, but we still do not know how these cognitive functions are made possible by the hippocampal neural circuit. Examination of hippocampal [...]

Objective: Radiation necrosis is becoming an increasingly prevalent complication in patients with brain tumors given the growing utility of stereotactic radiosurgery in modern treatment paradigms. Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive modality that has exhibited an efficacy comparable to craniotomy in treating radiation necrosis. No studies to date have compared their cost-effectiveness despite the significant additional expenses associated with MRgLITT use. This study aimed to evaluate the cost-effectiveness of MRgLITT versus craniotomy in patients with comparable presentations of radiation necrosis., Methods: The National Inpatient Sample (NIS) was queried from 2011 to 2020 for patients with radiation necrosis and treated using craniotomy or MRgLITT. Admission charges and costs were inflation adjusted to 2020 $US. Surgical cohorts were propensity score-matched according to demographic, clinical, and admission characteristics. Multivariable linear and logistic regression analyses identified associations between type of intervention and outcomes. A semi-Markov model was created to simulate treatment with craniotomy versus MRgLITT. Cost, transition probabilities, and health state utilities were derived from the NIS, individual patient outcomes from multiple institutions, and prospectively collected quality-of-life data from a single institution and verified against other studies. Monte Carlo simulation and probabilistic sensitivity analysis were used to evaluate the cost-effectiveness between the two modalities., Results: In the designated study period, 2869 patients had been admitted with brain tumor radiation necrosis and were managed with neurosurgical intervention. After propensity score matching, MRgLITT, relative to craniotomy, was independently associated with a shorter length of stay (LOS; β = -1.81, p = 0.002), lower odds of complications (OR 0.18, p = 0.033), and higher odds of home discharge (OR 3.05, p = 0.041), but there was no difference in total admission costs between the two modalities (β = $6229, p = 0.081). On Monte Carlo simulation, patients treated with MRgLITT had a lower probability of disease (radiation necrosis or tumor) recurrence (13.5% vs 22.0%, p < 0.001) but an equivalent mortality risk (22.8% vs 22.3%, p = 0.429) compared to the patients treated with craniotomy at the 1-year follow-up. Over a 4-year time horizon, MRgLITT had an incremental cost of -$25,685 and incremental effectiveness of 0.14 quality-adjusted life-year (QALY), resulting in an incremental cost-effectiveness ratio of -$183,464 per QALY relative to craniotomy., Conclusions: MRgLITT was a more cost-effective treatment strategy than craniotomy in the management of patients with brain tumor radiation necrosis. The cost-effectiveness of MRgLITT may be attributed to a shorter LOS, lower complication odds, and higher home discharge odds in the immediate postoperative period and a lower risk of disease recurrence over the long-term follow-up.

Objective: Broca's aphasia is a syndrome of impaired fluency with retained comprehension. The authors used an unbiased algorithm to examine which neuroanatomical areas are most likely to result in Broca's aphasia following surgical lesions., Methods: Patients were prospectively evaluated with standardized language batteries before and after surgery. Broca's area was defined anatomically as the pars opercularis and triangularis of the inferior frontal gyrus. Broca's aphasia was defined by the Western Aphasia Battery language assessment. Resections were outlined from MRI scans to construct 3D volumes of interest. These were aligned using a nonlinear transformation to Montreal Neurological Institute brain space. A voxel-based lesion-symptom mapping (VLSM) algorithm was used to test for areas statistically associated with Broca's aphasia when incorporated into a resection, as well as areas associated with deficits in fluency independent of Western Aphasia Battery classification. Postoperative MRI scans were reviewed in blinded fashion to estimate the percentage resection of Broca's area compared to areas identified using the VLSM algorithm., Results: A total of 289 patients had early language evaluations, of whom 19 had postoperative Broca's aphasia. VLSM analysis revealed an area that was highly correlated (p < 0.001) with Broca's aphasia, spanning ventral sensorimotor cortex and supramarginal gyri, as well as extending into subcortical white matter tracts. Reduced fluency scores were significantly associated with an overlapping region of interest. The fluency score was negatively correlated with fraction of resected precentral, postcentral, and supramarginal components of the VLSM area., Conclusions: Broca's aphasia does not typically arise from neurosurgical resections in Broca's area. When Broca's aphasia does occur after surgery, it is typically in the early postoperative period, improves by 1 month, and is associated with resections of ventral sensorimotor cortex and supramarginal gyri.

Measuring electrical potentials in the extracellular space of the brain is a popular technique because it can detect action potentials from putative individual neurons. Electrophysiology is undergoing a transformation where the number of recording channels, and thus number of neurons detected, is growing at a dramatic rate. This rapid scaling is paving the way for both new discoveries and commercial applications; however, as the number of channels increases there will be an increasing need to make these systems more power efficient. One area ripe for optimization are the signal acquisition specifications needed to detect and sort action potentials (i.e., "spikes") to putative single neuron sources. In this work, we take existing recordings collected using Intan hardware and modify them in a way that corresponds to reduced recording performance. The accuracy of these degraded recordings to spike sort using MountainSort4 is evaluated by comparing against expert labels. We show that despite reducing signal specifications by a factor of 2 or more, spike sorting accuracy does not change substantially. Specifically, reducing both sample rate and bit depth from 30 kHz and 16 bits to 12 kHz and 12 bits resulted in a 3% drop in spike sorting accuracy. Our results suggest that current neural acquisition systems are over-specified. These results may inform the design of next generation neural acquisition systems enabling higher channel count systems.

Objective. Intracranial neural recordings and electrical stimulation are tools used in an increasing range of applications, including intraoperative clinical mapping and monitoring, therapeutic neuromodulation, and brain computer interface control and feedback. However, many of these applications suffer from a lack of spatial specificity and localization, both in terms of sensed neural signal and applied stimulation. This stems from limited manufacturing processes of commercial-off-the-shelf (COTS) arrays unable to accommodate increased channel density, higher channel count, and smaller contact size. Approach. Here, we describe a manufacturing and assembly approach using thin-film microfabrication for 32-channel high density subdural micro-electrocorticography ( µ ECoG) surface arrays (contacts 1.2 mm diameter, 2 mm pitch) and intracranial electroencephalography (iEEG) depth arrays (contacts 0.5 mm × 1.5 mm, pitch 0.8 mm × 2.5 mm). Crucially, we tackle the translational hurdle and test these arrays during intraoperative studies conducted in four humans under regulatory approval. Main results. We demonstrate that the higher-density contacts provide additional unique information across the recording span compared to the density of COTS arrays which typically have electrode pitch of 8 mm or greater; 4 mm in case of specially ordered arrays. Our intracranial stimulation study results reveal that refined spatial targeting of stimulation elicits evoked potentials with differing spatial spread. Significance. Thin-film, μ ECoG and iEEG depth arrays offer a promising substrate for advancing a number of clinical and research applications reliant on high-resolution neural sensing and intracranial stimulation., (© 2021 IOP Publishing Ltd.)

The brain is a massively interconnected network of specialized circuits. Even primary sensory areas, once thought to support relatively simple, feed-forward processing, are now known to be parts of complex feedback circuits. All brain functions depend on millisecond timescale interactions across these brain networks. Current approaches cannot measure or manipulate such large-scale interactions. Here we demonstrate that polymer-based, penetrating, micro-electrode arrays can provide high quality neural recordings from awake, behaving animals over periods of months. Our results indicate that polymer electrodes are a viable substrate for the development of systems that can record from thousands of channels across months to years. This is our first step towards developing a 1000+ electrode system capable of providing high-quality, long-term neural recordings.