Sleep macro-architecture in patients with Parkinson's disease does not change during the first night of neurostimulation in a pilot study.

STUDY OBJECTIVES: A growing body of literature suggests that deep brain stimulation (DBS) to treat motor symptoms of Parkinson's disease (PD) may also ameliorate certain sleep deficits. Many foundational studies have examined the impact of stimulation on sleep following several months of therapy, leaving an open question regarding the time course for improvement. It is unknown whether sleep improvement will immediately follow onset of therapy or accrete over a prolonged period of stimulation. The objective of our study was to address this knowledge gap by assessing the impact of DBS on sleep macro-architecture during the first nights of stimulation. METHODS: Polysomnograms were recorded for three consecutive nights in 14 patients with advanced PD (10 male, 4 female; age: 53-74 years), with intermittent, unilateral subthalamic nucleus DBS on the final night or two. Sleep scoring was determined manually by a consensus of four experts. Sleep macro-architecture was objectively quantified using the percentage, latency, and mean bout length of wake after sleep onset (WASO) and on each stage of sleep (REM and NREM stages N1, N2, N3). RESULTS: Sleep was found to be highly disrupted in all nights. Sleep architecture on nights without stimulation was consistent with prior results in treatment naive patients with PD. No statistically significant difference was observed due to stimulation. CONCLUSIONS: These objective measures suggest that one night of intermittent subthreshold stimulation appears insufficient to impact sleep macro-architecture. CLINICAL TRIAL REGISTRATION: Name: Adaptive Neurostimulation to Restore Sleep in Parkinson's Disease; URL: https://clinicaltrials.gov/ct2/show/NCT04620551; Identifier: NCT04620551.

Spike ripples localize the epileptogenic zone best: an international intracranial study.

We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone (EZ) compared to other leading interictal biomarkers in a multicenter, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centers who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection (ILAE 1 outcome) and those with persistent seizures (ILAE 2-6) across sites and recording types. We also evaluated available interictal biomarkers: spike, spike-gamma, wideband high frequency oscillation (HFO, 80-500 Hz), ripple (80-250 Hz), and fast ripple (250-500 Hz) rates using previously validated automated detectors. The proportion of resected events was computed and compared across subject outcomes and biomarkers. 109 subjects were included. Most spike ripples were removed in subjects with ILAE 1 outcome (P < 0.001), and this was qualitatively observed across all sites and for depth and subdural electrodes (P < 0.001, P < 0.001). Among ILAE 1 subjects, the mean spike ripple rate was higher in the RV (0.66/min) than in the non-removed tissue (0.08/min, P < 0.001). A higher proportion of spike ripples were removed in subjects with ILAE 1 outcomes compared to ILAE 2-6 outcomes (P = 0.06). Among ILAE 1 subjects, the proportion of spike ripples removed was higher than the proportion of spikes (P < 0.001), spike-gamma (P < 0.001), wideband HFOs (P < 0.001), ripples (P = 0.009) and fast ripples (P = 0.009) removed. At the individual level, more subjects with ILAE 1 outcomes had the majority of spike ripples removed (79%, 38/48) than spikes (69%, P = 0.12), spike-gamma (69%, P = 0.12), wideband HFOs (63%, P = 0.03), ripples (45%, P = 0.01), or fast ripples (36%, P < 0.001) removed. Thus, in this large, multicenter cohort, when surgical resection was successful, the majority of spike ripples were removed. Further, automatically detected spike ripples have improved specificity for epileptogenic tissue compared to spikes, spike-gamma, wideband HFOs, ripples, and fast ripples.

High frequency oscillation network dynamics predict outcome in non-palliative epilepsy surgery.

High frequency oscillations are a promising biomarker of outcome in intractable epilepsy. Prior high frequency oscillation work focused on counting high frequency oscillations on individual channels, and it is still unclear how to translate those results into clinical care. We show that high frequency oscillations arise as network discharges that have valuable properties as predictive biomarkers. Here, we develop a tool to predict patient outcome before surgical resection is performed, based on only prospective information. In addition to determining high frequency oscillation rate on every channel, we performed a correlational analysis to evaluate the functional connectivity of high frequency oscillations in 28 patients with intracranial electrodes. We found that high frequency oscillations were often not solitary events on a single channel, but part of a local network discharge. Eigenvector and outcloseness centrality were used to rank channel importance within the connectivity network, then used to compare patient outcome by comparison with the seizure onset zone or a proportion within the proposed resected channels (critical resection percentage). Combining the knowledge of each patient's seizure onset zone resection plan along with our computed high frequency oscillation network centralities and high frequency oscillation rate, we develop a Naïve Bayes model that predicts outcome (positive predictive value: 100%) better than predicting based upon fully resecting the seizure onset zone (positive predictive value: 71%). Surgical margins had a large effect on outcomes: non-palliative patients in whom most of the seizure onset zone was resected ('definitive surgery', ≥ 80% resected) had predictable outcomes, whereas palliative surgeries (<80% resected) were not predictable. These results suggest that the addition of network properties of high frequency oscillations is more accurate in predicting patient outcome than seizure onset zone alone in patients with most of the seizure onset zone removed and offer great promise for informing clinical decisions in surgery for refractory epilepsy.

Estimation of Circular Statistics in the Presence of Measurement Bias.

Circular statistics and Rayleigh tests are important tools for analyzing cyclic events. However, current methods are not robust to significant measurement bias, especially incomplete or otherwise non-uniform sampling. One example is studying 24-cyclicity but having data not recorded uniformly over the full 24-hour cycle. Our objective is to present a robust method to estimate circular statistics and their statistical significance in the presence of incomplete or otherwise non-uniform sampling. Our method is to solve the underlying Fredholm Integral Equation for the more general problem, estimating probability distributions in the context of imperfect measurements, with our circular statistics in the presence of incomplete/non-uniform sampling being one special case. The method is based on linear parameterizations of the underlying distributions. We simulated the estimation error of our approach for several toy examples as well as for a real-world example: analyzing the 24-hour cyclicity of an electrographic biomarker of epileptic tissue controlled for states of vigilance. We also evaluated the accuracy of the Rayleigh test statistic versus the direct simulation of statistical significance. Our method shows a very low estimation error. In the real-world example, the corrected moments had a root mean square error of [Formula: see text]. In contrast, the Rayleigh test statistic overestimated the statistical significance and was thus not reliable. The presented methods thus provide a robust solution to computing circular moments even with incomplete or otherwise non-uniform sampling. Since Rayleigh test statistics cannot be used in this circumstance, direct estimation of significance is the preferable option for estimating statistical significance.

An Automated Algorithm for the Identification of Somatosensory Cortex Using Magnetoencephalography.

The localization of eloquent cortex is crucial for many neurosurgical applications, such as epilepsy and tumor resection. Non-invasive localization of these cortical areas using magnetoencephalography (MEG) is generally performed using equivalent current dipoles. While this method is clinically validated, source localization depends on several subjective parameters. This paper aimed to develop an automated algorithm for identifying the cortical area activated during a somatosensory task from MEG recordings. Our algorithm uses singular value decomposition to outline the cortical area involved in this task. For proof of concept, we evaluate our algorithm using data from 10 subjects with epilepsy. Our algorithm has a statistically significant overlap with the somatosensory cortex (the expected active area in healthy subjects) in 6 of 10 subjects. Having thus demonstrated proof of concept, we conclude that our algorithm is ready for further testing in a larger cohort of subjects.Clinical relevance- Our algorithm identifies the dominant cortical area and boundary of the cortical tissue involved in a task-related response.

The BEST Conceivable Way to Talk About Epilepsy Biomarkers.

The search for valid biomarkers to aid in epilepsy diagnosis and management is a major goal of the Epilepsy Research Benchmarks. Many papers and grants answer this call by searching for new biomarkers from a wide range of disciplines. However, the academic use of the word "biomarker" is often imprecise. Without proper definition, such work is not well-prepared to progress to the next step of translating these biomarkers into clinical use. In 2016, the Food and Drug Administration and National Institutes of Health collaborated to develop the BEST (Biomarkers, EndpointS, and other Tools) Resource as a guide to adopt formal definitions that aid in pushing successful biomarkers toward regulatory approval. Using the vignette of high-frequency oscillations, which have been proposed as a potential biomarker of several potential aspects of epilepsy, we demonstrate how improper use of the term "biomarker," and lack of a clear context of use, can lead to confusion and difficulty obtaining regulatory approval. Similar conditions are likely in many areas of biomarker research. This Resource should be adopted by all researchers developing epilepsy biomarkers. Adopting the BEST guidelines will improve reproducibility, guide research objectives toward translation, and better target the Epilepsy Benchmarks.

Evaluation of consensus sleep stage scoring of dysregulated sleep in Parkinson's disease.

OBJECTIVE: Sleep dysregulation in Parkinson's disease (PD) has been hypothesized to occur, in part, from dysfunction in the basal ganglia-cortical circuit. Assessment of this relationship requires accurate sleep stage determination, a known challenge in this clinical population. Our objective was to optimize the consensus on the sleep staging process and reduce interrater variability in a cohort of advanced PD subjects. METHODS: Fifteen PD subjects were enrolled from three sites in a clinical trial that involved recordings from subthalamic nucleus (STN) deep brain stimulation (DBS) leads (NCT04620551). Video polysomnography (vPSG) data for a total of 45 nights were analyzed. Four experienced scorers independently scored data on initial review. Epochs with less than 75% consensus were flagged for secondary review. In secondary review of discordant epochs, two of the original scorers re-assessed epochs, from which the final consensus stage was derived. RESULTS: Sleep stage classification agreement averaged 83.10% across all sleep stages on initial scoring (IS), and on secondary consensus scoring (CS) review, agreement reached 96.58%. Greatest disagreement was noted in determination of awake epochs (33.6% of discordant epochs) and non-rapid-eye-movement stage 2 (N2) epochs (31.8% of discordant epochs). Scoring discrepancy was resolved with direct measurement of cortical frequency and amplitudes, physiologic context of the epoch, and video review. CONCLUSION: Our method of multi-level initial and then secondary consensus review scoring resulted in consensus scoring agreement superior to conventional standards. This work features a custom-engineered vPSG software and review platform for integration of consensus sleep stage scoring in a multi-site clinical trial.

Interictal high frequency background activity as a biomarker of epileptogenic tissue.

High frequency oscillations (HFOs) are very brief events that are a well-established biomarker of the epileptogenic zone (EZ) but are rare and comprise only a tiny fraction of the total recorded EEG. We hypothesize that the interictal high frequency 'background' data, which has received little attention but represents the majority of the EEG record, also may contain additional, novel information for identifying the EZ. We analysed intracranial EEG (30-500 Hz frequency range) acquired from 24 patients who underwent resective surgery. We computed 38 quantitative features based on all usable, interictal data (63-307 h per subject), excluding all detected HFOs. We assessed association between each feature and the seizure onset zone (SOZ) and resected volume (RV) using logistic regression. A pathology score per channel was also created via principle component analysis and logistic regression, using hold-out-one-patient cross-validation to avoid in-sample training. Association of the pathology score with the SOZ and RV was quantified using an asymmetry measure. Many features were associated with the SOZ: 23/38 features had odds ratios >1.3 or <0.7 and 17/38 had odds ratios different than zero with high significance (P < 0.001/39, logistic regression with Bonferroni Correction). The pathology score, the rate of HFOs, and their channel-wise product were each strongly associated with the SOZ [median asymmetry ≥0.44, good surgery outcome patients; median asymmetry ≥0.40, patients with other outcomes; 95% confidence interval (CI) > 0.27 in both cases]. The pathology score and the channel-wise product also had higher asymmetry with respect to the SOZ than the HFO rate alone (median difference in asymmetry ≥0.18, 95% CI >0.05). These results support that the high frequency background data contains useful information for determining the EZ, distinct and complementary to information from detected HFOs. The concordance between the high frequency activity pathology score and the rate of HFOs appears to be a better biomarker of epileptic tissue than either measure alone.

