Axonal velocity distributions in neural feld equations

By modelling the average activity of large neuronal populations, continuum mean field models (MFMs) have become an increasingly important theoretical tool for understanding the emergent activity of cortical tissue. In order to be computationally tractable, long-range propagation of activity in MFMs is often approximated with partial differential equations (PDEs). However, PDE approximations in current use correspond to underlying axonal velocity distributions incompatible with experimental measurements. In order to rectify this deficiency, we here introduce novel propagation PDEs that give rise to smooth unimodal distributions of axonal conduction velocities. We also argue that velocities estimated from fibre diameters in slice and from latency measurements, respectively, relate quite differently to such distributions, a significant point for any phenomenological description. Our PDEs are then successfully fit to fibre diameter data from human corpus callosum and rat subcortical white matter. This allows for the first time to simulate long-range conduction in the mammalian brain with realistic, convenient PDEs. Furthermore, the obtained results suggest that the propagation of activity in rat and human differs significantly beyond mere scaling. The dynamical consequences of our new formulation are investigated in the context of a well known neural field model. On the basis of Turing instability analyses, we conclude that pattern formation is more easily initiated using our more realistic propagator. By increasing characteristic conduction velocities, a smooth transition can occur from self-sustaining bulk oscillations to travelling waves of various wavelengths, which may influence axonal growth during development. Our analytic results are also corroborated numerically using simulations on a large spatial grid. Thus we provide here a comprehensive analysis of empirically constrained activity propagation in the context of MFMs, which will allow more realistic studies of mammalian brain activity in the future.

Modulation of visually evoked cortical fMRI responses by phase of ongoing occipital alpha oscillations

Using simultaneous electroencephalography as a measure of ongoing activity and functional magnetic resonance imaging (fMRI) as a measure of the stimulus-driven neural response, we examined whether the amplitude and phase of occipital alpha oscillations at the onset of a brief visual stimulus affects the amplitude of the visually evoked fMRI response. When accounting for intrinsic coupling of alpha amplitude and occipital fMRI signal by modeling and subtracting pseudo-trials, no significant effect of prestimulus alpha amplitude on the evoked fMRI response could be demonstrated. Regarding the effect of alpha phase, we found that stimuli arriving at the peak of the alpha cycle yielded a lower blood oxygenation level-dependent (BOLD) fMRI response in early visual cortex (V1/V2) than stimuli presented at the trough of the cycle. Our results therefore show that phase of occipital alpha oscillations impacts the overall strength of a visually evoked response, as indexed by the BOLD signal. This observation complements existing evidence that alpha oscillations reflect periodic variations in cortical excitability and suggests that the phase of oscillations in postsynaptic potentials can serve as a mechanism of gain control for incoming neural activity. Finally, our findings provide a putative neural basis for observations of alpha phase dependence of visual perceptual performance.

Endogenous cholinergic tone modulates spontaneous network level neuronal activity in primary cortical cultures grown on multi-electrode arrays

Background Cortical cultures grown long-term on multi-electrode arrays (MEAs) are frequently and extensively used as models of cortical networks in studies of neuronal firing activity, neuropharmacology, toxicology and mechanisms underlying synaptic plasticity. However, in contrast to the predominantly asynchronous neuronal firing activity exhibited by intact cortex, electrophysiological activity of mature cortical cultures is dominated by spontaneous epileptiform-like global burst events which hinders their effective use in network-level studies, particularly for neurally-controlled animat (‘artificial animal’) applications. Thus, the identification of culture features that can be exploited to produce neuronal activity more representative of that seen in vivo could increase the utility and relevance of studies that employ these preparations. Acetylcholine has a recognised neuromodulatory role affecting excitability, rhythmicity, plasticity and information flow in vivo although its endogenous production by cortical cultures and subsequent functional influence upon neuronal excitability remains unknown. Results Consequently, using MEA electrophysiological recording supported by immunohistochemical and RT-qPCR methods, we demonstrate for the first time, the presence of intrinsic cholinergic neurons and significant, endogenous cholinergic tone in cortical cultures with a characterisation of the muscarinic and nicotinic components that underlie modulation of spontaneous neuronal activity. We found that tonic muscarinic ACh receptor (mAChR) activation affects global excitability and burst event regularity in a culture age-dependent manner whilst, in contrast, tonic nicotinic ACh receptor (nAChR) activation can modulate burst duration and the proportion of spikes occurring within bursts in a spatio-temporal fashion. Conclusions We suggest that the presence of significant endogenous cholinergic tone in cortical cultures and the comparability of its modulatory effects to those seen in intact brain tissues support emerging, exploitable commonalities between in vivo and in vitro preparations. We conclude that experimental manipulation of endogenous cholinergic tone could offer a novel opportunity to improve the use of cortical cultures for studies of network-level mechanisms in a manner that remains largely consistent with its functional role.

Complex spatiotemporal haemodynamic response following sensory stimulation in the awake rat

Detailed understanding of the haemodynamic changes that underlie non-invasive neuroimaging techniques such as blood oxygen level dependent functional magnetic resonance imaging is essential if we are to continue to extend the use of these methods for understanding brain function and dysfunction. The use of animal and in particular rodent research models has been central to these endeavours as they allow in-vivo experimental techniques that provide measurements of the haemodynamic response function at high temporal and spatial resolution. A limitation of most of this research is the use of anaesthetic agents which may disrupt or mask important features of neurovascular coupling or the haemodynamic response function. In this study we therefore measured spatiotemporal cortical haemodynamic responses to somatosensory stimulation in awake rats using optical imaging spectroscopy. Trained, restrained animals received non-noxious stimulation of the whisker pad via chronically implanted stimulating microwires whilst optical recordings were made from the contralateral somatosensory cortex through a thin cranial window. The responses we measure from un-anaesthetised animals are substantially different from those reported in previous studies which have used anaesthetised animals. These differences include biphasic response regions (initial increases in blood volume and oxygenation followed by subsequent decreases) as well as oscillations in the response time series of awake animals. These haemodynamic response features do not reflect concomitant changes in the underlying neuronal activity and therefore reflect neurovascular or cerebrovascular processes. These hitherto unreported hyperemic response dynamics may have important implications for the use of anaesthetised animal models for research into the haemodynamic response function.

Infra-red laser ablative micromachining of parylene-C on SiO2substrates for rapid prototyping, high yield, human neuronal cell patterning

Cell patterning commonly employs photolithographic methods for the micro fabrication of structures on silicon chips. These require expensive photo-mask development and complex photolithographic processing. Laser based patterning of cells has been studied in vitro and laser ablation of polymers is an active area of research promising high aspect ratios. This paper disseminates how 800 nm femtosecond infrared (IR) laser radiation can be successfully used to perform laser ablative micromachining of parylene-C on SiO2 substrates for the patterning of human hNT astrocytes (derived from the human teratocarcinoma cell line (hNT)) whilst 248 nm nanosecond ultra-violet laser radiation produces photo-oxidization of the parylene-C and destroys cell patterning. In this work, we report the laser ablation methods used and the ablation characteristics of parylene-C for IR pulse fluences. Results follow that support the validity of using IR laser ablative micromachining for patterning human hNT astrocytes cells. We disseminate the variation in yield of patterned hNT astrocytes on parylene-C with laser pulse spacing, pulse number, pulse fluence and parylene-C strip width. The findings demonstrate how laser ablative micromachining of parylene-C on SiO2 substrates can offer an accessible alternative for rapid prototyping, high yield cell patterning with broad application to multi-electrode arrays, cellular micro-arrays and microfluidics.

