Publications by authors named "Mark O Cunningham"

45 Publications

The role of astrocytes in seizure generation: insights from a novel in vitro seizure model based on mitochondrial dysfunction.

Brain 2019 02;142(2):391-411

Institute of Neuroscience, Newcastle University, The Medical School, Framlington Place, Newcastle upon Tyne, UK.

Approximately one-quarter of patients with mitochondrial disease experience epilepsy. Their epilepsy is often severe and resistant towards conventional antiepileptic drugs. Despite the severity of this epilepsy, there are currently no animal models available to provide a mechanistic understanding of mitochondrial epilepsy. We conducted neuropathological studies on patients with mitochondrial epilepsy and found the involvement of the astrocytic compartment. As a proof of concept, we developed a novel brain slice model of mitochondrial epilepsy by the application of an astrocytic-specific aconitase inhibitor, fluorocitrate, concomitant with mitochondrial respiratory inhibitors, rotenone and potassium cyanide. The model was robust and exhibited both face and predictive validity. We then used the model to assess the role that astrocytes play in seizure generation and demonstrated the involvement of the GABA-glutamate-glutamine cycle. Notably, glutamine appears to be an important intermediary molecule between the neuronal and astrocytic compartment in the regulation of GABAergic inhibitory tone. Finally, we found that a deficiency in glutamine synthetase is an important pathogenic process for seizure generation in both the brain slice model and the human neuropathological study. Our study describes the first model for mitochondrial epilepsy and provides a mechanistic insight into how astrocytes drive seizure generation in mitochondrial epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awy320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519661PMC
February 2019

Cannabis and epilepsy.

Pract Neurol 2018 Dec 18;18(6):465-471. Epub 2018 Oct 18.

School of Medicine, Discipline of Physiology, University of Dublin Trinity College, Dublin, Ireland.

Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs. It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in 2018 there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic. We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in 2019.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/practneurol-2018-002058DOI Listing
December 2018

On-Probe Neural Interface ASIC for Combined Electrical Recording and Optogenetic Stimulation.

IEEE Trans Biomed Circuits Syst 2018 06;12(3):576-588

Neuromodulation technologies are progressing from pacemaking and sensory operations to full closed-loop control. In particular, optogenetics-the genetic modification of light sensitivity into neural tissue allows for simultaneous optical stimulation and electronic recording. This paper presents a neural interface application-specified integrated circuit (ASIC) for intelligent optoelectronic probes. The architecture is designed to enable simultaneous optical neural stimulation and electronic recording. It provides four low noise (2.08  μV) recording channels optimized for recording local field potentials (LFPs) (0.1-300 Hz bandwidth, 5 mV range, sampled 10-bit@4 kHz), which are more stable for chronic applications. For stimulation, it provides six independently addressable optical driver circuits, which can provide both intensity (8-bit resolution across a 1.1 mA range) and pulse-width modulation for high-radiance light emitting diodes (LEDs). The system includes a fully digital interface using a serial peripheral interface (SPI) protocol to allow for use with embedded controllers. The SPI interface is embedded within a finite state machine (FSM), which implements a command interpreter that can send out LFP data whilst receiving instructions to control LED emission. The circuit has been implemented in a commercially available 0.35  μm CMOS technology occupying a 1.95 mm 1.10 mm footprint for mounting onto the head of a silicon probe. Measured results are given for a variety of bench-top, in vitro and in vivo experiments, quantifying system performance and also demonstrating concurrent recording and stimulation within relevant experimental models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBCAS.2018.2818818DOI Listing
June 2018

In vitro characterization of gamma oscillations in the hippocampal formation of the domestic chick.

Eur J Neurosci 2018 10 10;48(8):2807-2815. Epub 2018 Jan 10.

Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

Avian and mammalian brains have evolved independently from each other for about 300 million years. During that time, the hippocampal formation (HF) has diverged in morphology and cytoarchitecture, but seems to have conserved much of its function. It is therefore an open question how seemingly different neural organizations can generate the same function. A prominent feature of the mammalian hippocampus is that it generates different neural oscillations, including the gamma rhythm, which plays an important role in memory processing. In this study, we investigate whether the avian hippocampus also generates gamma oscillations, and whether similar pharmacological mechanisms are involved in this function. We investigated the existence of gamma oscillations in avian HF using in vitro electrophysiology in P0-P12 domestic chick (Gallus gallus domesticus) HF brain slices. Persistent gamma frequency oscillations were induced by the bath application of the cholinergic agonist carbachol, but not by kainate, a glutamate receptor agonist. Similar to other species, carbachol-evoked gamma oscillations were sensitive to GABA , AMPA/kainate and muscarinic (M1) receptor antagonism. Therefore, similar to mammalian species, muscarinic receptor-activated avian HF gamma oscillations may arise via a pyramidal-interneuron gamma (PING)-based mechanism. Gamma oscillations are most prominent in the ventromedial area of the hippocampal slices, and gamma power is reduced more laterally and dorsally in the HF. We conclude that similar micro-circuitry may exist in the avian and mammalian hippocampal formation, and this is likely to relate to the shared function of the two structures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.13773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220815PMC
October 2018

Enhanced interlaminar excitation or reduced superficial layer inhibition in neocortex generates different spike-and-wave-like electrographic events in vitro.

J Neurophysiol 2018 01 27;119(1):49-61. Epub 2017 Sep 27.

Hull York Medical School, University of York , Heslington , United Kingdom.

Acute in vitro models have revealed a great deal of information about mechanisms underlying many types of epileptiform activity. However, few examples exist that shed light on spike-and-wave (SpW) patterns of pathological activity. SpW are seen in many epilepsy syndromes, both generalized and focal, and manifest across the entire age spectrum. They are heterogeneous in terms of their severity, symptom burden, and apparent anatomical origin (thalamic, neocortical, or both), but any relationship between this heterogeneity and underlying pathology remains elusive. In this study we demonstrate that physiological delta-frequency rhythms act as an effective substrate to permit modeling of SpW of cortical origin and may help to address this issue. For a starting point of delta activity, multiple subtypes of SpW could be modeled computationally and experimentally by either enhancing the magnitude of excitatory synaptic events ascending from neocortical layer 5 to layers 2/3 or selectively modifying superficial layer GABAergic inhibition. The former generated SpW containing multiple field spikes with long interspike intervals, whereas the latter generated SpW with short-interval multiple field spikes. Both types had different laminar origins and each disrupted interlaminar cortical dynamics in a different manner. A small number of examples of human recordings from patients with different diagnoses revealed SpW subtypes with the same temporal signatures, suggesting that detailed quantification of the pattern of spikes in SpW discharges may be a useful indicator of disparate underlying epileptogenic pathologies. NEW & NOTEWORTHY Spike-and-wave-type discharges (SpW) are a common feature in many epilepsies. Their electrographic manifestation is highly varied, as are available genetic clues to associated underlying pathology. Using computational and in vitro models, we demonstrate that distinct subtypes of SpW are generated by lamina-selective disinhibition or enhanced interlaminar excitation. These subtypes could be detected in at least some noninvasive patient recordings, suggesting more detailed analysis of SpW may be useful in determining clinical pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/jn.00516.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5866469PMC
January 2018

A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

Cell Rep 2016 12;17(12):3269-3280

Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK. Electronic address:

The brain is made up of trillions of synaptic connections that together form neural networks needed for normal brain function and behavior. SLM2 is a member of a conserved family of RNA binding proteins, including Sam68 and SLM1, that control splicing of Neurexin1-3 pre-mRNAs. Whether SLM2 affects neural network activity is unknown. Here, we find that SLM2 levels are maintained by a homeostatic feedback control pathway that predates the divergence of SLM2 and Sam68. SLM2 also controls the splicing of Tomosyn2, LysoPLD/ATX, Dgkb, Kif21a, and Cask, each of which are important for synapse function. Cortical neural network activity dependent on synaptic connections between SLM2-expressing-pyramidal neurons and interneurons is decreased in Slm2-null mice. Additionally, these mice are anxious and have a decreased ability to recognize novel objects. Our data reveal a pathway of SLM2 homeostatic auto-regulation controlling brain network activity and behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2016.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199341PMC
December 2016

Neuronal oscillations: A physiological correlate for targeting mitochondrial dysfunction in neurodegenerative diseases?

Neuropharmacology 2016 Mar 28;102:48-58. Epub 2015 Oct 28.

Institute of Neuroscience, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

Increasingly in the realm of neurological disorders, particularly those involving neurodegeneration, mitochondrial dysfunction is emerging at the core of their pathogenic processes. Most of these diseases still lack effective treatment and are hampered by a shortfall in the development of novel medicines. Clearly new targets that translate well to the clinic are required. Physiological parameters in the form of neuronal network activity are increasingly being used as a therapeutic screening approach in drug development and disorders with mitochondrial dysfunction generally display neuronal network activity disturbance. However research directly linking the disturbances in neuronal network activity with mitochondrial dysfunction is only just starting to emerge. This review will summarize the breadth of knowledge linking neuronal network activity to mitochondrial dysfunction in neurodegenerative diseases and suggest potential avenues for exploration in respect to future drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2015.10.033DOI Listing
March 2016

Human brain slices for epilepsy research: Pitfalls, solutions and future challenges.

