Aberrant fast spiking interneuronal activity precedes seizure transitions in humans.

There is active debate regarding how GABAergic function changes during seizure initiation and propagation, and whether interneuronal activity drives or impedes the pathophysiology. Here, we track cell-type specific firing during spontaneous human seizures to identify neocortical mechanisms of inhibitory failure. Fast-spiking interneuron activity was maximal over 1 second before equivalent excitatory increases, and showed transitions to out-of-phase firing prior to local tissue becoming incorporated into the seizure-driving territory. Using computational modeling, we linked this observation to transient saturation block as a precursor to seizure invasion, as supported by multiple lines of evidence in the patient data. We propose that transient blocking of inhibitory firing due to selective fast-spiking interneuron saturation-resulting from intense excitatory synaptic drive-is a novel mechanism that contributes to inhibitory failure, allowing seizure propagation.

A Novel Quantitative Metric Based on a Complete and Unique Characterization of Neural Network Activity: 4D Shannon's Entropy.

The human brain comprises an intricate web of connections that generate complex neural networks capable of storing and processing information. This information depends on multiple factors, including underlying network structure, connectivity, and interactions; and thus, methods to characterize neural networks typically aim to unravel and interpret a combination of these factors. Here, we present four-dimensional (4D) Shannon's entropy, a novel quantitative metric of network activity based on the Triple Correlation Uniqueness (TCU) theorem. Triple correlation, which provides a complete and unique characterization of the network, relates three nodes separated by up to four spatiotemporal lags. Here, we evaluate the 4D entropy from the spatiotemporal lag probability distribution function (PDF) of the network activity's triple correlation. Given a spike raster, we compute triple correlation by iterating over time and space. Summing the contributions to the triple correlation over each of the spatial and temporal lag combinations generates a unique 4D spatiotemporal lag distribution, from which we estimate a PDF and compute Shannon's entropy. To outline our approach, we first compute 4D Shannon's entropy from feedforward motif-class patterns in a simulated spike raster. We then apply this methodology to spiking activity recorded from rat cortical cultures to compare our results to previously published results of pairwise (2D) correlated spectral entropy over time. We find that while first- and second-order metrics of activity (spike rate and cross-correlation) show agreement with previously published results, our 4D entropy computation (which also includes third-order interactions) reveals a greater depth of underlying network organization compared to published pairwise entropy. Ultimately, because our approach is based on the TCU, we propose that 4D Shannon's entropy is a more complete tool for neural network characterization.

Spatiotemporal spike-centered averaging reveals symmetry of temporal and spatial components of the spike-LFP relationship during human focal seizures.

The electrographic manifestation of neural activity can reflect the relationship between the faster action potentials of individual neurons and the slower fluctuations of the local field potential (LFP). This relationship is typically examined in the temporal domain using the spike-triggered average. In this study, we add a spatial component to this relationship. Here we first derive a theoretical model of the spike-LFP relationship across a macroelectrode. This mathematical derivation showed a special symmetry in the spike-LFP relationship wherein a sinc function in the temporal domain predicts a sinc function in the spatial domain. We show that this theoretical result is observed in a real-world system by characterizing the spike-LFP relationship using microelectrode array (MEA) recordings of human focal seizures. To do this, we present a approach, termed the spatiotemporal spike-centered average (st-SCA), that allows for visualization of the spike-LFP relationship in both the temporal and spatial domains. We applied this method to 25 MEA recordings obtained from seven patients with pharmacoresistant focal epilepsy. Of the five patients with MEAs implanted in recruited territory, three exhibited spatiotemporal patterns consistent with a sinc function, and two exhibited spatiotemporal patterns resembling deep wells of excitation. These results suggest that in some cases characterization of the spike-LFP relationship in the temporal domain is sufficient to predict the underlying spatial pattern. Finally, we discuss the biological interpretation of these findings and propose that the sinc function may reflect the role of mid-range excitatory connections during seizure activity.

Third-order motifs are sufficient to fully and uniquely characterize spatiotemporal neural network activity.

Neuroscientific analyses balance between capturing the brain's complexity and expressing that complexity in meaningful and understandable ways. Here we present a novel approach that fully characterizes neural network activity and does so by uniquely transforming raw signals into easily interpretable and biologically relevant metrics of network behavior. We first prove that third-order (triple) correlation describes network activity in its entirety using the triple correlation uniqueness theorem. Triple correlation quantifies the relationships among three events separated by spatial and temporal lags, which are triplet motifs. Classifying these motifs by their event sequencing leads to fourteen qualitatively distinct motif classes that embody well-studied network behaviors including synchrony, feedback, feedforward, convergence, and divergence. Within these motif classes, the summed triple correlations provide novel metrics of network behavior, as well as being inclusive of commonly used analyses. We demonstrate the power of this approach on a range of networks with increasingly obscured signals, from ideal noiseless simulations to noisy experimental data. This approach can be easily applied to any recording modality, so existing neural datasets are ripe for reanalysis. Triple correlation is an accessible signal processing tool with a solid theoretical foundation capable of revealing previously elusive information within recordings of neural networks.

PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS.

Peripheral nervous system (PNS) neurons support axon regeneration into adulthood, whereas central nervous system (CNS) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3-kinase (PI3K) and its product phosphatidylinositol (3,4,5)-trisphosphate (PIP3 ). We demonstrate that adult PNS neurons utilise two catalytic subunits of PI3K for axon regeneration: p110α and p110δ. However, in the CNS, axonal PIP3 decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in CNS neurons had no effect; however, expression of p110δ restored axonal PIP3 and increased regenerative axon transport. p110δ expression enhanced CNS regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal PIP3 as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.

Expression of Developmentally Important Axon Guidance Cues in the Adult Optic Chiasm.

Purpose: Regeneration of optic nerve axons after injury can be facilitated by several approaches, but misguidance at the optic chiasm is often observed. We characterized guidance cues in the embryonic visual system and adult optic chiasm before and after optic nerve crush (ONC) injury to better understand barriers to optic nerve regeneration in adults. Methods: Radial glial (RC2/BLBP/Slit1), developmental (Pax2) and extracellular markers (CSPG: H2B/CS-56) were assessed in C57BL/6J mice by immunohistochemistry. RC2, BLBP, Slit1, and CSPG are known inhibitory guidance cues while Pax2 is a permissive guidance cue. Results: At embryonic day 15.5 (E.15.5), RC2 and BLBP were identified superior to, and extending through, the optic chiasm. The optic chiasm was BLBP-ve in adult uninjured mice but BLBP+ve in adult mice 10 days after ONC injury. The reverse was true for RC2. Both BLBP and RC2 were absent in adult mice 6 weeks post-ONC. Slit1 was present in the optic chiasm midline and optic tracts in embryonic samples but was absent in uninjured adult tissue. Slit1 was observed superior to and at the midline of the optic chiasm 10 days post-ONC but absent 6 weeks after injury. Pax2 was expressed at the junction between the optic nerve and optic chiasm in embryonic brain tissue. In embryonic sections, CS-56 was observed at the junction between the optic chiasm and optic tract, and immediately superior to the optic chiasm. Both 2H6 and CS-56 staining was absent in uninjured and ONC-injured adult brains. Conclusion: Differences in guidance cue expression during development, in adulthood and after injury may contribute to misguidance of regenerating RGC axons in the adult optic chiasm.

Evaluating intraocular pressure-lowering solutions for the treatment of open-angle glaucoma: comparison between bimatoprost 0.03% and bimatoprost 0.01% - an observational switch study.

PURPOSE: The purpose of this study is to evaluate the intraocular pressure (IOP)-lowering efficacy of bimatoprost 0.01% solution in patients with primary open-angle glaucoma (POAG), who were switched from bimatoprost 0.03% solution, compared to patients with POAG who continued on bimatoprost 0.03% solution. METHODS: A retrospective review evaluated 35 patients (35 right eyes [OD], 34 left eyes [OS]) who remained on bimatoprost 0.03% and 30 patients (27 OD, 30 OS) who were switched to bimatoprost 0.01% during the period January 8, 2010 to December 26, 2012. Mean IOP was measured 6 and 3 months before the switch, at switch, and 3, 6, and 12 months after the switch. Hyperemia scores were recorded before and after the switch and were compared to a picture scale. RESULTS: Mean IOP in the group that switched was 16.96±5.03 mmHg in OD and 17.67±5.33 mmHg in OS at baseline. Mean IOP postswitch to bimatoprost 0.01% solution was 17.60±4.34 mmHg in OD and 17.00±3.37 mmHg in OS. IOP was not significantly reduced in either OD or OS postswitch to bimatoprost 0.01% (P1=0.5 OD, P2=0.2 OS). The hyperemia scores improved remarkably when bimatoprost 0.03% solution was switched to bimatoprost 0.01% solution (P<0.001). CONCLUSION: To our knowledge, this is the first switch study evaluating the hypotensive efficacy and tolerability of bimatoprost in a group of patients with open-angle glaucoma. In this study comparing bimatoprost 0.03% and 0.01% solution, we found improved tolerability postswitch to 0.01% from 0.03% bimatoprost, similar efficacy between the two concentrations before and after switch in the same patient population, and similar IOPs comparable to nonswitch bimatoprost 0.03% solution.