Effects of parylene-C photooxidation on serum-assisted glial and neuronal patterning

The increasing use of patterned neural networks in multielectrode arrays and similar devices drives the constant development and evaluation of new biomaterials. Recently, we presented a promising technique to guide neurons and glia reliably and effectively. Parylene-C, a common hydrophobic polymer, was photolithographically patterned on silicon oxide (SiO2) and subsequently activated via immersion in serum. In this article, we explore the effects of ultraviolet (UV)-induced oxidation on parylene's ability to pattern neurons and glia. We exposed parylene-C stripe patterns to increasing levels of UV radiation and found a dose-dependent reduction in the total mass of patterned cells, as well as a gradual loss of glial and neuronal conformity to the patterns. In contrast, nonirradiated patterns had superior patterning results and increased presence of cells. The reduced cell adhesion and patterning after the formation of aldehyde and carboxyl groups on UV-radiated parylene-C supports our hypothesis that cell adhesion and growth on parylene is facilitated by hydrophobic adsorption of serum proteins. We conclude that unlike other cell patterning schemes, our technique does not rely on photooxidation of the polymer. Nonetheless, the precise control of oxygenated groups on parylene could pave the way for the differential binding of proteins and other molecules on the surface, aiding in the adhesion of alternative cell types. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010

Controlled adhesion and growth of long term glial and neuronal cultures on Parylene-C

This paper explores the long term development of networks of glia and neurons on patterns of Parylene-C on a SiO2 substrate. We harvested glia and neurons from the Sprague-Dawley (P1–P7) rat hippocampus and utilized an established cell patterning technique in order to investigate cellular migration, over the course of 3 weeks. This work demonstrates that uncontrolled glial mitosis gradually disrupts cellular patterns that are established early during culture. This effect is not attributed to a loss of protein from the Parylene-C surface, as nitrogen levels on the substrate remain stable over 3 weeks. The inclusion of the anti-mitotic cytarabine (Ara-C) in the culture medium moderates glial division and thus, adequately preserves initial glial and neuronal conformity to underlying patterns. Neuronal apoptosis, often associated with the use of Ara-C, is mitigated by the addition of brain derived neurotrophic factor (BDNF). We believe that with the right combination of glial inhibitors and neuronal promoters, the Parylene-C based cell patterning method can generate structured, active neural networks that can be sustained and investigated over extended periods of time. To our knowledge this is the first report on the concurrent application of Ara-C and BDNF on patterned cell cultures.

Complex dynamics in simple systems with periodic parameter oscillations

We study systems with periodically oscillating parameters that can give way to complex periodic or nonperiodic orbits. Performing the long time limit, we can define ergodic averages such as Lyapunov exponents, where a negative maximal Lyapunov exponent corresponds to a stable periodic orbit. By this, extremely complicated periodic orbits composed of contracting and expanding phases appear in a natural way. Employing the technique of ϵ-uncertain points, we find that values of the control parameters supporting such periodic motion are densely embedded in a set of values for which the motion is chaotic. When a tiny amount of noise is coupled to the system, dynamics with positive and with negative nontrivial Lyapunov exponents are indistinguishable. We discuss two physical systems, an oscillatory flow inside a duct and a dripping faucet with variable water supply, where such a mechanism seems to be responsible for a complicated alternation of laminar and turbulent phases.

High-speed Keck spectroscopy of flares and oscillations in AE Aquarii

Using high-time-resolution (72 ms) spectroscopy of AE Aqr obtained with LRIS on Keck II we have determined the spectrum and spectral evolution of a small flare. Continuum and integrated line fluxes in the flare spectrum are measured, and the evolution of the flare is parametrized for future comparison with detailed models of the flares. We find that the velocities of the flaring components are consistent with those previously reported for AE Aqr by Welsh, Horne & Gomer and Horne. The characteristics of the 33-s oscillations are investigated: we derive the oscillation amplitude spectrum, and from that determine the spectrum of the heated regions on the rotating white dwarf. Blackbody fits to the major and minor pulse spectra and an analysis of the emission-line oscillation properties highlight the shortfalls in the simple hotspot model for the oscillations.

