Mapping interictal discharges using intracranial EEG-fMRI to predict postsurgical outcomes.

Various subjective and objective methods have been proposed to identify which interictal epileptiform discharge (IED)-related EEG-fMRI results are more likely to delineate seizure generating tissue in patients with drug-resistant focal epilepsy for the purposes of surgical planning. In this intracranial EEG-fMRI study, we evaluated the utility of these methods to localize clinically relevant regions pre-operatively and compared the extent of resection of these areas to post-operative outcome. Seventy patients admitted for intracranial video-EEG monitoring were recruited for a simultaneous intracranial EEG-fMRI study. For all analyses of blood oxygen level-dependent responses associated with IEDs, an experienced epileptologist identified the most Clinically Relevant brain activation cluster using available clinical information. The Maximum cluster (the cluster with the highest z-score) was also identified for all analyses and assigned to one of three confidence levels (low, medium, or high) based on the difference of the peak z-scores between the Maximum and Second Maximum cluster (the cluster with the second highest peak z-value). The distance was measured and compared between the peak voxel of the aforementioned clusters and the electrode contacts where the interictal discharge and seizure onset were recorded. In patients who subsequently underwent epilepsy surgery, the spatial concordance between the aforementioned clusters and the area of resection was determined and compared to post-operative outcome. We evaluated 106 different IEDs in 70 patients. Both subjective (identification of the Clinically Relevant cluster) and objective (Maximum cluster much more significant than the second maximum cluster) methods of culling non-localizing EEG-fMRI activation maps increased the spatial concordance between these clusters and the corresponding IED or seizure onset zone contacts. However, only the objective methods of identifying medium and high confidence maps resulted in a significant association between resection of the peak voxel of the Maximum cluster and post-operative outcome. Resection of this area was associated with good post-operative outcomes but was not sufficient for seizure freedom. On the other hand, we found that failure to resect the medium and high confidence Maximum clusters was associated with a poor post-surgical outcome (negative predictive value = 1.0, sensitivity = 1.0). Objective methods to identify higher confidence EEG-fMRI results are needed to localize areas necessary for good post-operative outcomes. However, resection of the peak voxel within higher confidence Maximum clusters is not sufficient for good outcomes. Conversely, failure to resect the peak voxel in these clusters is associated with a poor post-surgical outcome.

The hemodynamic response to co-occurring interictal epileptiform discharges and high-frequency oscillations localizes the seizure-onset zone.

OBJECTIVE: To use intracranial electroencephalography (EEG) to characterize functional magnetic resonance imaging (fMRI) activation maps associated with high-frequency oscillations (HFOs) (80-250 Hz) and examine their proximity to HFO- and seizure-generating tissue. METHODS: Forty-five patients implanted with intracranial depth electrodes underwent a simultaneous EEG-fMRI study at 3 T. HFOs were detected algorithmically from cleaned EEG and visually confirmed by an experienced electroencephalographer. HFOs that co-occurred with interictal epileptiform discharges (IEDs) were subsequently identified. fMRI activation maps associated with HFOs were generated that occurred either independently of IEDs or within ±200 ms of an IED. For all significant analyses, the Maximum, Second Maximum, and Closest activation clusters were identified, and distances were measured to both the electrodes where the HFOs were observed and the electrodes involved in seizure onset. RESULTS: We identified 108 distinct groups of HFOs from 45 patients. We found that HFOs with IEDs produced fMRI clusters that were closer to the local field potentials of the corresponding HFOs observed within the EEG than HFOs without IEDs. In addition to the fMRI clusters being closer to the location of the EEG correlate, HFOs with IEDs generated Maximum clusters with greater z-scores and larger volumes than HFOs without IEDs. We also observed that HFOs with IEDs resulted in more discrete activation maps. SIGNIFICANCE: Intracranial EEG-fMRI can be used to probe the hemodynamic response to HFOs. The hemodynamic response associated with HFOs that co-occur with IEDs better identifies known epileptic tissue than HFOs that occur independently.

Mesial temporal lobe spiking reveals distinct patterns of blood oxygen level-dependent functional magnetic resonance imaging activation using simultaneous intracranial electroencephalography-functional magnetic resonance imaging.

