Potential for unreliable interpretation of EEG recorded with microelectrodes

Purpose: Recent studies in epilepsy, cognition, and brain machine interfaces have shown the utility of recording intracranial electroencephalography (iEEG) with greater spatial resolution. Many of these studies utilize microelectrodes connected to specialized amplifiers that are optimized for such recordings. We recently measured the impedances of several commercial microelectrodes and demonstrated that they will distort iEEG signals if connected to clinical EEG amplifiers commonly used in most centers. In this study we demonstrate the clinical implications of this effect and identify some of the potential difficulties in using microelectrodes. Methods: Human iEEG data were digitally filtered to simulate the signal recorded by a hybrid grid (two macroelectrodes and eight microelectrodes) connected to a standard EEG amplifier. The filtered iEEG data were read by three trained epileptologists, and high frequency oscillations (HFOs) were detected with a well-known algorithm. The filtering method was verified experimentally by recording an injected EEG signal in a saline bath with the same physical acquisition system used to generate the model. Several electrodes underwent scanning electron microscopy (SEM). Key Findings: Macroelectrode recordings were unaltered compared to the source iEEG signal, but microelectrodes attenuated low frequencies. The attenuated signals were difficult to interpret: all three clinicians changed their clinical scoring of slowing and seizures when presented with the same data recorded on different sized electrodes. The HFO detection algorithm was oversensitive with microelectrodes, classifying many more HFOs than when the same data were recorded with macroelectrodes. In addition, during experimental recordings the microelectrodes produced much greater noise as well as large baseline fluctuations, creating sharply contoured transients, and superimposed “false” HFOs. SEM of these microelectrodes demonstrated marked variability in exposed electrode surface area, lead fractures, and sharp edges. Significance: Microelectrodes should not be used with low impedance (<1 GΩ) amplifiers due to severe signal attenuation and variability that changes clinical interpretations. The current method of preparing microelectrodes can leave sharp edges and nonuniform amounts of exposed wire. Even when recorded with higher impedance amplifiers, microelectrode data are highly prone to artifacts that are difficult to interpret. Great care must be taken when analyzing iEEG from high impedance microelectrodes

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area

Modeling focal epileptic activity in the Wilson-Cowan model with depolarization block

Measurements of neuronal signals during human seizure activity and evoked epileptic activity in experimental models suggest that, in these pathological states, the individual nerve cells experience an activity driven depolarization block, i.e. they saturate. We examined the effect of such a saturation in the Wilson–Cowan formalism by adapting the nonlinear activation function; we substituted the commonly applied sigmoid for a Gaussian function. We discuss experimental recordings during a seizure that support this substitution. Next we perform a bifurcation analysis on the Wilson–Cowan model with a Gaussian activation function. The main effect is an additional stable equilibrium with high excitatory and low inhibitory activity. Analysis of coupled local networks then shows that such high activity can stay localized or spread. Specifically, in a spatial continuum we show a wavefront with inhibition leading followed by excitatory activity. We relate our model simulations to observations of spreading activity during seizures

Spontaneous and visually driven high‐frequency oscillations in the occipital cortex: Intracranial recording in epileptic patients

High‐frequency oscillations (HFOs) at ≥80 Hz of nonepileptic nature spontaneously emerge from human cerebral cortex. In 10 patients with extraoccipital lobe epilepsy, we compared the spectral‐spatial characteristics of HFOs spontaneously arising from the nonepileptic occipital cortex with those of HFOs driven by a visual task as well as epileptogenic HFOs arising from the extraoccipital seizure focus. We identified spontaneous HFOs at ≥80 Hz with a mean duration of 330 ms intermittently emerging from the occipital cortex during interictal slow‐wave sleep. The spectral frequency band of spontaneous occipital HFOs was similar to that of visually driven HFOs. Spontaneous occipital HFOs were spatially sparse and confined to smaller areas, whereas visually driven HFOs involved the larger areas including the more rostral sites. Neither spectral frequency band nor amplitude of spontaneous occipital HFOs significantly differed from those of epileptogenic HFOs. Spontaneous occipital HFOs were strongly locked to the phase of delta activity, but the strength of δ‐phase coupling decayed from 1 to 3 Hz. Conversely, epileptogenic extraoccipital HFOs were locked to the phase of delta activity about equally in the range from 1 to 3 Hz. The occipital cortex spontaneously generates physiological HFOs which may stand out on electrocorticography traces as prominently as pathological HFOs arising from elsewhere; this observation should be taken into consideration during presurgical evaluation. Coupling of spontaneous delta and HFOs may increase the understanding of significance of δ‐oscillations during slow‐wave sleep. Further studies are warranted to determine whether δ‐phase coupling distinguishes physiological from pathological HFOs or simply differs across anatomical locations. Hum Brain Mapp , 2012. © 2011 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90310/1/21233_ftp.pd

A closed loop brain-machine interface for epilepsy control using dorsal column electrical stimulation