J Neurosci Methods 2016 Feb 3;260:221-32. Epub 2015 Oct 3.

Institute of Neuroscience, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

Increasingly, neuroscientists are taking the opportunity to use live human tissue obtained from elective neurosurgical procedures for electrophysiological studies in vitro. Access to this valuable resource permits unique studies into the network dynamics that contribute to the generation of pathological electrical activity in the human epileptic brain. Whilst this approach has provided insights into the mechanistic features of electrophysiological patterns associated with human epilepsy, it is not without technical and methodological challenges. This review outlines the main difficulties associated with working with epileptic human brain slices from the point of collection, through the stages of preparation, storage and recording. Moreover, it outlines the limitations, in terms of the nature of epileptic activity that can be observed in such tissue, in particular, the rarity of spontaneous ictal discharges, we discuss manipulations that can be utilised to induce such activity. In addition to discussing conventional electrophysiological techniques that are routinely employed in epileptic human brain slices, we review how imaging and multielectrode array recordings could provide novel insights into the network dynamics of human epileptogenesis. Acute studies in human brain slices are ultimately limited by the lifetime of the tissue so overcoming this issue provides increased opportunity for information gain. We review the literature with respect to organotypic culture techniques that may hold the key to prolonging the viability of this material. A combination of long-term culture techniques, viral transduction approaches and electrophysiology in human brain slices promotes the possibility of large scale monitoring and manipulation of neuronal activity in epileptic microcircuits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2015.09.021DOI Listing
February 2016

Epilepsy in adults with mitochondrial disease: A cohort study.

Ann Neurol 2015 Dec 17;78(6):949-57. Epub 2015 Nov 17.

Wellcome Trust Center for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom.

Objective: The aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.

Methods: We prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7-year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke-like episode, and death.

Results: Overall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke-like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).

Interpretation: Epilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke-like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737309PMC
December 2015

Ontogeny of kainate-induced gamma oscillations in the rat CA3 hippocampus in vitro.

Front Cell Neurosci 2015 20;9:195. Epub 2015 May 20.

INMED, INSERM U-901 Marseille, France ; Aix-Marseille University Marseille, France ; Laboratory of Neurobiology, Kazan Federal University Kazan, Russia.

GABAergic inhibition, which is instrumental in the generation of hippocampal gamma oscillations, undergoes significant changes during development. However, the development of hippocampal gamma oscillations remains largely unknown. Here, we explored the developmental features of kainate-induced oscillations (KA-Os) in CA3 region of rat hippocampal slices. Up to postnatal day P5, the bath application of kainate failed to evoke any detectable oscillations. KA-Os emerged by the end of the first postnatal week; these were initially weak, slow (20-25 Hz, beta range) and were poorly synchronized with CA3 units and synaptic currents. Local field potential (LFP) power, synchronization of units and frequency of KA-Os increased during the second postnatal week to attain gamma (30-40 Hz) frequency by P15-21. Both beta and gamma KA-Os are characterized by alternating sinks and sources in the pyramidal cell layer, likely generated by summation of the action potential-associated currents and GABAergic synaptic currents, respectively. Blockade of GABA(A) receptors with gabazine completely suppressed KA-Os at all ages indicating that GABAergic mechanisms are instrumental in their generation. Bumetanide, a NKCC1 chloride co-transporter antagonist which renders GABAergic responses inhibitory in the immature hippocampal neurons, failed to induce KA-Os at P2-4 indicating that the absence of KA-Os in neonates is not due to depolarizing actions of GABA. The linear developmental profile, electrographic features and pharmacological properties indicate that CA3 hippocampal beta and gamma KA-Os are fundamentally similar in their generative mechanisms and their delayed onset and developmental changes likely reflect the development of perisomatic GABAergic inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncel.2015.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438719PMC
June 2015

The contribution of raised intraneuronal chloride to epileptic network activity.

J Neurosci 2015 May;35(20):7715-26

Institute of Neuroscience, Medical School, Newcastle upon Tyne, NE2 4HH, United Kingdom, and

Altered inhibitory function is an important facet of epileptic pathology. A key concept is that GABAergic activity can become excitatory if intraneuronal chloride rises. However, it has proved difficult to separate the role of raised chloride from other contributory factors in complex network phenomena, such as epileptic pathology. Therefore, we asked what patterns of activity are associated with chloride dysregulation by making novel use of Halorhodopsin to load clusters of mouse pyramidal cells artificially with Cl(-). Brief (1-10 s) activation of Halorhodopsin caused substantial positive shifts in the GABAergic reversal potential that were proportional to the charge transfer during the illumination and in adult neocortical pyramidal neurons decayed with a time constant of τ = 8.0 ± 2.8s. At the network level, these positive shifts in EGABA produced a transient rise in network excitability, with many distinctive features of epileptic foci, including high-frequency oscillations with evidence of out-of-phase firing (Ibarz et al., 2010). We show how such firing patterns can arise from quite small shifts in the mean intracellular Cl(-) level, within heterogeneous neuronal populations. Notably, however, chloride loading by itself did not trigger full ictal events, even with additional electrical stimulation to the underlying white matter. In contrast, when performed in combination with low, subepileptic levels of 4-aminopyridine, Halorhodopsin activation rapidly induced full ictal activity. These results suggest that chloride loading has at most an adjunctive role in ictogenesis. Our simulations also show how chloride loading can affect the jitter of action potential timing associated with imminent recruitment to an ictal event (Netoff and Schiff, 2002).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.4105-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438123PMC
May 2015

Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease.

Neuropathol Appl Neurobiol 2016 Feb 30;42(2):180-93. Epub 2015 May 30.

Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.

Aims: Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA. Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ-aminobutyric acid (GABA)-ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease.

Methods: Histochemical, immunohistochemical and immunofluorescent assays were performed on post-mortem brain tissue from 10 patients and 10 age-matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABAergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring.

Results: We observed significant, global reductions in complex I expression within GABAergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344A>G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABAergic cell density showed a dramatic reduction in cell density suggesting interneurone loss.

Conclusions: We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/nan.12238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4772453PMC
February 2016

What is a seizure network? Very fast oscillations at the interface between normal and epileptic brain.

Adv Exp Med Biol 2014 ;813:71-80

IBM T.J. Watson Research Center, Yorktown Heights, NY, 10598, USA,

Although there is a great multiplicity of normal brain electrical activities, one can observe defined, relatively abrupt, transitions between apparently normal rhythms and clearly abnormal, higher amplitude, "epileptic" signals; transitions occur over tens of ms to many seconds. Transitional activity typically consists of low-amplitude very fast oscillations (VFO). Examination of this VFO provides insight into system parameters that differentiate the "normal" from the "epileptic." Remarkably, VFO in vitro is generated by principal neuron gap junctions, and occurs readily when chemical synapses are suppressed, tissue pH is elevated, and [Ca(2+)]o is low. Because VFO originates in principal cell axons that fire at high frequencies, excitatory synapses may experience short-term plasticity. If the latter takes the form of potentiation of recurrent synapses on principal cells, and depression of these on inhibitory interneurons, then the stage is set for synchronized bursting - if [Ca(2+)]o recovers sufficiently. Our hypothesis can be tested (in part) in patients, once it is possible to measure brain tissue parameters (pH, [Ca(2+)]o) simultaneously with ECoG.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-94-017-8914-1_6DOI Listing
November 2014

Peritumoral epilepsy: relating form and function for surgical success.

Epilepsy Behav 2014 Sep 2;38:53-61. Epub 2014 Jun 2.

Institute of Neuroscience, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

Seizures are a prominent symptom in patients with both primary and secondary brain tumors. Medical management of seizure control in this patient group is problematic as the mechanisms linking tumorigenesis and epileptogenesis are poorly understood. It is possible that several mechanisms contribute to tumor-associated epileptic zone formation. In this review, we discuss key candidates that may be implicated in peritumoral epileptogenesis and, in so doing, hope to highlight areas for future research. Furthermore, we summarize the current role of antiepileptic medications in this type of epilepsy and examine the changes in surgical practice which may lead to improved seizure rates after tumor surgery. Lastly, we speculate on possible future preoperative and intraoperative considerations for improving seizure control after tumor resection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2014.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265733PMC
September 2014

Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX): comparing multi-electrode recordings from simulated and biological mammalian cortical tissue.

Brain Struct Funct 2015 Jul 27;220(4):2333-53. Epub 2014 May 27.

School of Computing Science, Newcastle University, Claremont Tower, Newcastle upon Tyne, NE1 7RU, UK,

Local field potentials (LFPs) sampled with extracellular electrodes are frequently used as a measure of population neuronal activity. However, relating such measurements to underlying neuronal behaviour and connectivity is non-trivial. To help study this link, we developed the Virtual Electrode Recording Tool for EXtracellular potentials (VERTEX). We first identified a reduced neuron model that retained the spatial and frequency filtering characteristics of extracellular potentials from neocortical neurons. We then developed VERTEX as an easy-to-use Matlab tool for simulating LFPs from large populations (>100,000 neurons). A VERTEX-based simulation successfully reproduced features of the LFPs from an in vitro multi-electrode array recording of macaque neocortical tissue. Our model, with virtual electrodes placed anywhere in 3D, allows direct comparisons with the in vitro recording setup. We envisage that VERTEX will stimulate experimentalists, clinicians, and computational neuroscientists to use models to understand the mechanisms underlying measured brain dynamics in health and disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00429-014-0793-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481302PMC
July 2015

Gap junction networks can generate both ripple-like and fast ripple-like oscillations.

