Months-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes.

We introduce Ultra-Flexible Tentacle Electrodes (UFTEs), packing many independent fibers with the smallest possible footprint without limitation in recording depth using a combination of mechanical and chemical tethering for insertion. We demonstrate a scheme to implant UFTEs simultaneously into many brain areas at arbitrary locations without angle-of-insertion limitations, and a 512-channel wireless logger. Immunostaining reveals no detectable chronic tissue damage even after several months. Mean spike signal-to-noise ratios are 1.5-3x compared to the state-of-the-art, while the highest signal-to-noise ratios reach 89, and average cortical unit yields are ~1.75/channel. UFTEs can track the same neurons across sessions for at least 10 months (longest duration tested). We tracked inter- and intra-areal neuronal ensembles (neurons repeatedly co-activated within 25 ms) simultaneously from hippocampus, retrosplenial cortex, and medial prefrontal cortex in freely moving rodents. Average ensemble lifetimes were shorter than the durations over which we can track individual neurons. We identify two distinct classes of ensembles. Those tuned to sharp-wave ripples display the shortest lifetimes, and the ensemble members are mostly hippocampal. Yet, inter-areal ensembles with members from both hippocampus and cortex have weak tuning to sharp wave ripples, and some have unusual months-long lifetimes. Such inter-areal ensembles occasionally remain inactive for weeks before re-emerging.

Top-down modulation of visual cortical stimulus encoding and gamma independent of firing rates.

Neurons in primary visual cortex integrate sensory input with signals reflecting the animal's internal state to support flexible behavior. Internal variables, such as expectation, attention, or current goals, are imposed in a top-down manner via extensive feedback projections from higher-order areas. We optogenetically activated a high-order visual area, area 21a, in the lightly anesthetized cat (OptoTD), while recording from neuronal populations in V1. OptoTD induced strong, up to several fold, changes in gamma-band synchronization together with much smaller changes in firing rate, and the two effects showed no correlation. OptoTD effects showed specificity for the features of the simultaneously presented visual stimuli. OptoTD-induced changes in gamma synchronization, but not firing rates, were predictive of simultaneous changes in the amount of encoded stimulus information. Our findings suggest that one important role of top-down signals is to modulate synchronization and the information encoded by populations of sensory neurons.

Centripetal integration of past events in hippocampal astrocytes regulated by locus coeruleus.

An essential feature of neurons is their ability to centrally integrate information from their dendrites. The activity of astrocytes, in contrast, has been described as mostly uncoordinated across cellular compartments without clear central integration. Here we report conditional integration of calcium signals in astrocytic distal processes at their soma. In the hippocampus of adult mice of both sexes, we found that global astrocytic activity, as recorded with population calcium imaging, reflected past neuronal and behavioral events on a timescale of seconds. Salient past events, indicated by pupil dilations, facilitated the propagation of calcium signals from distal processes to the soma. Centripetal propagation to the soma was reproduced by optogenetic activation of the locus coeruleus, a key regulator of arousal, and reduced by pharmacological inhibition of α1-adrenergic receptors. Together, our results suggest that astrocytes are computational units of the brain that slowly and conditionally integrate calcium signals upon behaviorally relevant events.

Recording Quality Is Systematically Related to Electrode Impedance.

Extracellular recordings with planar microelectrodes are the gold standard technique for recording the fast action potentials of neurons in the intact brain. The introduction of microfabrication techniques has revolutionized the in vivo recording of neuronal activity and introduced high-density, multi-electrode arrays that increase the spatial resolution of recordings and the number of neurons that can be simultaneously recorded. Despite these innovations, there is still debate about the ideal electrical transfer characteristics of extracellular electrodes. This uncertainty is partly due to the lack of systematic studies comparing electrodes with different characteristics, particularly for chronically implanted arrays over extended time periods. Here a high-density, flexible, and thin-film array is fabricated and tested, containing four distinct electrode types differing in surface material and surface topology and, thus, impedance. It is found that recording quality is strongly related to electrode impedance with signal amplitude and unit yield negatively correlated to impedance. Electrode impedances are stable for the duration of the experiment (up to 12 weeks) and recording quality does not deteriorate. The findings support the expectation from the theory that recording quality will increase as impedance decreases.

Linking brain activity across scales with simultaneous opto- and electrophysiology.

The brain enables adaptive behavior via the dynamic coordination of diverse neuronal signals across spatial and temporal scales: from fast action potential patterns in microcircuits to slower patterns of distributed activity in brain-wide networks. Understanding principles of multiscale dynamics requires simultaneous monitoring of signals in multiple, distributed network nodes. Combining optical and electrical recordings of brain activity is promising for collecting data across multiple scales and can reveal aspects of coordinated dynamics invisible to standard, single-modality approaches. We review recent progress in combining opto- and electrophysiology, focusing on mouse studies that shed new light on the function of single neurons by embedding their activity in the context of brain-wide activity patterns. Optical and electrical readouts can be tailored to desired scales to tackle specific questions. For example, fast dynamics in single cells or local populations recorded with multi-electrode arrays can be related to simultaneously acquired optical signals that report activity in specified subpopulations of neurons, in non-neuronal cells, or in neuromodulatory pathways. Conversely, two-photon imaging can be used to densely monitor activity in local circuits while sampling electrical activity in distant brain areas at the same time. The refinement of combined approaches will continue to reveal previously inaccessible and under-appreciated aspects of coordinated brain activity.

The diversity and specificity of functional connectivity across spatial and temporal scales.