OBJECTIVE: Temporal lobe epilepsy (TLE) has a high probability of becoming drug resistant and is frequently considered for surgical intervention. However, 30% of TLE cases have nonlesional magnetic resonance imaging (MRI) scans, which is associated with worse surgical outcomes. Characterizing interactions between temporal and extratemporal structures in these patients may help understand these poor outcomes. Simultaneous intracranial electroencephalography-functional MRI (iEEG-fMRI) can measure the hemodynamic changes associated with interictal epileptiform discharges (IEDs) recorded directly from the brain. This study was designed to characterize the whole brain patterns of IED-associated fMRI activation recorded exclusively from the mesial temporal lobes of patients with nonlesional TLE. METHODS: Eighteen patients with nonlesional TLE undergoing iEEG monitoring with mesial temporal IEDs underwent simultaneous iEEG-fMRI at 3 T. IEDs were marked, and statistically significant clusters of fMRI activation were identified. The locations of IED-associated fMRI activation for each patient were determined, and patients were grouped based on the location and pattern of fMRI activation. RESULTS: Two patterns of IED-associated fMRI activation emerged: primarily localized (n = 7), where activation was primarily located within the ipsilateral temporal lobe, and primarily diffuse (n = 11), where widespread bilateral extratemporal activation was detected. The primarily diffuse group reported significantly fewer focal to bilateral tonic-clonic seizures and had better postsurgical outcomes. SIGNIFICANCE: Simultaneous iEEG-fMRI can measure the hemodynamic changes associated with focal IEDs not visible on scalp EEG, such as those arising from the mesial temporal lobe. Significant fMRI activation associated with these IEDs was observed in all patients. Two distinct patterns of IED-associated activation were seen: primarily localized to the ipsilateral temporal lobe and more widespread, bilateral activation. Patients with widespread IED associated-activation had fewer focal to bilateral tonic-clonic seizures and better postsurgical outcome, which may suggest a neuroprotective mechanism limiting the spread of ictal events.

Localization of interictal discharge origin: A simultaneous intracranial electroencephalographic-functional magnetic resonance imaging study.

OBJECTIVE: Scalp electroencephalographic (EEG)-functional magnetic resonance imaging (fMRI) studies suggest that the maximum blood oxygen level-dependent (BOLD) response to an interictal epileptiform discharge (IED) identifies the area of IED generation. However, the maximum BOLD response has also been reported in distant, seemingly irrelevant areas. Given the poor postoperative outcomes associated with extra-temporal lobe epilepsy, we hypothesized this finding is more common when analyzing extratemporal IEDs as compared to temporal IEDs. We further hypothesized that a subjective, holistic assessment of other significant BOLD clusters to identify the most clinically relevant cluster could be used to overcome this limitation and therefore better identify the likely origin of an IED. Specifically, we also considered the second maximum cluster and the cluster closest to the electrode contacts where the IED was observed. METHODS: Maps of significant IED-related BOLD activation were generated for 48 different IEDs recorded from 33 patients who underwent intracranial EEG-fMRI. The locations of the maximum, second maximum, and closest clusters were identified for each IED. An epileptologist, blinded to these cluster assignments, selected the most clinically relevant BOLD cluster, taking into account all available clinical information. The distances between these BOLD clusters and their corresponding IEDs were then measured. RESULTS: The most clinically relevant cluster was the maximum cluster for 56% (27/48) of IEDs, the second maximum cluster for 13% (6/48) of IEDs, and the closest cluster for 31% (15/48) of IEDs. The maximum clusters were closer to IED contacts for temporal than for extratemporal IEDs (p = .022), whereas the most clinically relevant clusters were not significantly different (p = .056). SIGNIFICANCE: The maximum BOLD response to IEDs may not always be the most indicative of IED origin. We propose that available clinical information should be used in conjunction with EEG-fMRI data to identify a BOLD cluster representative of the IED origin.

Patient specific hemodynamic response functions associated with interictal discharges recorded via simultaneous intracranial EEG-fMRI.