Eur J Neurosci 2014 Jan 14;39(1):46-60. Epub 2013 Oct 14.

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.

Fast ripples (FRs) are network oscillations, defined variously as having frequencies of > 150 to > 250 Hz, with a controversial mechanism. FRs appear to indicate a propensity of cortical tissue to originate seizures. Here, we demonstrate field oscillations, at up to 400 Hz, in spontaneously epileptic human cortical tissue in vitro, and present a network model that could explain FRs themselves, and their relation to 'ordinary' (slower) ripples. We performed network simulations with model pyramidal neurons, having axons electrically coupled. Ripples (< 250 Hz) were favored when conduction of action potentials, axon to axon, was reliable. Whereas ripple population activity was periodic, firing of individual axons varied in relative phase. A switch from ripples to FRs took place when an ectopic spike occurred in a cell coupled to another cell, itself multiply coupled to others. Propagation could then start in one direction only, a condition suitable for re-entry. The resulting oscillations were > 250 Hz, were sustained or interrupted, and had little jitter in the firing of individual axons. The form of model FR was similar to spontaneously occurring FRs in excised human epileptic tissue. In vitro, FRs were suppressed by a gap junction blocker. Our data suggest that a given network can produce ripples, FRs, or both, via gap junctions, and that FRs are favored by clusters of axonal gap junctions. If axonal gap junctions indeed occur in epileptic tissue, and are mediated by connexin 26 (recently shown to mediate coupling between immature neocortical pyramidal cells), then this prediction is testable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejn.12386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4026274PMC
January 2014

Do cortical gamma oscillations promote or suppress perception? An under-asked question with an over-assumed answer.

Front Hum Neurosci 2013 Sep 20;7:595. Epub 2013 Sep 20.

Institute of Neuroscience, Faculty of Medical Sciences, Newcastle University Medical School Newcastle Upon Tyne, UK.

Cortical gamma oscillations occur alongside perceptual processes, and in proportion to perceptual salience. They have a number of properties that make them ideal candidates to explain perception, including incorporating synchronized discharges of neural assemblies, and their emergence over a fast timescale consistent with that of perception. These observations have led to widespread assumptions that gamma oscillations' role is to cause or facilitate conscious perception (i.e., a "positive" role). While the majority of the human literature on gamma oscillations is consistent with this interpretation, many or most of these studies could equally be interpreted as showing a suppressive or inhibitory (i.e., "negative") role. For example, presenting a stimulus and recording a response of increased gamma oscillations would only suggest a role for gamma oscillations in the representation of that stimulus, and would not specify what that role were; if gamma oscillations were inhibitory, then they would become selectively activated in response to the stimulus they acted to inhibit. In this review, we consider two classes of gamma oscillations: "broadband" and "narrowband," which have very different properties (and likely roles). We first discuss studies on gamma oscillations that are non-discriminatory, with respect to the role of gamma oscillations, followed by studies that specifically support specifically a positive or negative role. These include work on perception in healthy individuals, and in the pathological contexts of phantom perception and epilepsy. Reference is based as much as possible on magnetoencephalography (MEG) and electroencephalography (EEG) studies, but we also consider evidence from invasive recordings in humans and other animals. Attempts are made to reconcile findings within a common framework. We conclude with a summary of the pertinent questions that remain unanswered, and suggest how future studies might address these.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnhum.2013.00595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3778316PMC
September 2013

A neocortical delta rhythm facilitates reciprocal interlaminar interactions via nested theta rhythms.

J Neurosci 2013 Jun;33(26):10750-61

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom.

Delta oscillations (1-4 Hz) associate with deep sleep and are implicated in memory consolidation and replay of cortical responses elicited during wake states. A potent local generator has been characterized in thalamus, and local generators in neocortex have been suggested. Here we demonstrate that isolated rat neocortex generates delta rhythms in conditions mimicking the neuromodulatory state during deep sleep (low cholinergic and dopaminergic tone). The rhythm originated in an NMDA receptor-driven network of intrinsic bursting (IB) neurons in layer 5, activating a source of GABAB receptor-mediated inhibition. In contrast, regular spiking (RS) neurons in layer 5 generated theta-frequency outputs. In layer 2/3 principal cells, outputs from IB cells associated with IPSPs, whereas those from layer 5 RS neurons related to nested bursts of theta-frequency EPSPs. Both interlaminar spike and field correlations revealed a sequence of events whereby sparse spiking in layer 2/3 was partially reflected back from layer 5 on each delta period. We suggest that these reciprocal, interlaminar interactions may represent a "Helmholtz machine"-like process to control synaptic rescaling during deep sleep.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0735-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693056PMC
June 2013

Rates and rhythms: a synergistic view of frequency and temporal coding in neuronal networks.

