Matt Stead

Synchrony in normal and focal epileptic brain: the seizure onset zone is functionally disconnected.

Synchronization of local and distributed neuronal assemblies is thought to underlie fundamental brain processes such as perception, learning, and cognition. In neurological disease, neuronal synchrony can be altered and in epilepsy may play an important role in the generation of seizures. Linear cross-correlation and mean phase coherence of local field potentials (LFPs) are commonly used measures of neuronal synchrony and have been studied extensively in epileptic brain. Multiple studies have reported that epileptic brain is characterized by increased neuronal synchrony except possibly prior to seizure onset when synchrony may decrease. Previous studies using intracranial electroencephalography (EEG), however, have been limited to patients with epilepsy. Here we investigate neuronal synchrony in epileptic and control brain using intracranial EEG recordings from patients with medically resistant partial epilepsy and control subjects with intractable facial pain. For both epilepsy and control patients, average LFP synchrony decreases with increasing interelectrode distance. Results in epilepsy patients show lower LFP synchrony between seizure-generating brain and other brain regions. This relative isolation of seizure-generating brain underlies the paradoxical finding that control patients without epilepsy have greater average LFP synchrony than patients with epilepsy. In conclusion, we show that in patients with focal epilepsy, the region of epileptic brain generating seizures is functionally isolated from surrounding brain regions. We further speculate that this functional isolation may contribute to spontaneous seizure generation and may represent a clinically useful electrophysiological signature for mapping epileptic brain.

Data mining neocortical high-frequency oscillations in epilepsy and controls.

Transient high-frequency (100-500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100-250 Hz) and fast ripple (250-500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100-500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.

Large-scale electrophysiology: acquisition, compression, encryption, and storage of big data.

The use of large-scale electrophysiology to obtain high spatiotemporal resolution brain recordings (>100 channels) capable of probing the range of neural activity from local field potential oscillations to single-neuron action potentials presents new challenges for data acquisition, storage, and analysis. Our group is currently performing continuous, long-term electrophysiological recordings in human subjects undergoing evaluation for epilepsy surgery using hybrid intracranial electrodes composed of up to 320 micro- and clinical macroelectrode arrays. DC-capable amplifiers, sampling at 32kHz per channel with 18-bits of A/D resolution are capable of resolving extracellular voltages spanning single-neuron action potentials, high frequency oscillations, and high amplitude ultra-slow activity, but this approach generates 3 terabytes of data per day (at 4 bytes per sample) using current data formats. Data compression can provide several practical benefits, but only if data can be compressed and appended to files in real-time in a format that allows random access to data segments of varying size. Here we describe a state-of-the-art, scalable, electrophysiology platform designed for acquisition, compression, encryption, and storage of large-scale data. Data are stored in a file format that incorporates lossless data compression using range-encoded differences, a 32-bit cyclically redundant checksum to ensure data integrity, and 128-bit encryption for protection of patient information.

Long-term Outcomes After Nonlesional Extratemporal Lobe Epilepsy Surgery

IMPORTANCE A focal lesion detected by use of magnetic resonance imaging (MRI) is a favorable prognostic finding for epilepsy surgery. Patients with normal MRI findings and extratemporal lobe epilepsy have less favorable outcomes. Most studies investigating the outcomes of patients with normal MRI findings who underwent (nonlesional) extratemporal epilepsy surgery are confined to a highly select group of patients with limited follow-up. OBJECTIVE To evaluate noninvasive diagnostic test results and their association with excellent surgical outcomes (defined using Engel classes I-IIA of surgical outcomes) in a group of patients with medically resistant nonlesional extratemporal epilepsy. DESIGN A retrospective study. SETTING Mayo Clinic, Rochester, Minnesota. PARTICIPANTS From 1997 through 2002, we identified 85 patients with medically resistant extratemporal lobe epilepsy who had normal MRI findings. Based on a standardized presurgical evaluation and review at a multidisciplinary epilepsy surgery conference, some of these patients were selected for intracranial electroencephalographic (EEG) monitoring and epilepsy surgery. EXPOSURE Nonlesional extratemporal lobe epilepsy surgery. MAIN OUTCOMES AND MEASURES The results of noninvasive diagnostic tests and the clinical variables potentially associated with excellent surgical outcome were examined in patients with a minimum follow-up of 1 year (mean follow-up, 9 years). RESULTS Based on the noninvasive diagnostic test results, a clear hypothesis for seizure origin was possible for 47 of the 85 patients (55%), and 31 of these 47 patients (66%) proceeded to intracranial EEG monitoring. For 24 of these 31 patients undergoing long-term intracranial EEG (77%), a seizure focus was identified and surgically resected. Of these 24 patients, 9 (38%) had an excellent outcome after resective epilepsy surgery. All patients with an excellent surgical outcome had at least 10 years of follow-up. Univariate analysis showed that localized interictal epileptiform discharges on scalp EEGs were associated with an excellent surgical outcome. CONCLUSIONS AND RELEVANCE Scalp EEG was the most useful test for identifying patients with normal MRI findings and extratemporal lobe epilepsy who were likely to have excellent outcomes after epilepsy surgery. Extending outcome analysis beyond the resective surgery group to the entire group of patients who were evaluated further highlights the challenge that these patients pose. Although 9 of 24 patients undergoing resective surgery (38%) had excellent outcomes, only 9 of 31 patients undergoing intracranial EEG (29%) and only 9 of 85 patient with nonlesional extratemporal lobe epilepsy (11%) had long-term excellent outcomes.

Spatiotemporal neuronal correlates of seizure generation in focal epilepsy

Purpose:  Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathologic brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. Although in vivo recordings of single‐neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long‐term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure‐onset zone.

Deep Brain Stimulation in Tourette Syndrome: A Description of 3 Patients With Excellent Outcome

Tourette syndrome (TS) is a complex neuropsychiatric disorder often starting in childhood and characterized by the presence of multiple motor and vocal tics and psychiatric comorbidities. Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects, prompting trials of deep brain stimulation (DBS) as an alternative therapy. It remains unclear which of the various nuclear targets is most effective in TS. We describe 3 patients with TS who underwent DBS targeting the bilateral thalamic centromedian/parafascicular complex (CM/Pf) with an excellent clinical outcome. At 1-year follow-up, the mean reduction in the total Yale Global Tic Severity Scale score in the 3 patients was 70% (range, 60%-80%).Our study further supports the role of the CM/Pf DBS target in medically intractable TS.

On the Recording Reference Contribution to EEG Correlation, Phase Synchorony, and Coherence

The degree of synchronization in electroencephalography (EEG) signals is commonly characterized by the time-series measures, namely, correlation, phase synchrony, and magnitude squared coherence (MSC). However, it is now well established that the interpretation of the results from these measures are confounded by the recording reference signal and that this problem is not mitigated by the use of other EEG montages, such as bipolar and average reference. In this paper, we analyze the impact of reference signal amplitude and power on EEG signal correlation, phase synchrony, and MSC. We show that, first, when two nonreferential signals have negative correlation, the phase synchrony and the absolute value of the correlation of the two referential signals may have two regions of behavior characterized by a monotonic decrease to zero and then a monotonic increase to one as the amplitude of the reference signal varies in [0, +∞). It is notable that even a small change of the amplitude may lead to significant impact on these two measures. Second, when two nonreferential signals have positive correlation, the correlation and phase-synchrony values of the two referential signals can monotonically increase to one (or monotonically decrease to some positive value and then monotonically increase to one) as the amplitude of the reference signal varies in [0, + ∞). Third, when two nonreferential signals have negative cross-power, the MSC of the two referential signals can monotonically decrease to zero and then monotonically increase to one as reference signal power varies in [0, + ∞). Fourth, when two nonreferential signals have positive cross-power, the MSC of the two referential signals can monotonically increase to one as the reference signal power varies in [0, + ∞). In general, the reference signal with small amplitude or power relative to the signals of interest may decrease or increase the values of correlation, phase synchrony, and MSC. However, the reference signal with high relative amplitude or power will always increase each of the three measures. In our previous paper, we developed a method to identify and extract the reference signal contribution to intracranial EEG (iEEG) recordings. In this paper, we apply this approach to referential iEEG recorded from human subjects and directly investigate the contribution of recording reference on correlation, phase synchrony, and MSC. The experimental results demonstrate the significant impact that the recording reference may have on these bivariate measures.

Automatic Identification and Removal of Scalp Reference Signal for Intracranial EEGs Based on Independent Component Analysis

The pursuit of an inactive recording reference is one of the oldest technical problems in electroencephalography (EEG). Since commonly used cephalic references contaminate EEG and can lead to misinterpretation, extraction of the reference contribution is of fundamental interest. Here, we apply independent component analysis (ICA) to intracranial recordings and propose two methods to automatically identify and remove the reference based on the assumption that the scalp reference is independent from the local and distributed intracranial sources. This assumption, supported by our results, is generally valid because the reference scalp electrode is relatively electrically isolated from the intracranial electrodes by the skulls high resistivity. We point out that the linear model is underdetermined when the reference is considered as a source, and discuss one special underdetermined case for which a unique class of outputs can be separated. For this case most ICA algorithms can be applied, and we argue that intracranial or scalp EEGs follow this special case. We apply the two proposed methods to intracranial EEGs from three patients undergoing evaluation for epilepsy surgery, and compare the results to bipolar and average reference recordings. The proposed methods should have wide application in quantitative EEG studies.

Increased cortical extracellular adenosine correlates with seizure termination.

Seizures are currently defined by their electrographic features. However, neuronal networks are intrinsically dependent on neurotransmitters of which little is known regarding their periictal dynamics. Evidence supports adenosine as having a prominent role in seizure termination, as its administration can terminate and reduce seizures in animal models. Furthermore, microdialysis studies in humans suggest that adenosine is elevated periictally, but the relationship to the seizure is obscured by its temporal measurement limitations. Because electrochemical techniques can provide vastly superior temporal resolution, we test the hypothesis that extracellular adenosine concentrations rise during seizure termination in an animal model and humans using electrochemistry.

Electrophysiological biomarkers of epilepsy.

In patients being evaluated for epilepsy and in animal models of epilepsy, electrophysiological recordings are carried to capture seizures to determine the existence of epilepsy. Electroencephalography recordings from the scalp, or sometimes directly from the brain, are also used to locate brain areas where seizure begins, and in surgical treatment help plan the area for resection. As seizures are unpredictable and can occur infrequently, ictal recordings are not ideal in terms of time, cost, or risk when, for example, determining the efficacy of existing or new anti-seizure drugs, evaluating potential anti-epileptogenic interventions, or for prolonged intracerebral electrode studies. Thus, there is a need to identify and validate other electrophysiological biomarkers of epilepsy that could be used to diagnose, treat, cure, and prevent epilepsy. Electroencephalography recordings in the epileptic brain contain other interictal electrophysiological disturbances that can occur more frequently than seizures, such as interictal spikes (IIS) and sharp waves, and from invasive studies using wide bandwidth recording and small diameter electrodes, the discovery of pathological high-frequency oscillations (HFOs) and microseizures. Of IIS, HFOs, and microseizures, a significant amount of recent research has focused on HFOs in the pathophysiology of epilepsy. Results from studies in animals with epilepsy and presurgical patients have consistently found a strong association between HFOs and epileptogenic brain tissue that suggest HFOs could be a potential biomarker of epileptogenicity and epileptogenesis. Here, we discuss several aspects of HFOs, as well as IIS and microseizures, and the evidence that supports their role as biomarkers of epilepsy.