Simultaneous collection of scalp EEG and fMRI has become an important tool for studying the hemodynamic changes associated with interictal epileptiform discharges (IEDs) in persons with epilepsy, and has become a standard presurgical assessment tool in some centres. We previously demonstrated that performing EEG-fMRI using intracranial electrodes (iEEG-fMRI) is of low risk to patients in our research centre, and offers unique insight into BOLD signal changes associated with IEDs recorded from very discrete sources. However, it is unknown whether the BOLD response corresponding to IEDs recorded by iEEG-fMRI follows the canonical hemodynamic response. We therefore scanned 11 presurgical epilepsy patients using iEEG-fMRI, and assessed the hemodynamic response associated with individual IEDs using two methods: assessment of BOLD signal changes associated with isolated IEDs at the location of the active intracranial electrode, and by estimating subject-specific impulse response functions to isolated IEDs. We found that the hemodynamic response associated with the intracranially recorded discharges varied by patient and by spike location. The observed shape and timing differences also deviated from the canonical hemodynamic response function traditionally used in many fMRI experiments. It is recommended that future iEEG-fMRI studies of IEDs use a flexible hemodynamic response model when performing parametric tests to accurately characterize these data.

Interdisciplinary views of fNIRS: Current advancements, equity challenges, and an agenda for future needs of a diverse fNIRS research community.

Functional Near-Infrared Spectroscopy (fNIRS) is an innovative and promising neuroimaging modality for studying brain activity in real-world environments. While fNIRS has seen rapid advancements in hardware, software, and research applications since its emergence nearly 30 years ago, limitations still exist regarding all three areas, where existing practices contribute to greater bias within the neuroscience research community. We spotlight fNIRS through the lens of different end-application users, including the unique perspective of a fNIRS manufacturer, and report the challenges of using this technology across several research disciplines and populations. Through the review of different research domains where fNIRS is utilized, we identify and address the presence of bias, specifically due to the restraints of current fNIRS technology, limited diversity among sample populations, and the societal prejudice that infiltrates today's research. Finally, we provide resources for minimizing bias in neuroscience research and an application agenda for the future use of fNIRS that is equitable, diverse, and inclusive.

Feasibility of an intracranial EEG-fMRI protocol at 3T: risk assessment and image quality.

Integrating intracranial EEG (iEEG) with functional MRI (iEEG-fMRI) may help elucidate mechanisms underlying the generation of seizures. However, the introduction of iEEG electrodes in the MR environment has inherent risk and data quality implications that require consideration prior to clinical use. Previous studies of subdural and depth electrodes have confirmed low risk under specific circumstances at 1.5T and 3T. However, no studies have assessed risk and image quality related to the feasibility of a full iEEG-fMRI protocol. To this end, commercially available platinum subdural grid/strip electrodes (4×5 grid or 1×8 strip) and 4 or 6-contact depth electrodes were secured to the surface of a custom-made phantom mimicking the conductivity of the human brain. Electrode displacement, temperature increase of electrodes and surrounding phantom material, and voltage fluctuations in electrode contacts were measured in a GE Discovery MR750 3T MR scanner during a variety of imaging sequences, typical of an iEEG-fMRI protocol. An electrode grid was also used to quantify the spatial extent of susceptibility artifact. The spatial extent of susceptibility artifact in the presence of an electrode was also assessed for typical imaging parameters that maximize BOLD sensitivity at 3T (TR=1500 ms; TE=30 ms; slice thickness=4mm; matrix=64×64; field-of-view=24 cm). Under standard conditions, all electrodes exhibited no measurable displacement and no clinically significant temperature increase (<1°C) during scans employed in a typical iEEG-fMRI experiment, including 60 min of continuous fMRI. However, high SAR sequences, such as fast spin-echo (FSE), produced significant heating in almost all scenarios (>2.0°C) that in some cases exceeded 10°C. Induced voltages in the frequency range that could elicit neuronal stimulation (<10 kHz) were well below the threshold of 100 mV. fMRI signal intensity was significantly reduced within 20mm of the electrodes for the imaging parameters used in this study. Thus, for the conditions tested, a full iEEG-fMRI protocol poses a low risk at 3T; however, fMRI sensitivity may be reduced immediately adjacent to the electrodes. In addition, high SAR sequences must be avoided.