Neuron 2012 Aug;75(4):572-83

Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

In the CNS, activity of individual neurons has a small but quantifiable relationship to sensory representations and motor outputs. Coactivation of a few 10s to 100s of neurons can code sensory inputs and behavioral task performance within psychophysical limits. However, in a sea of sensory inputs and demand for complex motor outputs how is the activity of such small subpopulations of neurons organized? Two theories dominate in this respect: increases in spike rate (rate coding) and sharpening of the coincidence of spiking in active neurons (temporal coding). Both have computational advantages and are far from mutually exclusive. Here, we review evidence for a bias in neuronal circuits toward temporal coding and the coexistence of rate and temporal coding during population rhythm generation. The coincident expression of multiple types of gamma rhythm in sensory cortex suggests a mechanistic substrate for combining rate and temporal codes on the basis of stimulus strength.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2012.08.004DOI Listing
August 2012

Glissandi: transient fast electrocorticographic oscillations of steadily increasing frequency, explained by temporally increasing gap junction conductance.

Epilepsia 2012 Jul 12;53(7):1205-14. Epub 2012 Jun 12.

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.

Purpose: We describe a form of very fast oscillation (VFO) in patient electrocorticography (ECoG) recordings, that can occur prior to ictal events, in which the frequency increases steadily from ≈ 30-40 to >120 Hz, over a period of seconds. We dub these events "glissandi" and describe a possible model for them.

Methods: Four patients with epilepsy had presurgical evaluations (with ECoG obtained in two of them), and excised tissue was studied in vitro, from three of the patients. Glissandi were seen spontaneously in vitro, associated with ictal events-using acute slices of rat neocortex-and they were simulated using a network model of 15,000 detailed layer V pyramidal neurons, coupled by gap junctions.

Key Findings: Glissandi were observed to arise from human temporal neocortex. In vitro, they lasted 0.2-4.1 s, prior to ictal onset. Similar events were observed in the rat in vitro in layer V of frontal neocortex when alkaline solution was pressure-ejected; glissandi persisted when γ-aminobutyric acid A (GABA(A)), GABA(B), and N-methyl-d-aspartate (NMDA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were blocked. Nonalkaline conditions prevented glissando generation. In network simulations it was found that steadily increasing gap junction conductance would lead to the observed steady increase in VFO field frequency. This occurred because increasing gap junction conductance shortened the time required for an action potential to cross from cell to cell.

Significance: The in vitro and modeling data are consistent with the hypothesis that glissandi arise when pyramidal cell gap junction conductances rise over time, possibly as a result of an alkaline fluctuation in brain pH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2012.03530.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389590PMC
July 2012

Dual γ rhythm generators control interlaminar synchrony in auditory cortex.

J Neurosci 2011 Nov;31(47):17040-51

Institute of Neuroscience, Newcastle University, Newcastle, NE2 4HH, United Kingdom.

Rhythmic activity in populations of cortical neurons accompanies, and may underlie, many aspects of primary sensory processing and short-term memory. Activity in the gamma band (30 Hz up to >100 Hz) is associated with such cognitive tasks and is thought to provide a substrate for temporal coupling of spatially separate regions of the brain. However, such coupling requires close matching of frequencies in co-active areas, and because the nominal gamma band is so spectrally broad, it may not constitute a single underlying process. Here we show that, for inhibition-based gamma rhythms in vitro in rat neocortical slices, mechanistically distinct local circuit generators exist in different laminae of rat primary auditory cortex. A persistent, 30-45 Hz, gap-junction-dependent gamma rhythm dominates rhythmic activity in supragranular layers 2/3, whereas a tonic depolarization-dependent, 50-80 Hz, pyramidal/interneuron gamma rhythm is expressed in granular layer 4 with strong glutamatergic excitation. As a consequence, altering the degree of excitation of the auditory cortex causes bifurcation in the gamma frequency spectrum and can effectively switch temporal control of layer 5 from supragranular to granular layers. Computational modeling predicts the pattern of interlaminar connections may help to stabilize this bifurcation. The data suggest that different strategies are used by primary auditory cortex to represent weak and strong inputs, with principal cell firing rate becoming increasingly important as excitation strength increases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2209-11.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654396PMC
November 2011

Mitochondria and cortical gamma oscillations: food for thought?