Preictal variability of high-frequency oscillation rates in refractory epilepsy.

OBJECTIVE: High-frequency oscillations (HFOs) have shown promising utility in the spatial localization of the seizure onset zone for patients with focal refractory epilepsy. Comparatively few studies have addressed potential temporal variations in HFOs, or their role in the preictal period. Here, we introduce a novel evaluation of the instantaneous HFO rate through interictal and peri-ictal epochs to assess their usefulness in identifying imminent seizure onset. METHODS: Utilizing an automated HFO detector, we analyzed intracranial electroencephalographic data from 30 patients with refractory epilepsy undergoing long-term presurgical evaluation. We evaluated HFO rates both as a 30-minute average and as a continuous function of time and used nonparametric statistical methods to compare individual and population-level differences in rate during peri-ictal and interictal periods. RESULTS: Mean HFO rate was significantly higher for all epochs in seizure onset zone channels versus other channels. Across the 30 patients of our cohort, we found no statistically significant differences in mean HFO rate during preictal and interictal epochs. For continuous HFO rates in seizure onset zone channels, however, we found significant population-wide increases in preictal trends relative to interictal periods. Using a data-driven analysis, we identified a subset of 11 patients in whom either preictal HFO rates or their continuous trends were significantly increased relative to those of interictal baseline and the rest of the population. SIGNIFICANCE: These results corroborate existing findings that HFO rates within epileptic tissue are higher during interictal periods. We show this finding is also present in preictal, ictal, and postictal data, and identify a novel biomarker of preictal state: an upward trend in HFO rate leading into seizures in some patients. Overall, our findings provide preliminary evidence that HFOs can function as a temporal biomarker of seizure onset.

Distinguishing false and true positive detections of high frequency oscillations.

OBJECTIVE: High frequency oscillations (HFOs) are a promising biomarker of tissue that instigates seizures. However, ambiguous data and random background fluctuations can cause any HFO detector (human or automated) to falsely label non-HFO data as an HFO (a false positive detection). The objective of this paper was to identify quantitative features of HFOs that distinguish between true and false positive detections. APPROACH: Feature selection was performed using background data in multi-day, interictal intracranial recordings from ten patients. We selected the feature most similar between randomly selected segments of background data and HFOs detected in surrogate background data (false positive detections by construction). We then compared these results with fuzzy clustering of detected HFOs in clinical data to verify the feature's applicability. We validated the feature is sensitive to false versus true positive HFO detections by using an independent data set (six subjects) scored for HFOs by three human reviewers. Lastly, we compared the effect of redacting putative false positive HFO detections on the distribution of HFOs across channels and their association with seizure onset zone (SOZ) and resected volume (RV). MAIN RESULTS: Of the 15 analyzed features, the analysis selected only skewness of the curvature (skewCurve). The feature was validated in human scored data to be associated with distinguishing true and false positive HFO detections. Automated HFO detections with higher skewCurve were more focal based on entropy measures and had increased localization to both the SOZ and RV. SIGNIFICANCE: We identified a quantitative feature of HFOs which helps distinguish between true and false positive detections. Redacting putative false positive HFO detections improves the specificity of HFOs as a biomarker of epileptic tissue.

Quantifying epileptogenesis in rats with spontaneous and responsive brain state dynamics.

There is a crucial need to identify biomarkers of epileptogenesis that will help predict later development of seizures. This work identifies two novel electrophysiological biomarkers that quantify epilepsy progression in a rat model of epileptogenesis. The long-term tetanus toxin rat model was used to show the development and remission of epilepsy over several weeks. We measured the response to periodic electrical stimulation and features of spontaneous seizure dynamics over several weeks. Both biomarkers showed dramatic changes during epileptogenesis. Electrically induced responses began to change several days before seizures began and continued to change until seizures resolved. These changes were consistent across animals and allowed development of an algorithm that could differentiate which animals would later develop epilepsy. Once seizures began, there was a progression of seizure dynamics that closely follows recent theoretical predictions, suggesting that the underlying brain state was changing over time. This research demonstrates that induced electrical responses and seizure onset dynamics are useful biomarkers to quantify dynamical changes in epileptogenesis. These tools hold promise for robust quantification of the underlying epileptogenicity and prediction of later development of seizures.

A taxonomy of seizure dynamotypes.

Seizures are a disruption of normal brain activity present across a vast range of species and conditions. We introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory. The 'dynamotype' of a seizure is the dynamic composition that defines its observable characteristics, including how it starts, evolves and ends. Analyzing over 2000 focal-onset seizures from multiple centers, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients' dynamotypes evolve during their lifetime and display complex but systematic variations including hierarchy (certain types are more common), non-bijectivity (a patient may display multiple types) and pairing preference (multiple types may occur during one seizure). TSD provides a way to stratify patients in complement to present clinical classifications, a language to describe the most critical features of seizure dynamics, and a framework to guide future research focused on dynamical properties.

Epileptic seizures have been recognized for centuries. But it was only in the 1930s that it was realized that seizures are the result of out-of-control electrical activity in the brain. By placing electrodes on the scalp, doctors can identify when and where in the brain a seizure begins. But they cannot tell much about how the seizure behaves, that is, how it starts, stops or spreads to other areas. This makes it difficult to control and prevent seizures. It also helps explain why almost a third of patients with epilepsy continue to have seizures despite being on medication. Saggio, Crisp et al. have now approached this problem from a new angle using methods adapted from physics and engineering. In these fields, "dynamics research" has been used with great success to predict and control the behavior of complex systems like electrical power grids. Saggio, Crisp et al. reasoned that applying the same approach to the brain would reveal the dynamics of seizures and that such information could then be used to categorize seizures into groups with similar properties. This would in effect create for seizures what the periodic table is for the elements. Applying the dynamics research method to seizure data from more than a hundred patients from across the world revealed 16 types of seizure dynamics. These "dynamotypes" had distinct characteristics. Some were more common than others, and some tended to occur together. Individual patients showed different dynamotypes over time. By constructing a way to classify seizures based on the relationships between the dynamotypes, Saggio, Crisp et al. provide a new tool for clinicians and researchers studying epilepsy. Previous clinical tools have focused on the physical symptoms of a seizure (referred to as the phenotype) or its potential genetic causes (genotype). The current approach complements these tools by adding the dynamotype: how seizures start, spread and stop in the brain. This approach has the potential to lead to new branches of research and better understanding and treatment of seizures.

Viability of Preictal High-Frequency Oscillation Rates as a Biomarker for Seizure Prediction.

Motivation: There is an ongoing search for definitive and reliable biomarkers to forecast or predict imminent seizure onset, but to date most research has been limited to EEG with sampling rates <1,000 Hz. High-frequency oscillations (HFOs) have gained acceptance as an indicator of epileptic tissue, but few have investigated the temporal properties of HFOs or their potential role as a predictor in seizure prediction. Here we evaluate time-varying trends in preictal HFO rates as a potential biomarker of seizure prediction. Methods: HFOs were identified for all interictal and preictal periods with a validated automated detector in 27 patients who underwent intracranial EEG monitoring. We used LASSO logistic regression with several features of the HFO rate to distinguish preictal from interictal periods in each individual. We then tested these models with held-out data and evaluated their performance with the area-under-the-curve (AUC) of their receiver-operating curve (ROC). Finally, we assessed the significance of these results using non-parametric statistical tests. Results: There was variability in the ability of HFOs to discern preictal from interictal states across our cohort. We identified a subset of 10 patients in whom the presence of the preictal state could be successfully predicted better than chance. For some of these individuals, average AUC in the held-out data reached higher than 0.80, which suggests that HFO rates can significantly differentiate preictal and interictal periods for certain patients. Significance: These findings show that temporal trends in HFO rate can predict the preictal state better than random chance in some individuals. Such promising results indicate that future prediction efforts would benefit from the inclusion of high-frequency information in their predictive models and technological architecture.

A New Theory of Gender Dysphoria Incorporating the Distress, Social Behavioral, and Body-Ownership Networks.

When postmortem studies related to transgender individuals were first published, little was known about the function of the various identified nuclei. Now, over 2 decades later, significant progress has been made associating function with specific brain regions, as well as in identifying networks associated with groups of behaviors. However, much of this progress has not been integrated into the general conceptualization of gender dysphoria in humans. I hypothesize that in individuals with gender dysphoria, the aspects of chronic distress, gender atypical behavior, and incongruence between perception of gender identity and external primary sex characteristics are all directly related to functional differences in associated brain networks. I evaluated previously published neuroscience data related to these aspects and the associated functional networks, along with other relevant information. I find that the brain networks that give individuals their ownership of body parts, that influence gender typical behavior, and that are involved in chronic distress are different in individuals with and without gender dysphoria, leading to a new theory-that gender dysphoria is a sensory perception condition, an alteration in the sense of gender influenced by the reflexive behavioral responses associated with each of these networks. This theory builds upon previous work that supports the relevance of the body-ownership network and that questions the relevance of cerebral sexual dimorphism in regard to gender dysphoria. However, my theory uses a hierarchical executive function model to incorporate multiple reflexive factors (body ownership, gender typical/atypical behavior, and chronic distress) with the cognitive, reflective process of gender identity.

Redaction of false high frequency oscillations due to muscle artifact improves specificity to epileptic tissue.

OBJECTIVE: High Frequency Oscillations (HFOs) are a promising biomarker of epilepsy. HFOs are typically acquired on intracranial electrodes, but contamination from muscle artifacts is still problematic in HFO analysis. This paper evaluates the effect of myogenic artifacts on intracranial HFO detection and how to remove them. METHODS: Intracranial EEG was recorded in 31 patients. HFOs were detected for the entire recording using an automated algorithm. When available, simultaneous scalp EEG was used to identify periods of muscle artifact. Those markings were used to train an automated scalp EMG detector and an intracranial EMG detector. Specificity to epileptic tissue was evaluated by comparison with seizure onset zone and resected volume in patients with good outcome. RESULTS: EMG artifacts are frequent and produce large numbers of false HFOs, especially in the anterior temporal lobe. The scalp and intracranial EMG detectors both had high accuracy. Removing false HFOs improved specificity to epileptic tissue. CONCLUSIONS: Evaluation of HFOs requires accounting for the effect of muscle artifact. We present two tools that effectively mitigate the effect of muscle artifact on HFOs. SIGNIFICANCE: Removing muscle artifacts improves the specificity of HFOs to epileptic tissue. Future HFO work should account for this effect, especially when using automated algorithms or when scalp electrodes are not present.

Chemical biomarkers of epileptogenesis and ictogenesis in experimental epilepsy.