Fireballs and oscillations in AE Aqr

From rapid spectroscopy of AE Aqr we determined the variable component of a flare spectrum. The hot spot model is inconsistent with the oscillation amplitude spectra, line oscillations require a more detailed model. This work will be submitted shortly to MNRAS.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Fibroblast growth factor 2 maintains the neurogenic capacity of embryonic neural progenitor cells in vitro but changes their neuronal subtype specification

Many in vitro systems used to examine multipotential neural progenitor cells (NPCs) rely on mitogens including fibroblast growth factor 2 (FGF2) for their continued expansion. However, FGF2 has also been shown to alter the expression of transcription factors (TFs) that determine cell fate. Here, we report that NPCs from the embryonic telencephalon grown without FGF2 retain many of their in vivo characteristics, making them a good model for investigating molecular mechanisms involved in cell fate specification and differentiation. However, exposure of cortical NPCs to FGF2 results in a profound change in the types of neurons generated, switching them from a glutamatergic to a GABAergic phenotype. This change closely correlates with the dramatic upregulation of TFs more characteristic of ventral telencephalic NPCs. In addition, exposure of cortical NPCs to FGF2 maintains their neurogenic potential in vitro, and NPCs spontaneously undergo differentiation following FGF2 withdrawal. These results highlight the importance of TFs in determining the types of neurons generated by NPCs in vitro. In addition, they show that FGF2, as well as acting as a mitogen, changes the developmental capabilities of NPCs. These findings have implications for the cell fate specification of in vitro-expanded NPCs and their ability to generate specific cell types for therapeutic applications. Disclosure of potential conflicts of interest is found at the end of this article.

Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability

Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg2+-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg2+-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg2+-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.

Oscillations in the open solar magnetic flux with a period of 1.68 years: imprint on galactic cosmic rays and implications for heliospheric shielding

An understanding of how the heliosphere modulates galactic cosmic ray (GCR) fluxes and spectra is important, not only for studies of their origin, acceleration and propagation in our galaxy, but also for predicting their effects (on technology and on the Earth’s environment and organisms) and for interpreting abundances of cosmogenic isotopes in meteorites and terrestrial reservoirs. In contrast to the early interplanetary measurements, there is growing evidence for a dominant role in GCR shielding of the total open magnetic flux, which emerges from the solar atmosphere and enters the heliosphere. In this paper, we relate a strong 1.68- year oscillation in GCR fluxes to a corresponding oscillation in the open solar magnetic flux and infer cosmic-ray propagation paths confirming the predictions of theories in which drift is important in modulating the cosmic ray flux.

Dayside ionospheric convection changes in response to long-period interplanetary Magnetic field oscillations: Determination of the ionospheric phase velocity

Ground magnetic field perturbations recorded by the CANOPUS magnetometer network in the 7 to 13 MLT sector are used to examine how reconfigurations of the dayside polar ionospheric flow take place in response to north-south changes of the IMF. During the 6-hour interval in question IMF Bz oscillates between ±7 nT with about a 1-hour period. Corresponding variations in the ground magnetic disturbance are observed which we infer are due to changes in ionospheric flow. Cross correlation of the data obtained from two ground stations at 73.5° magnetic latitude, but separated by ∼2 hours in MLT, shows that changes in the flow are initiated in the prenoon sector (∼10 MLT) and then spread outward toward dawn and dusk with a phase speed of ∼5 km s−1 over the longitude range ∼8 to 12 MLT, slowing to ∼2 km s−1 outside this range. Cross correlating the data from these ground stations with IMP 8 IMF Bz records produces a MLT variation in the ground response delay relative to the IMF which is compatible with these deduced phase speeds. We interpret these observations in terms of the ionospheric response to the onset, expansion and decay of magnetic reconnection at the dayside magnetopause.