John G. R. Jefferys

Electrical stimulation of excitable tissue: design of efficacious and safe protocols

The physical basis for electrical stimulation of excitable tissue, as used by electrophysiological researchers and clinicians in functional electrical stimulation, is presented with emphasis on the fundamental mechanisms of charge injection at the electrode/tissue interface. Faradaic and non-Faradaic charge transfer mechanisms are presented and contrasted. An electrical model of the electrode/tissue interface is given. The physical basis for the origin of electrode potentials is given. Various methods of controlling charge delivery during pulsing are presented. Electrochemical reversibility is discussed. Commonly used electrode materials and stimulation protocols are reviewed in terms of stimulation efficacy and safety. Principles of stimulation of excitable tissue are reviewed with emphasis on efficacy and safety. Mechanisms of damage to tissue and the electrode are reviewed.

Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro

Coherent oscillations, in which ensembles of neurons fire in a repeated and synchronous manner, are thought to be important in higher brain functions. In the hippocampus, these discharges are categorized according to their frequency as theta (4–10 Hz), gamma (20–80 Hz) and high-frequency (∼200 Hz) discharges, and they occur in relation to different behavioural states. The synaptic bases of theta and gamma rhythms have been extensively studied, but the cellular bases for high-frequency oscillations are not understood. Here we report that high-frequency network oscillations are present in rat brain slices in vitro, occurring as a brief series of repetitive population spikes at 150–200 Hz in all hippocampal principal cell layers. Moreover, this synchronous activity is not mediated through the more commonly studied modes of chemical synaptic transmission, but is in fact a result of direct electrotonic coupling of neurons, most likely through gap-junctional connections. Thus high-frequency oscillations synchronize the activity of electrically coupled subsets of principal neurons within the well-documented synaptic network of the hippocampus.

Effects of uniform extracellular DC electric fields on excitability in rat hippocampal slices in vitro

The effects of uniform steady state (DC) extracellular electric fields on neuronal excitability were characterized in rat hippocampal slices using field, intracellular and voltage‐sensitive dye recordings. Small electric fields (<|40| mV mm−1), applied parallel to the somato‐dendritic axis, induced polarization of CA1 pyramidal cells; the relationship between applied field and induced polarization was linear (0.12 ± 0.05 mV per mV mm−1 average sensitivity at the soma). The peak amplitude and time constant (15–70 ms) of membrane polarization varied along the axis of neurons with the maximal polarization observed at the tips of basal and apical dendrites. The polarization was biphasic in the mid‐apical dendrites; there was a time‐dependent shift in the polarity reversal site. DC fields altered the thresholds of action potentials evoked by orthodromic stimulation, and shifted their initiation site along the apical dendrites. Large electric fields could trigger neuronal firing and epileptiform activity, and induce long‐term (>1 s) changes in neuronal excitability. Electric fields perpendicular to the apical–dendritic axis did not induce somatic polarization, but did modulate orthodromic responses, indicating an effect on afferents. These results demonstrate that DC fields can modulate neuronal excitability in a time‐dependent manner, with no clear threshold, as a result of interactions between neuronal compartments, the non‐linear properties of the cell membrane, and effects on afferents.

High-frequency population oscillations are predicted to occur in hippocampal pyramidal neuronal networks interconnected by axoaxonal gap junctions.

In hippocampal slices, high-frequency (125-333 Hz) synchronized oscillations have been shown to occur amongst populations of pyramidal neurons, in a manner that is independent of chemical synaptic transmission, but which is dependent upon gap junctions. At the intracellular level, high-frequency oscillations are associated with full-sized action potentials and with fast prepotentials. Using simulations of two pyramidal neurons, we previously argued that the submillisecond synchrony, and the rapid time-course of fast prepotentials, could be explained, in principle, if the requisite gap junctions were located between pyramidal cell axons. Here, we use network simulations (3072 pyramidal cells) to explore further the hypothesis that gap junctions occur between axons and could explain high-frequency oscillations. We show that, in randomly connected networks with an average of two gap junctions per cell, or less, synchronized network bursts can arise without chemical synapses, with frequencies in the experimentally observed range (spectral peaks 125-182 Hz). These bursts are associated with fast prepotentials (or partial spikes and spikelets) as observed in physiological recordings. The critical assumptions we must make for the oscillations to occur are: (i) there is a background of ectopic axonal spikes, which can occur at low frequency (one event per 25 s per axon); (ii) the gap junction resistance is small enough that a spike in one axon can induce a spike in the coupled axon at short latency (in the model, a resistance of 273 M omega works, with an associated latency of 0.25 ms). We predict that axoaxonal gap junctions, in combination with recurrent excitatory synapses, can induce the occurrence of high-frequency population spikes superimposed on epileptiform field potentials.

Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice

Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.