Although electrical neurostimulation has been proposed as an alternative treatment for drug-resistant cases of epilepsy, current procedures such as deep brain stimulation, vagus, and trigeminal nerve stimulation are effective only in a fraction of the patients. Here we demonstrate a closed loop brain-machine interface that delivers electrical stimulation to the dorsal column (DCS) of the spinal cord to suppress epileptic seizures. Rats were implanted with cortical recording microelectrodes and spinal cord stimulating electrodes, and then injected with pentylenetetrazole to induce seizures. Seizures were detected in real time from cortical local field potentials, after which DCS was applied. This method decreased seizure episode frequency by 44% and seizure duration by 38%. We argue that the therapeutic effect of DCS is related to modulation of cortical theta waves, and propose that this closed-loop interface has the potential to become an effective and semi-invasive treatment for refractory epilepsy and other neurological disorders.We are grateful for the assistance from Jim Meloy for the design and production of the multielectrode arrays as well as setup development and maintenance, Laura Oliveira, Terry Jones, and Susan Halkiotis for administrative assistance and preparation of the manuscript. This work was funded by a grant from The Hartwell Foundation.info:eu-repo/semantics/publishedVersio

Evaluating the arcuate fasciculus with combined diffusion‐weighted MRI tractography and electrocorticography

The conventional model of language‐related brain structure describing the arcuate fasciculus as a key white matter tract providing a direct connection between Wernicke's region and Broca's area has been called into question. Specifically, the inferior precentral gyrus, possessing both primary motor (Brodmann Area [BA] 4) and premotor cortex (BA 6), has been identified as a potential alternative termination. The authors initially localized cortical sites involved in language using measurement of event‐related gamma‐activity on electrocorticography (ECoG). The authors then determined whether language‐related sites of the temporal lobe were connected, via white matter structures, to the inferior frontal gyrus more tightly than to the precentral gyrus. The authors found that language‐related sites of the temporal lobe were far more likely to be directly connected to the inferior precentral gyrus through the arcuate fasciculus. Furthermore, tractography was a significant predictor of frontal language‐related ECoG findings. Analysis of an interaction between anatomy and tractography in this model revealed tractrography to have the highest predictive value for language‐related ECoG findings of the precentral gyrus. This study failed to support the conventional model of language‐related brain structure. More feasible models should include the inferior precentral gyrus as a termination of the arcuate fasciculus. The exact functional significance of direct connectivity between temporal language‐related sites and the precentral gyrus requires further study. Hum Brain Mapp 35:2333–2347, 2014 . © 2013 Wiley Periodicals, Inc .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106959/1/hbm22331.pd

Single-neuron dynamics in human focal epilepsy

Epileptic seizures are traditionally characterized as the ultimate expression of monolithic, hypersynchronous neuronal activity arising from unbalanced runaway excitation. Here we report the first examination of spike train patterns in large ensembles of single neurons during seizures in persons with epilepsy. Contrary to the traditional view, neuronal spiking activity during seizure initiation and spread was highly heterogeneous, not hypersynchronous, suggesting complex interactions among different neuronal groups even at the spatial scale of small cortical patches. In contrast to earlier stages, seizure termination is a nearly homogenous phenomenon followed by an almost complete cessation of spiking across recorded neuronal ensembles. Notably, even neurons outside the region of seizure onset showed significant changes in activity minutes before the seizure. These findings suggest a revision of current thinking about seizure mechanisms and point to the possibility of seizure prevention based on spiking activity in neocortical neurons

Spatial characterization of interictal high frequency oscillations in epileptic neocortex

Interictal high frequency oscillations (HFOs), in particular those with frequency components in excess of 200 Hz, have been proposed as important biomarkers of epileptic cortex as well as the genesis of seizures. We investigated the spatial extent, classification and distribution of HFOs using a dense 4 × 4 mm2 two dimensional microelectrode array implanted in the neocortex of four patients undergoing epilepsy surgery. The majority (97%) of oscillations detected included fast ripples and were concentrated in relatively few recording sites. While most HFOs were limited to single channels, ∼10% occurred on a larger spatial scale with simultaneous but morphologically distinct detections in multiple channels. Eighty per cent of these large-scale events were associated with interictal epileptiform discharges. We propose that large-scale HFOs, rather than the more frequent highly focal events, are the substrates of the HFOs detected by clinical depth electrodes. This feature was prominent in three patients but rarely seen in only one patient recorded outside epileptogenic cortex. Additionally, we found that HFOs were commonly associated with widespread interictal epileptiform discharges but not with locally generated ‘microdischarges’. Our observations raise the possibility that, rather than being initiators of epileptiform activity, fast ripples may be markers of a secondary local response

Controversies on the network theory of epilepsy : Debates held during the ICTALS 2019 conference

Acknowledgements We would like to acknowledge the contributions of the discussants to the exposition and discussion of the six debate topics. The discussants for debates 1-6 were Fabrice Wendling, Mark Cook, Mark Richardson, Thorsten Rings, Klaus Lehnertz and Piotr Suffczynski, respectively. Funding for ICTALS 2019 was received from the following foundations and industry partners: UCB S.A. (Belgium), American Epilepsy Society (AES), Epilepsy Innovation Institute (Ei2) and Epilepsy Foundation of America (EFA), NeuraLynx (Bozeman, MT, USA) and LivaNova (London, UK). The contribution of HZ was supported by award R01NS109062 from the National Institutes of Health, MG by the EPSRC via grants EP/P021417/1 and EP/N014391/1 and a Wellcome Trust Institutional Strategic Support Award (WT105618MA), and PJ by awards from the Ministry of Health of the Czech Republic AZV 17-28427A and the Czech Science Foundation 20-25298S. The opinions expressed in this article do not necessarily reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.Peer reviewedPostprin

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings

Objective. Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. Approach. We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400-micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. Main results. Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. Significance. Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings