Identification and classification of pathology and artifacts for human intracranial cognitive research.

Intracranial electroencephalography (iEEG) presents a unique opportunity to extend human neuroscientific understanding. However, typically iEEG is collected from patients diagnosed with focal drug-resistant epilepsy (DRE) and contains transient bursts of pathological activity. This activity disrupts performances on cognitive tasks and can distort findings from human neurophysiology studies. In addition to manual marking by a trained expert, numerous IED detectors have been developed to identify these pathological events. Even so, the versatility and usefulness of these detectors is limited by training on small datasets, incomplete performance metrics, and lack of generalizability to iEEG. Here, we employed a large annotated public iEEG dataset from two institutions to train a random forest classifier (RFC) to distinguish data segments as either 'non-cerebral artifact' (n = 73,902), 'pathological activity' (n = 67,797), or 'physiological activity' (n = 151,290). We found our model performed with an accuracy of 0.941, specificity of 0.950, sensitivity of 0.908, precision of 0.911, and F1 score of 0.910, averaged across all three event types. We extended the generalizability of our model to continuous bipolar data collected in a task-state at a different institution with a lower sampling rate and found our model performed with an accuracy of 0.789, specificity of 0.806, and sensitivity of 0.742, averaged across all three event types. Additionally, we created a custom graphical user interface to implement our classifier and enhance usability.

ONE-TIME PAROXYSM of ARTISTIC TALENT in FOCAL EPILEPSY.

Despite having unremarkable artistic talent, an 8-year-old male with chronic focal epilepsy from the right lateral frontal lobe drew a complex visual pattern during a 15-minute spell when he looked physically unwell. He underwent epilepsy surgery shortly thereafter and has been seizure-free since. In the ensuing 16 years of follow-up there have been no other such artistic incidents. We deduce that emergence of paroxysmal de novo artistic ability in our patient was caused by seizure discharge disinhibiting the ipsilateral parietal cortex and/or transient ictal engagement of distant salience and default mode sites.

Cognitive and functional status in late-onset Lennox-Gastaut syndrome: Variation on a classic phenotype.

Lennox-Gastaut syndrome (LGS) denotes a refractory epileptic encephalopathy of childhood onset with the triad of generalized slow spike-wave (GSSW) on interictal scalp electroencephalogram (EEG), multiple seizure types, and intellectual impairment. The neurobiology of LGS is said to sustain abnormal patterns of brain activity and connectivity that ultimately impair normal cerebral developmental mechanisms. However, we describe eight patients from our combined practice who presented with electroclinical findings consistent with LGS but without significant cognitive impairment. All patients fulfilled the other criteria of LGS with multiple seizure types (three or more of generalized tonic-clonic, atonic, tonic, myoclonic, and atypical absence) and GSSW activity on EEG. Four subjects completed high school, two completed some college, two acquired college degrees, and all performed basic and instrumental activities of daily living (ADL) independently. Magnetic resonance imaging (MRI) was normal in all patients. We speculate that a variation of the classic phenotype of LGS can present with preserved cognitive and functional status, often with onset in the second decade of life, and associated with normal brain imaging.

Critique of the 2017 epileptic seizure and epilepsy classifications.

This article critiques the International League Against Epilepsy (ILAE) 2015-2017 classifications of epilepsy, epileptic seizures, and status epilepticus. It points out the following shortcomings of the ILAE classifications: (1) they mix semiological terms with epileptogenic zone terminology; (2) simple and widely accepted terminology has been replaced by complex terminology containing less information; (3) seizure evolution cannot be described in any detail; (4) in the four-level epilepsy classification, level two (epilepsy category) overlaps almost 100% with diagnostic level one (seizure type); and (5) the design of different classifications with distinct frameworks for newborns, adults, and patients in status epilepticus is confusing. The authors stress the importance of validating the new ILAE classifications and feel that the decision of Epilepsia to accept only manuscripts that use the ILAE classifications is premature and regrettable.

The interictal mesial temporal lobe epilepsy network.

OBJECTIVE: Identification of patient-specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network. METHODS: Intracranial recordings from 10 medically refractory MTLE patients were analyzed. In each patient, hour-long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150-millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize the MTLE network at group level. RESULTS: We generated the first graph of connectivity across a cohort of MTLE patients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians. SIGNIFICANCE: Apart from identifying interictal measures that can model patient-specific epileptogenic networks, we also produce a group map of network connectivity from a cohort of MTLE patients.

Focal Changes to Human Electrocorticography With Drowsiness: A Novel Measure of Local Sleep.

Drowsiness may be defined as the progressive loss of cortical processing efficiency that occurs with time passing while awake. This loss of cortical processing efficiency is reflected in focal changes to the electroencephalogram, including islands of increased delta power concurrent with drop-offs in neuronal activity (i.e., focal cortical inactivity). The authors hypothesized that these focal changes are evidenced at individual electrodes by combination of increased instantaneous amplitude in delta band and decreased instantaneous frequency in theta-alpha band, permitting their categorization as "active" and "inactive." An analysis of records from six patients with refractory epilepsy undergoing video-electrocorticographic monitoring was conducted. Feature extraction and state classification on multiple recordings revealed focal changes consistent with the hypothesis, as well as progressively increased numbers of inactive electrodes with time awake. The implications of these findings on the study of sleep, and particularly local sleep, are discussed.

A simple clinical score for prediction of nonepileptic seizures.

Psychogenic nonepileptic seizures (PNES), often mistaken for epilepsy in community practice, require inpatient video-EEG (VEEG) monitoring for diagnostic confirmation. We developed a simple score designed for use in an outpatient setting to predict the subsequent VEEG diagnosis of PNES. We retrospectively compared fifty-five consecutive patients with VEEG-proven PNES (N1=55) with a group of randomly selected patients with VEEG-proven epilepsy (N2=55). Patients were divided into two groups: I) a 'truly retrospective' group of 27 patients with PNES and 27 patients with epilepsy whose data served to develop the score, and II) a 'pseudoprospective' group of 28 patients each with PNES and epilepsy to whom the score was applied. Six features in the history of the Group I cohort appeared more prominent in patients with PNES than patients with epilepsy and were assigned escalating numerical values as follows: number of declared drug allergies (0, 0.5, 1), number of declared comorbidities (0, 0.5, 1), number of previous invasive medical interventions of any type (0, 0.5, 1), and a history of significant psychological or physical trauma (0 or 1). In addition, a score was assigned to verbal description of the seizures themselves as being consistent (=0), atypical (=1), or indeterminate (=0.5) for epilepsy. The values were added to yield an omnibus score ranging from 0 to 6. Scoring of Group II subjects in a blinded fashion revealed that in general patients with PNES had higher scores, and the majority obtained a score >2; most patients with epilepsy scored <1.5. Group difference in the mean between the PNES and epilepsy cohort was highly significant (p<0.0001, Wilcoxon rank-sum test). Our score is a simple clinical instrument based on the patient history that may find use in the triage of patients awaiting hospitalization for VEEG and in pre-VEEG counseling.

Reactivation of visual-evoked activity in human cortical networks.

In the absence of sensory input, neuronal networks are far from being silent. Whether spontaneous changes in ongoing activity reflect previous sensory experience or stochastic fluctuations in brain activity is not well understood. Here we demonstrate reactivation of stimulus-evoked activity that is distributed across large areas in the human brain. We performed simultaneous electrocorticography recordings from occipital, parietal, temporal, and frontal areas in awake humans in the presence and absence of sensory stimulation. We found that, in the absence of visual input, repeated exposure to brief natural movies induces robust stimulus-specific reactivation at individual recording sites. The reactivation sites were characterized by greater global connectivity compared with those sites that did not exhibit reactivation. Our results indicate a surprising degree of short-term plasticity across multiple networks in the human brain as a result of repeated exposure to unattended information.

Proposal: different types of alteration and loss of consciousness in epilepsy.

There are at least five types of alterations of consciousness that occur during epileptic seizures: auras with illusions or hallucinations, dyscognitive seizures, epileptic delirium, dialeptic seizures, and epileptic coma. Each of these types of alterations of consciousness has a specific semiology and a distinct pathophysiologic mechanism. In this proposal we emphasize the need to clearly define each of these alterations/loss of consciousness and to apply this terminology in semiologic descriptions and classifications of epileptic seizures. The proposal is a consensus opinion of experienced epileptologists, and it is hoped that it will lead to systematic studies that will allow a scientific characterization of the different types of alterations/loss of consciousness described in this article.

Pearls & Oy-sters: Mesial Temporal Seizures in the Absence of the Mesial Temporal Lobe. Seizure Onset vs Seizure Network

Seizure semiology represents the clinical expression of the activation of the several brain regions comprising an epileptic network. In mesial temporal lobe epilepsy (MTLE), this network includes the insular-opercular-neocortical temporal-hippocampal (IONTH) regions. In this study, we present the case of a patient with pharmacoresistant seizures characterized by nausea, lip-smacking, semipurposeful hand movements, and speechlessness, suggesting dominant hemisphere MTLE, with scalp video-EEG findings and left hippocampal sclerosis on brain MRI confirming the diagnosis. She underwent anterior temporal lobectomy with amygdalohippocampectomy and was seizure-free for 14 years before relapsing. Recurrent seizure semiology was similar to preoperative seizures, that is, consistent with left MTLE, despite the medial temporal lobe missing. Seizures were therefore assumed to arise from remnant portions of the IONTH network-the insula, operculum, and posterolateral temporal neocortex. Reinvestigation including MEG localization of spikes and acute MRI changes following a seizure cluster suggested a left opercular region epilepsy. Our patient thus demonstrated the principle that seizures with mesial temporal characteristics may arise from outside the mesial temporal lobe (MTL). MTLE semiology arises from the activation of a set of structures (the seizure network) associated with the MTL, which can be triggered by foci both within and outside the MTL itself, and indeed even in its absence. However, it is not necessary to resect the entire extended network to bring about extended periods of seizure freedom in patients with refractory MTLE.

Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study.

PURPOSE: To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE). METHODS: Multicenter retrospective review of medical records and electroencephalography (EEG) reports in 10 academic medical centers in North America and Europe, including 58 subjects, representing 60 episodes of RSE that were identified between 1999 and 2012. Seven episodes occurred after anoxic brain injury. KEY FINDINGS: Permanent control of RSE was achieved in 57% (34 of 60) of episodes. Ketamine was felt to have contributed to permanent control ("possible" or "likely" responses) in 32% (19 of 60) including seven (12%) in which ketamine was the last drug added (likely responses). Four of the seven likely responses, but none of the 12 possible ones, occurred in patients with postanoxic brain injury. No likely responses were observed when infusion rates were lower than 0.9 mg/kg/h, when ketamine was introduced at least 8 days after SE onset, or after failure of seven or more drugs. Ketamine was discontinued due to possible adverse events in five patients. Complications were mostly attributed to concurrent drugs, especially other anesthetics. Mortality rate was 43% (26 of 60), but was lower when SE was controlled within 24 h of ketamine initiation (16% vs. 56%, p = 0.0047). SIGNIFICANCE: Ketamine appears to be a relatively effective and safe drug for the treatment of RSE. This retrospective series provides preliminary data on effective dose and appropriate time of intervention to aid in the design of a prospective trial to further define the role of ketamine in the treatment of RSE.

Stereotactic EEG Practices: A Survey of United States Tertiary Referral Epilepsy Centers.

PURPOSE: Stereotactic EEG (SEEG) is being increasingly used in the intracranial evaluation of refractory epilepsy in the United States. In this study, the authors describe current practice of SEEG among National Association of Epilepsy Centers tertiary referral (level IV) centers. METHODS: Using the Survey Monkey platform, a survey was sent to all National Association of Epilepsy Centers level IV center directors. RESULTS: Of 192 centers polled, 104 directors completed the survey (54% response rate). Ninety-two percent currently perform SEEG. Of these, 55% of institutions reported that greater than 75% of their invasive electrode cases used SEEG. Stereotactic EEG was commonly used over subdural electrodes in cases of suspected mesial temporal lobe epilepsy (87%), nonlesional frontal lobe epilepsy (79%), insular epilepsy (100%), and individuals with prior epilepsy surgery (74%). Most centers (72%) used single-lead electrocardiogram monitoring concurrently with SEEG, but less than half used continuous pulse oximetry (47%) and only a few used respiratory belts (3%). Other significant intercenter technical variabilities included electrode nomenclature and choice of reference electrode. Patient care protocols varied among centers in patient-to-nurse ratio and allowed patient activity. Half of all centers had personnel who had prior experience in SEEG (50.5%); 20% of centers had adopted SEEG without any formal training. CONCLUSIONS: Stereotactic EEG has become the principal method for intracranial EEG monitoring in the majority of epilepsy surgery centers in the United States. Most report similar indications for use of SEEG, though significant variability exists in the utilization of concurrent cardiopulmonary monitoring as well as several technical and patient care practices. There is significant variability in level of background training in SEEG among practitioners. The study highlights the need for consensus statements and guidelines to benchmark SEEG practice and develop uniform standards in the United States.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

Neurophysiological brain mapping of human sleep-wake states.

OBJECTIVE: We recently proposed a spectrum-based model of the awake intracranial electroencephalogram (iEEG) (Kalamangalam et al., 2020), based on a publicly-available normative database (Frauscher et al., 2018). The latter has been expanded to include data from non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (von Ellenrieder et al., 2020), and the present work extends our methods to those data. METHODS: Normalized amplitude spectra on semi-logarithmic axes from all four arousal states (wake, N2, N3 and REM) were averaged region-wise and fitted to a multi-component Gaussian distribution. A reduced model comprising five key parameters per brain region was color-coded on to cortical surface models. RESULTS: The lognormal Gaussian mixture model described the iEEG accurately from all brain regions, in all sleep-wake states. There was smooth variation in model parameters as sleep and wake states yielded to each other. Specific observations unrelated to the model were that the primary cortical areas of vision, motor function and audition, in addition to the hippocampus, did not participate in the 'awakening' of the cortex during REM sleep. CONCLUSIONS: Despite the significant differences in the appearance of the time-domain EEG in wakefulness and sleep, the iEEG in all arousal states was successfully described by a parametric spectral model of low dimension. SIGNIFICANCE: Spectral variation in the iEEG is continuous in space (across different cortical regions) and time (stage of circadian cycle), arguing for a 'continuum' hypothesis in the generative processes of sleep and wakefulness in human brain.

Functional Connectivity in Dorsolateral Frontal Cortex: Intracranial Electroencephalogram Study.

Motivation: Mechanisms underlying the variation in the appearance of electroencephalogram (EEG) over human head are not well characterized. We hypothesized that spatial variation of the EEG, being ultimately linked to variations in cortical neurobiology, was dependent on cortical connectivity patterns. Specifically, we explored the relationship of resting-state functional connectivity derived from intracranial EEG (iEEG) data in seven (N = 7) human epilepsy patients with the intrinsic dynamic variability of the local iEEG. We asked whether primary and association brain areas over the lateral frontal lobe-due to their sharply different connectivity patterns-were thus dissociable in "EEG space." Methods: Functional connectivity between pairs of subdural grid electrodes was averaged to yield an electrode connectivity (EC) whose time-average yielded mean electrode connectivity (mEC), compared with that electrode's time-averaged sample entropy (SE; mean electrode sample entropy, mESE). Results: We found that mEC and mESE were generally in inverse proportion to each other. Extreme values of mEC and mESE occurred over the Rolandic region and were part of a more general rostrocaudal gradient observed in all patients, with larger (smaller) values of mEC (mESE) occurring anteriorly. Conclusions: Brain networks influence brain dynamics. Over the lateral frontal lobe, mEC and mESE demonstrate a rostrocaudal topography, consistent with current notions regarding the structural and functional parcellation of the human frontal lobe. Our findings distinguish the frontal association cortex from primary sensorimotor cortex, effectively "diagnosing" Rolandic iEEG independent of the classical mu rhythm associated with the latter brain region. Impact statement Electroencephalographic rhythms (electroencephalogram [EEG]) exhibit well-recognized spatial variation over the brain surface. How such variation pertains to the biology of the cortex is poorly understood. Here we identify a novel relationship between sample entropy of the local EEG and the connectivity of that local cortical region to the rest of the brain. Due to the differing connectivities of primary and association motor areas, our methods identify new differences in the EEG arising from those respective brain areas. Our work demonstrates that aspects of brain dynamics (i.e., EEG entropy) may be understood in terms of brain architecture (i.e., functional connectivity) and vice versa.

Temporal lobe white matter asymmetry and language laterality in epilepsy patients.

Recent studies using diffusion tensor imaging (DTI) have advanced our knowledge of the organization of white matter subserving language function. It remains unclear, however, how DTI may be used to predict accurately a key feature of language organization: its asymmetric representation in one cerebral hemisphere. In this study of epilepsy patients with unambiguous lateralization on Wada testing (19 left and 4 right lateralized subjects; no bilateral subjects), the predictive value of DTI for classifying the dominant hemisphere for language was assessed relative to the existing standard-the intra-carotid Amytal (Wada) procedure. Our specific hypothesis is that language laterality in both unilateral left- and right-hemisphere language dominant subjects may be predicted by hemispheric asymmetry in the relative density of three white matter pathways terminating in the temporal lobe implicated in different aspects of language function: the arcuate (AF), uncinate (UF), and inferior longitudinal fasciculi (ILF). Laterality indices computed from asymmetry of high anisotropy AF pathways, but not the other pathways, classified the majority (19 of 23) of patients using the Wada results as the standard. A logistic regression model incorporating information from DTI of the AF, fMRI activity in Broca's area, and handedness was able to classify 22 of 23 (95.6%) patients correctly according to their Wada score. We conclude that evaluation of highly anisotropic components of the AF alone has significant predictive power for determining language laterality, and that this markedly asymmetric distribution in the dominant hemisphere may reflect enhanced connectivity between frontal and temporal sites to support fluent language processes. Given the small sample reported in this preliminary study, future research should assess this method on a larger group of patients, including subjects with bi-hemispheric dominance.

Extracranial Interictal and Ictal EEG in sEEG Planning.

Analysis of scalp electroencephalogram (EEG) findings is indispensable to investigation of epilepsy surgery candidates. Maxima of slowing and epileptiform spiking on interictal EEG reflect gross localization of core epileptogenic regions within a network. Important negative scalp EEG findings are those associated with deep foci. Ictal EEG is important in confirming concordance with interictal EEG and other ancillary data. Generalized interictal and ictal EEG findings may occur in epilepsies that are otherwise focal. Detailed individual analyses of scalp EEG features are prelude to a more global synthesis, whose coherence in suggesting plausible network hypothesis presage a subsequently successful scalp EEG evaluation.

A neurophysiological brain map: Spectral parameterization of the human intracranial electroencephalogram.

OBJECTIVE: A library of intracranial electroencephalography (iEEG) from the normal human brain has recently been made publicly available (Frauscher et al., 2018). The library - which we term the Montreal Neurological Institute Atlas (MNIA) - comprises 30 hours of iEEG from over a hundred epilepsy patients. We present a Fourier spectrum-based model of low dimension that summarizes all of MNIA into a neurophysiological 'brain map'. METHODS: Normalized amplitude spectra of the MNIA data were modelled as log-normal distributions around individual canonical Berger frequencies. The latter were concatenated to yield the composite spectrum with high accuracy. Key model parameters were color-coded into a visual representation on cortical surface models. RESULTS: Each brain region has its own spectral characteristics that together yield a novel composite intracranial EEG brain map. CONCLUSIONS: iEEG from normal brain regions can be accurately modelled with a small number of independent parameters. Our model is based in the canonical Berger bands and naturally suits clinical electroencephalography. SIGNIFICANCE: Due to its applicability to iEEG from all sampled regions, the model suggests a certain universality to brain rhythm generation that is independent of precise cortical location. More generally, our results are a novel abstraction of resting cortical dynamics that may help diagnostics in epileptology, in addition to informing structure-function relationships in the field of human brain mapping.

Montages for Noninvasive EEG Recording.

Identifying the localization, distribution, and polarity of waveforms are the prime goals of clinical scalp EEG analysis. Appropriate choices of bipolar and referential montages are keys to emphasizing the diagnostic features of interest, and demand some understanding of the spatiotemporal physical behavior of the underlying neuronal generators. Several examples drawn from canonical epilepsy syndromes are used to illustrate this general message.