Intracranial EEG-fMRI analysis of focal epileptiform discharges in humans.

PURPOSE: Combining intracranial electroencephalography (iEEG) with functional magnetic resonance imaging (fMRI) is of interest in epilepsy studies as it would allow the detection of much smaller interictal epileptiform discharges than can be recorded using scalp EEG-fMRI. This may help elucidate the spatiotemporal mechanisms underlying the generation of interictal discharges. To our knowledge, iEEG-fMRI has never been performed at 3 Tesla (3T) in humans. We report our findings relating to spike-associated blood oxygen level-dependent (BOLD) signal changes in two subjects. METHODS: iEEG-fMRI at 3T was performed in two subjects. Twelve channels of iEEG were recorded from subdural strips implanted on the left posterior temporal and middle frontal lobes in a 20-year-old female with bilateral periventricular gray matter heterotopia. Twenty channels of iEEG were recorded bilaterally from two subdural strips laid anterior-posterior along mesial temporal surfaces in a 29-year-old woman with bilateral temporal seizures and mild left amygdalar enlargement on MRI. Functional MRI (fMRI) statistical maps were generated and thresholded at p = 0.01. KEY FINDINGS: No adverse events were noted. A total of 105 interictal discharges were recorded in the posterior middle temporal gyrus of Subject 1. In Subject 2, 478 discharges were recorded from both mesial temporal surfaces (n = 194 left, 284 right). The right and left discharges were modeled separately, as they were independent. Subject 1 showed spike-associated BOLD signal increases in the left superior temporal region, left middle frontal gyrus, and right parietal lobe. BOLD decreases were seen in the right frontal and parietal lobes. In Subject 2, BOLD signal increases were seen in both mesial temporal lobes, which when left and right spikes were modeled independently, were greater on the side of the discharge. In addition, striking BOLD signal decreases were observed in the thalamus and posterior cingulate gyrus. SIGNIFICANCE: iEEG-fMRI can be performed at 3T with low risk. Notably, runs of only 5 or 10 min of EEG-fMRI were performed as part of our implementation protocol, yet a significant number of epileptiform discharges were recorded, allowing meaningful analyses. With these studies, we have shown that deactivation can be seen in individual subjects with focal epileptiform discharges. These preliminary observations suggest a novel mechanism through which focal interictal discharges may have widespread cortical and subcortical influences.

Effect of Training on Visual Identification of High Frequency Oscillations-A Delphi-Style Intervention.

OBJECTIVE: We examined the effect of a simple Delphi-method feedback on visual identification of high frequency oscillations (HFOs) in the ripple (80-250 Hz) band, and assessed the impact of this training intervention on the interrater reliability and generalizability of HFO evaluations. METHODS: We employed a morphology detector to identify potential HFOs at two thresholds and presented them to visual reviewers to assess the probability of each epoch containing an HFO. We recruited 19 board-certified epileptologists with various levels of experience to complete a series of HFO evaluations during three sessions. A Delphi-style intervention was used to provide feedback on the performance of each reviewer relative to their peers. A delayed-intervention paradigm was used, in which reviewers received feedback either before or after the second session. ANOVAs were used to assess the effect of the intervention on the reviewers' evaluations. Generalizability theory was used to assess the interrater reliability before and after the intervention. RESULTS: The intervention, regardless of when it occurred, resulted in a significant reduction in the variability between reviewers in both groups (p GroupDI = 0.037, p GroupEI = 0.003). Prior to the delayed-intervention, the group receiving the early intervention showed a significant reduction in variability (p GroupEI = 0.041), but the delayed-intervention group did not (p GroupDI = 0.414). Following the intervention, the projected number of reviewers required to achieve strong generalizability decreased from 35 to 16. SIGNIFICANCE: This study shows a robust effect of a Delphi-style intervention on the interrater variability, reliability, and generalizability of HFO evaluations. The observed decreases in HFO marking discrepancies across 14 of the 15 reviewers are encouraging: they are necessarily associated with an increase in interrater reliability, and therefore with a corresponding decrease in the number of reviewers required to achieve strong generalizability. Indeed, the reliability of all reviewers following the intervention was similar to that of experienced reviewers prior to intervention. Therefore, a Delphi-style intervention could be implemented either to sufficiently train any reviewer, or to further refine the interrater reliability of experienced reviewers. In either case, a Delphi-style intervention would help facilitate the standardization of HFO evaluations and its implementation in clinical care.