High-Frequency Oscillations as a New Biomarker in Epilepsy

The discovery that electroencephalography (EEG) contains useful information at frequencies above the traditional 80Hz limit has had a profound impact on our understanding of brain function. In epilepsy, high‐frequency oscillations (HFOs, >80Hz) have proven particularly important and useful. This literature review describes the morphology, clinical meaning, and pathophysiology of epileptic HFOs. To record HFOs, the intracranial EEG needs to be sampled at least at 2,000Hz. The oscillatory events can be visualized by applying a high‐pass filter and increasing the time and amplitude scales, or EEG time‐frequency maps can show the amount of high‐frequency activity. HFOs appear excellent markers for the epileptogenic zone. In patients with focal epilepsy who can benefit from surgery, invasive EEG is often required to identify the epileptic cortex, but current information is sometimes inadequate. Removal of brain tissue generating HFOs has been related to better postsurgical outcome than removing the seizure onset zone, indicating that HFOs may mark cortex that needs to be removed to achieve seizure control. The pathophysiology of epileptic HFOs is challenging, probably involving populations of neurons firing asynchronously. They differ from physiological HFOs in not being paced by rhythmic inhibitory activity and in their possible origin from population spikes. Their link to the epileptogenic zone argues that their study will teach us much about the pathophysiology of epileptogenesis and ictogenesis. HFOs show promise for improving surgical outcome and accelerating intracranial EEG investigations. Their potential needs to be assessed by future research. Ann Neurol 2012;71:169–178

Hippocampal slices from prion protein null mice: disrupted Ca2+-activated K+ currents

The intrinsic properties of hippocampal CA1 pyramidal cells were examined in mice lacking prion protein (PrP-null). The resting potentials, time constants, amplitude of the medium afterhyperpolarization (AHP) and spike firing accommodation did not differ from the control group. The PrP-null group differed in having lower input resistances, a lack of the late AHP and of a charybdotoxin-sensitive summated AHP. We propose that CA(2+)-activated K+ currents, in particular IAHP, are disrupted in PrP-null mice.

Spatiotemporal patterns of γ frequency oscillations tetanically induced in the rat hippocampal slice

1 We used transverse and longitudinal rat hippocampal slices to study the synchronization of γ frequency (> 20 Hz) oscillations, across distances of up to 4.5 mm. γ oscillations were evoked in the CA1 region by tetanic stimulation at one or two sites simultaneously, and were associated with population spikes. Tetanic stimuli that were strong enough to induce oscillations were associated with depolarization of both pyramidal cells and interneurones, largely produced by activation of metabotropic glutamate receptors. 2 Computer simulations of γ oscillations were also performed in a model with pyramidal cells and interneurones, arranged in a chain of five cell groups. This model had suggested previously that interneurone networks alone could generate synchronous γ oscillations locally, but that pyramidal cell firing, by inducing spike doublets in interneurones, was necessary for the occurrence of highly correlated oscillations with small phase lag (< 2.5 ms), in a distributed network possessing long axon conduction delays. 3 In both experiment and model, pyramidal cell spikes occurred in phase with local population spikes, as did the first spike of the interneurone doublet. 4 The conductance of the interneurone α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor‐mediated conductance was manipulated in the model, while the relation between oscillations at opposite ends of the chain was examined. When the conductance was large enough for doublet firing to be synaptically induced in interneurones, oscillation phase lags were < 2.25 ms across the chain. As predicted, experimental blockade of AMPA receptors resulted in increased phase lags between two sites oscillating simultaneously, compared with control conditions. 5 Both in model and in experiment, when stimuli to the two ends of the network were slightly different, cross‐network synchronization occurred with a shorter phase lag at high frequencies than at lower frequencies. 6 These data suggest that, while interneurone networks alone can generate locally synchronized γ oscillations, firing of pyramidal cells, and the synaptically induced doublet firing in interneurones, contribute to the stability and tight synchrony of the oscillations in distributed networks.

Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity

Neurons are extraordinarily complicated devices, in which physical and chemical processes are intercoupled, in spatially non-uniform manner, over distances of millimeters or more, and over time scales of < 1 msec up to the lifetime of the animal. The fact that neuronal populations generating most brain activities of interest are very large-perhaps many millions of cells-makes the task of analysis seem hopeless. Yet, during at least some population activities, neuronal networks oscillate synchronously. The emergence of such oscillations generates precise temporal relationship between neuronal inputs and outputs, thus rendering tractable the analysis of network function at a cellular level. We illustrate this idea with a review of recent data and a network model of synchronized gamma frequency (> 20 Hz) oscillations in vitro, and discuss how these and other oscillations may relate to recent data on back-propagating, action potentials, dendritic Ca2+ transients, long-term potentiation and GABAA receptor-mediated synaptic potentials.

Simulation of Gamma Rhythms in Networks of Interneurons and Pyramidal Cells

Networks of hippocampal interneurons, with pyramidal neuronspharmacologically disconnected, can generate gamma-frequency(20 Hz and above) oscillations. Experiments and models have shownhow the network frequency depends on excitation of the interneurons,and on the parameters of GABA{\rm A}-mediated IPSCs betweenthe interneurons (conductance and time course). Herewe use network simulations to investigate how pyramidal cells, connected tothe interneurons and to each other throughAMPA-type and/or NMDA-type glutamatereceptors, might modify the interneuron network oscillation. With orwithout AMPA-receptor mediated excitation of the interneurons, the pyramidal cells and interneurons fired in phaseduring the gamma oscillation. Synaptic excitation of the interneuronsby pyramidal cellscaused them to fire spike doublets or short bursts at gammafrequencies, thereby slowing the population rhythm.Rhythmic synchronized IPSPs allowed the pyramidal cells toencode their mean excitation by their phase of firing relativeto the population waves.Recurrent excitation between the pyramidal cells couldmodify the phase of firing relative to the population waves.Our model suggests that pools of synaptically interconnectedinhibitory cells are sufficient to produce gamma frequency rhythms,but the network behavior can be modified by participation ofpyramidal cells.