Macroscopic neuroimaging modalities in humans have revealed the organization of brain-wide activity into distributed functional networks that re-organize according to behavioral demands. However, the inherent coarse-graining of macroscopic measurements conceals the diversity and specificity in responses and connectivity of many individual neurons contained in each local region. New invasive approaches in animals enable recording and manipulating neural activity at meso- and microscale resolution, with cell-type specificity and temporal precision down to milliseconds. Determining how brain-wide activity patterns emerge from interactions across spatial and temporal scales will allow us to identify the key circuit mechanisms contributing to global brain states and how the dynamic activity of these states enables adaptive behavior.

Opto-E-Dura: A Soft, Stretchable ECoG Array for Multimodal, Multiscale Neuroscience.

Soft, stretchable materials hold great promise for the fabrication of biomedical devices due to their capacity to integrate gracefully with and conform to biological tissues. Conformal devices are of particular interest in the development of brain interfaces where rigid structures can lead to tissue damage and loss of signal quality over the lifetime of the implant. Interfaces to study brain function and dysfunction increasingly require multimodal access in order to facilitate measurement of diverse physiological signals that span the disparate temporal and spatial scales of brain dynamics. Here the Opto-e-Dura, a soft, stretchable, 16-channel electrocorticography array that is optically transparent is presented. Its compatibility with diverse optical and electrical readouts is demonstrated enabling multimodal studies that bridge spatial and temporal scales. The device is chronically stable for weeks, compatible with wide-field and 2-photon calcium imaging and permits the repeated insertion of penetrating multielectrode arrays. As the variety of sensors and effectors realizable on soft, stretchable substrates expands, similar devices that provide large-scale, multimodal access to the brain will continue to improve fundamental understanding of brain function.

Stimulus-induced visual cortical networks are recapitulated by spontaneous local and interareal synchronization.

Intrinsic covariation of brain activity has been studied across many levels of brain organization. Between visual areas, neuronal activity covaries primarily among portions with similar retinotopic selectivity. We hypothesized that spontaneous interareal coactivation is subserved by neuronal synchronization. We performed simultaneous high-density electrocorticographic recordings across the dorsal aspect of several visual areas in one hemisphere in each of two awake monkeys to investigate spatial patterns of local and interareal synchronization. We show that stimulation-induced patterns of interareal coactivation were reactivated in the absence of stimulation for the visual quadrant covered. Reactivation occurred through both interareal cofluctuation of local activity and interareal phase synchronization. Furthermore, the trial-by-trial covariance of the induced responses recapitulated the pattern of interareal coupling observed during stimulation, i.e., the signal correlation. Reactivation-related synchronization showed distinct peaks in the theta, alpha, and gamma frequency bands. During passive states, this rhythmic reactivation was augmented by specific patterns of arrhythmic correspondence. These results suggest that networks of intrinsic covariation observed at multiple levels and with several recording techniques are related to synchronization and that behavioral state may affect the structure of intrinsic dynamics.

Individual variability in functional connectivity predicts performance of a perceptual task.

People differ in their ability to perform novel perceptual tasks, both during initial exposure and in the rate of improvement with practice. It is also known that regions of the brain recruited by particular tasks change their activity during learning. Here we investigate neural signals predictive of individual variability in performance. We used resting-state functional MRI to assess functional connectivity before training on a novel visual discrimination task. Subsequent task performance was related to functional connectivity measures within portions of visual cortex and between visual cortex and prefrontal association areas. Our results indicate that individual differences in performing novel perceptual tasks can be related to individual differences in spontaneous cortical activity.

Increased functional connectivity indicates the severity of cognitive impairment in multiple sclerosis.

Correlations in spontaneous brain activity provide powerful access to large-scale organizational principles of the CNS. However, making inferences about cognitive processes requires a detailed understanding of the link between these couplings and the structural integrity of the CNS. We studied the impact of multiple sclerosis, which leads to the severe disintegration of the central white matter, on functional connectivity patterns in spontaneous cortical activity. Using a data driven approach based on the strength of a salient pattern of cognitive pathology, we identified distinct networks that exhibit increases in functional connectivity despite the presence of strong and diffuse reductions of the central white-matter integrity. The default mode network emerged as a core target of these connectivity modulations, showing enhanced functional coupling in bilateral inferior parietal cortex, posterior cingulate, and medial prefrontal cortex. These findings imply a complex and diverging relation of anatomical and functional connectivity in early multiple sclerosis and, thus, add an important observation for understanding how cognitive abilities and CNS integrity may be reflected in the intrinsic covariance of functional signals.

Learning sculpts the spontaneous activity of the resting human brain.

The brain is not a passive sensory-motor analyzer driven by environmental stimuli, but actively maintains ongoing representations that may be involved in the coding of expected sensory stimuli, prospective motor responses, and prior experience. Spontaneous cortical activity has been proposed to play an important part in maintaining these ongoing, internal representations, although its functional role is not well understood. One spontaneous signal being intensely investigated in the human brain is the interregional temporal correlation of the blood-oxygen level-dependent (BOLD) signal recorded at rest by functional MRI (functional connectivity-by-MRI, fcMRI, or BOLD connectivity). This signal is intrinsic and coherent within a number of distributed networks whose topography closely resembles that of functional networks recruited during tasks. While it is apparent that fcMRI networks reflect anatomical connectivity, it is less clear whether they have any dynamic functional importance. Here, we demonstrate that visual perceptual learning, an example of adult neural plasticity, modifies the resting covariance structure of spontaneous activity between networks engaged by the task. Specifically, after intense training on a shape-identification task constrained to one visual quadrant, resting BOLD functional connectivity and directed mutual interaction between trained visual cortex and frontal-parietal areas involved in the control of spatial attention were significantly modified. Critically, these changes correlated with the degree of perceptual learning. We conclude that functional connectivity serves a dynamic role in brain function, supporting the consolidation of previous experience.