EEG differentiates left and right imagined Lower Limb movement.

BACKGROUND: Identifying which EEG signals distinguish left from right leg movements in imagined lower limb movement is crucial to building an effective and efficient brain-computer interface (BCI). Past findings on this issue have been mixed, partly due to the difficulty in collecting and isolating the relevant information. The purpose of this study was to contribute to this new and important literature. RESEARCH QUESTION: Can left versus right imagined stepping be differentiated using the alpha, beta, and gamma frequencies of EEG data at four electrodes (C1, C2, PO3, and PO4)? METHODS: An experiment was conducted with a sample of 16 healthy male participants. They imagined left and right lower limb movements across 60 trials at two time periods separated by one week. Participants were fitted with a 64-electrode headcap, lay supine on a specially designed device and then completed the imagined task while observing a customized computer-generated image of a human walking to signify the left and right steps, respectively. RESULTS: Findings showed that eight of the twelve frequency bands from 4 EEG electrodes were significant in differentiating imagined left from right lower limb movement. Using these data points, a neural network analysis resulted in an overall participant average test classification accuracy of left versus right movements at 63 %. SIGNIFICANCE: Our study provides support for using the alpha, beta and gamma frequency bands at the sensorimotor areas (C1 and C2 electrodes) and incorporating information from the parietal/occipital lobes (PO3 and PO4 electrodes) for focused, real-time EEG signal processing to assist in creating a BCI for those with lower limb compromised mobility.

fMRI-Informed EEG for brain mapping of imagined lower limb movement: Feasibility of a brain computer interface.

BACKGROUND: EEG and fMRI have contributed greatly to our understanding of brain activity and its link to behaviors by helping to identify both when and where the activity occurs. This is particularly important in the development of brain-computer interfaces (BCIs), where feed forward systems gather data from imagined brain activity and then send that information to an effector. The purpose of this study was to develop and evaluate a computational approach that enables an accurate mapping of spatial brain activity (fMRI) in relation to the temporal receptors (EEG electrodes) associated with imagined lower limb movement. NEW METHOD: EEG and fMRI data from 16 healthy, male participants while imagining lower limb movement were used for this purpose. A combined analysis of fMRI data and EEG electrode locations was developed to identify EEG electrodes with a high likelihood of capturing imagined lower limb movement originating from various clusters of brain activity. This novel feature selection tool was used to develop an artificial neural network model to classify right and left lower limb movement. RESULTS: Results showed that left versus right lower limb imagined movement could be classified with 66.5% accuracy using this approach. Comparison with existing methods: Adopting a purely data-driven approach for feature selection to use in the right/left classification task resulted in the same accuracy (66.6%) but with reduced interpretability. CONCLUSIONS: The developed fMRI-informed EEG approach could pave the way towards improved brain computer interfaces for lower limb movement while also being applicable to other systems where fMRI could be helpful to inform EEG acquisition and processing.

Differentiating the Brain's involvement in Executed and Imagined Stepping using fMRI.

The purpose of this study was to extend the extant literature regarding brain areas that are activated during executed and imagined lower limb movement. Past research suggests that stepping, as a cyclical movement, should activate the motor control areas of the brain that integrates smooth movements with spinal cord nerves. The neuronal activity needed to imagine that same activity is likely to recruit additional sensory-motor areas that provide initiation and inhibition signals, making this task take on a neuronal activity pattern that is more similar to discrete movements. To assess this research question, 16 participants took part in the current study where they executed and imagined stepping, with movement at the hip, knee, and ankle joints, while viewing a computer-generated image of a human walking. A block design with a total of 10 blocks for rest and task for each condition was used. Rest blocks lasted 18 seconds, followed by an 18-second display of the visual stimulus. Results showed that in the executed condition, areas of the brain that are most prominently associated with sensory-motor activity were activated. In the imagined condition areas of the brain associated with movement control, inhibition of movement, and the integration of sensory input and motor output (parietal and occipital) were also activated. These findings contribute to the literature identifying brain areas that are activated in lower limb locomotion.

Graph index complexity as a novel surrogate marker of high frequency oscillations in delineating the seizure onset zone.

OBJECTIVE: To investigate the Graph Index Complexity (uGIC) as a marker of high frequency oscillatory (HFO) activity, the seizure onset zone (SOZ), and surgical outcome. METHODS: The SOZ, rates of HFOs at two thresholds (broad, strict), and uGIC were determined using EEG data from 41 patients. The correlation between HFOs and uGIC were calculated. HFOs and uGIC were compared within and outside the SOZ. Postsurgical outcome was compared to the colocalization of HFOs and resected SOZ. RESULTS: There was significant correlation between uGIC and both broad (r = 0.69, p < 0.0005) and strict HFOs (r = 0.48, p < 0.0005). All were significantly greater within the SOZ overall, but only in 17/41 (strict, uGIC) or 18/41 (broad) patients. HFO markers were significantly greater within the SOZ for 8/15 patients with positive postsurgical outcomes, but not for any patients with negative outcomes (0/5). CONCLUSION: The uGIC is a marker of HFO activity, while HFOs and uGIC are markers of the SOZ overall. Colocalization of HFOs and the SOZ has strong positive predictive value for postsurgical outcome, but poor negative predictive value. SIGNIFICANCE: The uGIC is an objective surrogate marker of HFO activity independent of identifying discrete HFO events.

Manipulating visual scanpaths during facial emotion perception modulates functional brain activation in schizophrenia patients and controls.

Individuals with schizophrenia exhibit deficits in facial emotion processing, which have been associated with abnormalities in visual gaze behavior and functional brain activation. However, the relationship between gaze behavior and brain activation in schizophrenia remains unexamined. Studies in healthy individuals and other clinical samples indicate a relationship between gaze behavior and functional activation in brain regions implicated in facial emotion processing deficits in schizophrenia (e.g., fusiform gyrus), prompting the question of whether a similar relationship exists in schizophrenia. This study examined whether manipulating visual scanpaths during facial emotion perception would modulate functional brain activation in a sample of 23 schizophrenia patients and 26 community controls. Participants underwent functional magnetic resonance imaging (MRI) while viewing pictures of emotional faces. During the typical viewing condition, a fixation cue directed participants' gaze primarily to the eyes and mouth, whereas during the atypical viewing condition gaze was directed to peripheral features. Both viewing conditions elicited a robust response throughout face-processing regions. Typical viewing led to greater activation in visual association cortex including the right inferior occipital gyrus/occipital face area, whereas atypical viewing elicited greater activation in primary visual cortex and regions involved in attentional control. There were no between-groups activation differences in response to faces or interaction between group and gaze manipulation. The results indicate that gaze behavior modulates functional activation in early face-processing regions in individuals with and without schizophrenia, suggesting that abnormal gaze behavior in schizophrenia may contribute to activation abnormalities during facial emotion perception. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Errors in proprioceptive matching post-stroke are associated with impaired recruitment of parietal, supplementary motor, and temporal cortices.

Deficits in proprioception, the ability to discriminate the relative position and movement of our limbs, affect ~50% of stroke patients and reduce functional outcomes. Our lack of knowledge of the anatomical correlates of proprioceptive processing limits our understanding of the impact that such deficits have on recovery. This research investigated the relationship between functional impairment in brain activity and proprioception post-stroke. We developed a novel device and task for arm position matching during functional MRI (fMRI), and investigated 16 subjects with recent stroke and nine healthy age-matched controls. The stroke-affected arm was moved by an experimenter (passive arm), and subjects were required to match the position of this limb with the opposite arm (active arm). Brain activity during passive and active arm movements was determined, as well as activity in association with performance error. Passive arm movement in healthy controls was associated with activity in contralateral primary somatosensory (SI) and motor cortices (MI), bilateral parietal cortex, supplementary (SMA) and premotor cortices, secondary somatosensory cortices (SII), and putamen. Active arm matching was associated with activity in contralateral SI, MI, bilateral SMA, premotor cortex, putamen, and ipsilateral cerebellum. In subjects with stroke, similar patterns of activity were observed. However, in stroke subjects, greater proprioceptive error was associated with less activity in ipsilesional supramarginal and superior temporal gyri, and lateral thalamus. During active arm movement, greater proprioceptive error was associated with less activity in bilateral SMA and ipsilesional premotor cortex. Our results enhance our understanding of the correlates of proprioception within the temporal parietal cortex and supplementary/premotor cortices. These findings also offer potential targets for therapeutic intervention to improve proprioception in recovering stroke patients and thus improve functional outcome.