Epilepsy produces chronic chemical changes induced by altered cellular structures, and acute ones produced by conditions leading into individual seizures. Here, we aim to quantify 24 molecules simultaneously at baseline and during periods of lowered seizure threshold in rats. Using serial hippocampal microdialysis collections starting two weeks after the pilocarpine-induced status epilepticus, we evaluated how this chronic epilepsy model affects molecule levels and their interactions. Then, we quantified the changes occurring when the brain moves into a pro-seizure state using a novel model of physiological ictogenesis. Compared with controls, pilocarpine animals had significantly decreased baseline levels of adenosine, homovanillic acid, and serotonin, but significantly increased levels of choline, glutamate, phenylalanine, and tyrosine. Step-wise linear regression identified that choline, homovanillic acid, adenosine, and serotonin are the most important features to characterize the difference in the extracellular milieu between pilocarpine and control animals. When increasing the hippocampal seizure risk, the concentrations of normetanephrine, serine, aspartate, and 5-hydroxyindoleacetic acid were the most prominent; however, there were no specific, consistent changes prior to individual seizures.

Variability in the location of high frequency oscillations during prolonged intracranial EEG recordings.

The rate of interictal high frequency oscillations (HFOs) is a promising biomarker of the seizure onset zone, though little is known about its consistency over hours to days. Here we test whether the highest HFO-rate channels are consistent across different 10-min segments of EEG during sleep. An automated HFO detector and blind source separation are applied to nearly 3000 total hours of data from 121 subjects, including 12 control subjects without epilepsy. Although interictal HFOs are significantly correlated with the seizure onset zone, the precise localization is consistent in only 22% of patients. The remaining patients either have one intermittent source (16%), different sources varying over time (45%), or insufficient HFOs (17%). Multiple HFO networks are found in patients with both one and multiple seizure foci. These results indicate that robust HFO interpretation requires prolonged analysis in context with other clinical data, rather than isolated review of short data segments.

Emergence of Narrowband High Frequency Oscillations from Asynchronous, Uncoupled Neural Firing.

Previous experimental studies have demonstrated the emergence of narrowband local field potential oscillations during epileptic seizures in which the underlying neural activity appears to be completely asynchronous. We derive a mathematical model explaining how this counterintuitive phenomenon may occur, showing that a population of independent, completely asynchronous neurons may produce narrowband oscillations if each neuron fires quasi-periodically, without requiring any intrinsic oscillatory cells or feedback inhibition. This quasi-periodicity can occur through cells with similar frequency-current ([Formula: see text]-[Formula: see text]) curves receiving a similar, high amount of uncorrelated synaptic noise. Thus, this source of oscillatory behavior is distinct from the usual cases (pacemaker cells entraining a network, or oscillations being an inherent property of the network structure), as it requires no oscillatory drive nor any specific network or cellular properties other than cells that repetitively fire with continual stimulus. We also deduce bounds on the degree of variability in neural spike-timing which will permit the emergence of such oscillations, both for action potential- and postsynaptic potential-dominated LFPs. These results suggest that even an uncoupled network may generate collective rhythms, implying that the breakdown of inhibition and high synaptic input often observed during epileptic seizures may generate narrowband oscillations. We propose that this mechanism may explain why so many disparate epileptic and normal brain mechanisms can produce similar high frequency oscillations.

THE INTRINSIC VALUE OF HFO FEATURES AS A BIOMARKER OF EPILEPTIC ACTIVITY.

High frequency oscillations (HFOs) are a promising biomarker of epileptic brain tissue and activity. HFOs additionally serve as a prototypical example of challenges in the analysis of discrete events in high-temporal resolution, intracranial EEG data. Two primary challenges are 1) dimensionality reduction, and 2) assessing feasibility of classification. Dimensionality reduction assumes that the data lie on a manifold with dimension less than that of the features space. However, previous HFO analysis have assumed a linear manifold, global across time, space (i.e. recording electrode/channel), and individual patients. Instead, we assess both a) whether linear methods are appropriate and b) the consistency of the manifold across time, space, and patients. We also estimate bounds on the Bayes classification error to quantify the distinction between two classes of HFOs (those occurring during seizures and those occurring due to other processes). This analysis provides the foundation for future clinical use of HFO features and guides the analysis for other discrete events, such as individual action potentials or multi-unit activity.