Brain 2011 Feb;134(Pt 2):330-2

Institute of Neuroscience, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awq382DOI Listing
February 2011

Fast oscillatory activity induced by kainate receptor activation in the rat basolateral amygdala in vitro.

Eur J Neurosci 2011 Mar 24;33(5):914-22. Epub 2011 Jan 24.

Institute of Neuroscience, Newcastle University, Framlington Place, Newcastle upon Tyne, UK.

The basolateral amygdala (BLA) has a fundamental role in affective processing. In vivo studies have revealed rhythmic population activity of a similar type to that seen in the hippocampus and cortical areas during learning tasks. The amygdala contains densely interconnected networks of inhibitory interneurons similar to those responsible for fast network activity generation in the hippocampus and other cortical structures. Here we report that neuronal networks of the BLA in isolation generate persistent, gamma frequency (30-80 Hz) oscillations upon kainate receptor activation with kainic acid. We show that, like other cortical structures, BLA oscillations are completely dependent upon γ-aminobutyric acid (GABA)ergic inhibition. GABA(A) receptor blockade abolished all oscillations, and the activity was also sensitive to the barbiturate, pentobarbital. Blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors had no significant effect on gamma activity. However, the GluR5-containing kainate receptor-specific antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4-dione (UBP302) abolished oscillations-evidence that glutamatergic receptor involvement is predominantly kainate receptor mediated. The mixed AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxalone-2,3-dione disodium (NBQX) abolished all oscillatory activity in 8/14 of slices tested. In the remaining slices, gamma frequency activity was abolished to reveal a low-amplitude, NMDA receptor-dependent, beta frequency (10-20 Hz) oscillation. Gamma oscillations are abolished by gap junction blockade. While these data show the BLA capable of generating gamma rhythms in common with other cortical areas studied to date, the network mechanisms appear to be different, suggesting a unique network structure underlies amygdala rhythmogenesis. Understanding how BLA networks produce synchronous activity is paramount to understanding how the BLA executes influence on important cognitive processes such as emotional learning.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1460-9568.2010.07582.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627304PMC
March 2011

Chemical synaptic and gap junctional interactions between principal neurons: partners in epileptogenesis.

Neural Netw 2011 Aug 1;24(6):515-25. Epub 2010 Dec 1.

Department of Physical Sciences, IBM T.J. Watson Research Center, Yorktown Heights, NY 10598, USA.

Field potential signals, corresponding to electrographic seizures in cortical structures, often contain two components, which sometimes appear to be separable and other times to be superimposed. The first component consists of low-amplitude very fast oscillations (VFO, >70-80 Hz); the second component consists of larger amplitude transients, lasting tens to hundreds of ms, and variously called population spikes, EEG spikes, or bursts--terms chosen in part because of the cellular correlates of the field events. To first approximation, the two components arise because of distinctive types of cellular interactions: gap junctions for VFO (a model of which is reviewed in the following), and recurrent synaptic excitation and/or inhibition for the transients. With in vitro studies of epileptic human neocortical tissue, it is possible to elicit VFO alone, or VFO superimposed on a large transient, but not a large transient without the VFO. If such observations prove to be general, they would imply that gap junction-mediated interactions are the primary factor in epileptogenesis. It appears to be the case then, that in the setting of seizure initiation (but not necessarily under physiological conditions), the gain of gap junction-mediated circuits can actually be larger than the gain in excitatory synaptic circuits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neunet.2010.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070189PMC
August 2011

Multiple origins of the cortical γ rhythm.

Dev Neurobiol 2011 Jan;71(1):92-106

Institute of Neuroscience, The Medical School, Newcastle University, Newcastle Upon Tyne NE2 4HH, United Kingdom.

Gamma rhythms (30-80 Hz) are a near-ubiquitous feature of neuronal population activity in mammalian cortices. Their dynamic properties permit the synchronization of neuronal responses to sensory input within spatially distributed networks, transient formation of local neuronal "cell assemblies," and coherent response patterns essential for intercortical regional communication. Each of these phenomena form part of a working hypothesis for cognitive function in cortex. All forms of physiological gamma rhythm are inhibition based, being characterized by rhythmic trains of inhibitory postsynaptic potentials in populations of principal neurons. It is these repeating periods of relative enhancement and attenuation of the responsivity of major cell groups in cortex that provides a temporal structure shared across many millions of neurons. However, when considering the origins of these repeating trains of inhibitory events considerable divergence is seen depending on cortical region studied and mode of activation of gamma rhythm generating networks. Here, we review the evidence for involvement of multiple subtypes of interneuron and focus on different modes of activation of these cells. We conclude that most massively parallel brain regions have different mechanisms of gamma rhythm generation, that different mechanisms have distinct functional correlates, and that switching between different local modes of gamma generation may be an effective way to direct cortical communication streams. Finally, we suggest that developmental disruption of the endophenotype for certain subsets of gamma-generating interneuron may underlie cognitive deficit in psychiatric illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dneu.20814DOI Listing
January 2011

Cholinergic neuromodulation controls directed temporal communication in neocortex in vitro.

Front Neural Circuits 2010 22;4. Epub 2010 Mar 22.

Institute of Neuroscience, The Medical School, Newcastle University Newcastle, UK.

Acetylcholine is the primary neuromodulator involved in cortical arousal in mammals. Cholinergic modulation is involved in conscious awareness, memory formation and attention - processes that involve intercommunication between different cortical regions. Such communication is achieved in part through temporal structuring of neuronal activity by population rhythms, particularly in the beta and gamma frequency ranges (12-80 Hz). Here we demonstrate, using in vitro and in silico models, that spectrally identical patterns of beta2 and gamma rhythms are generated in primary sensory areas and polymodal association areas by fundamentally different local circuit mechanisms: Glutamatergic excitation induced beta2 frequency population rhythms only in layer 5 association cortex whereas cholinergic neuromodulation induced this rhythm only in layer 5 primary sensory cortex. This region-specific sensitivity of local circuits to cholinergic modulation allowed for control of the extent of cortical temporal interactions. Furthermore, the contrasting mechanisms underlying these beta2 rhythms produced a high degree of directionality, favouring an influence of association cortex over primary auditory cortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncir.2010.00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856628PMC
July 2011

Spatiotemporal patterns of electrocorticographic very fast oscillations (> 80 Hz) consistent with a network model based on electrical coupling between principal neurons.

Epilepsia 2010 Aug 7;51(8):1587-97. Epub 2009 Dec 7.

Department of Physical Sciences, IBM T.J. Watson Research Center, Yorktown Heights, New York 10598, USA.

Purpose: We sought to characterize spatial and temporal patterns of electrocorticography (ECoG) very fast oscillations (> ∼80 Hz, VFOs) prior to seizures in human frontotemporal neocortex, and to develop a testable network model of these patterns.

Methods: ECoG data were recorded with subdural grids from two preoperative patients with seizures of frontal lobe onset in an epilepsy monitoring unit. VFOs were recorded from rat neocortical slices. A "cellular automaton" model of network oscillations was developed, extending ideas of Traub et al. (Neuroscience, 92, 1999, 407) and Lewis & Rinzel (Network: Comput Neural Syst, 11, 2000, 299); this model is based on postulated electrical coupling between pyramidal cell axons.

Results: Layer 5 of rat neocortex, in vitro, can generate VFOs when chemical synapses are blocked. Human epileptic neocortex, in situ, produces preseizure VFOs characterized by the sudden appearance of "blobs" of activity that evolve into spreading wavefronts. When wavefronts meet, they coalesce and propagate perpendicularly but never pass through each other. This type of pattern has been described by Lewis & Rinzel in cellular automaton models with spatially localized connectivity, and is demonstrated here with 120,000- to 5,760,000-cell models. We provide a formula for estimating VFO period from structural parameters and estimate the spatial scale of the connectivity.

Discussion: These data provide further evidence, albeit indirect, that preseizure VFOs are generated by networks of pyramidal neurons coupled by gap junctions, each predominantly confined to pairs of neurons having somata separated by < ∼1-2 mm. Plausible antiepileptic targets are tissue mechanisms, such as pH regulation, that influence gap-junction conductance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1528-1167.2009.02420.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892641PMC
August 2010

A nonsynaptic mechanism underlying interictal discharges in human epileptic neocortex.

Proc Natl Acad Sci U S A 2010 Jan 4;107(1):338-43. Epub 2009 Dec 4.

Institute of Neuroscience, The Medical School, Framlington Place, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.

Very fast oscillations (VFOs, >80 Hz) are important for physiological brain processes and, in excess, with certain epilepsies. Putative mechanisms for VFO include interneuron spiking and network activity in coupled pyramidal cell axons. It is not known whether either, or both, of these apply in pathophysiological conditions. Spontaneously occurring interictal discharges occur in human tissue in vitro, resected from neocortical epileptic foci. VFO associated with these discharges was manifest in both field potential and, with phase delay, in excitatory synaptic inputs to fast spiking interneurons. Recruitment of somatic pyramidal cell and interneuron spiking was low, with no correlation between VFO power and synaptic inputs to principal cells. Reducing synaptic inhibition failed to affect VFO occurrence, but they were abolished by reduced gap junction conductance. These data suggest a lack of a causal role for interneurons, and favor a nonsynaptic pyramidal cell network origin for VFO in epileptic human neocortex.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.0912652107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806783PMC
January 2010