Generalizability of High Frequency Oscillation Evaluations in the Ripple Band.

Objective: We examined the interrater reliability and generalizability of high-frequency oscillation (HFO) visual evaluations in the ripple (80-250 Hz) band, and established a framework for the transition of HFO analysis to routine clinical care. We were interested in the interrater reliability or epoch generalizability to describe how similar the evaluations were between reviewers, and in the reviewer generalizability to represent the consistency of the internal threshold each individual reviewer. Methods: We studied 41 adult epilepsy patients (mean age: 35.6 years) who underwent intracranial electroencephalography. A morphology detector was designed and used to detect candidate HFO events, lower-threshold events, and distractor events. These events were subsequently presented to six expert reviewers, who visually evaluated events for the presence of HFOs. Generalizability theory was used to characterize the epoch generalizability (interrater reliability) and reviewer generalizability (internal threshold consistency) of visual evaluations, as well as to project the numbers of epochs, reviewers, and datasets required to achieve strong generalizability (threshold of 0.8). Results: The reviewer generalizability was almost perfect (0.983), indicating there were sufficient evaluations to determine the internal threshold of each reviewer. However, the interrater reliability for 6 reviewers (0.588) and pairwise interrater reliability (0.322) were both poor, indicating that the agreement of 6 reviewers is insufficient to reliably establish the presence or absence of individual HFOs. Strong interrater reliability (≥0.8) was projected as requiring a minimum of 17 reviewers, while strong reviewer generalizability could be achieved with <30 epoch evaluations per reviewer. Significance: This study reaffirms the poor reliability of using small numbers of reviewers to identify HFOs, and projects the number of reviewers required to overcome this limitation. It also provides a set of tools which may be used for training reviewers, tracking changes to interrater reliability, and for constructing a benchmark set of epochs that can serve as a generalizable gold standard, against which other HFO detection algorithms may be compared. This study represents an important step toward the reconciliation of important but discordant findings from HFO studies undertaken with different sets of HFOs, and ultimately toward transitioning HFO analysis into a meaningful part of the clinical epilepsy workup.

Interrater reliability of visually evaluated high frequency oscillations.

OBJECTIVE: High frequency oscillations (HFOs) and interictal epileptiform discharges (IEDs) have been shown to be markers of epileptogenic regions. However, there is currently no 'gold standard' for identifying HFOs. Accordingly, we aimed to formally characterize the interrater reliability of HFO markings to validate the current practices. METHODS: A morphology detector was implemented to detect events (candidate HFOs, lower-threshold events, and distractors) from the intracranial EEG (iEEG) of ten patients. Six electroencephalographers visually evaluated these events for the presence of HFOs and IEDs. Interrater reliability was calculated using pairwise Cohen's Kappa (κ) and intraclass correlation coefficients (ICC). RESULTS: The HFO evaluation distributions were significantly different for most pairs of reviewers (p<0.05; 11/15 pairs). Interrater reliability was poor for HFOs alone (κmean=0.403; ICC=0.401) and HFO+IEDs (κmean=0.568; ICC=0.570). CONCLUSIONS: The current practice of using two visual reviewers to identify HFOs is prone to bias arising from the poor agreement between reviewers, limiting the extrinsic validity of studies using these markers. SIGNIFICANCE: The poor interrater reliability underlines the need for a framework to reconcile the important findings of existing studies. The present epoched design is an ideal candidate for the implementation of such a framework.

Pre-ictal BOLD alterations: Two cases of patients with focal epilepsy.

The pre-ictal state is of interest for better understanding pathophysiological processes leading up to seizures and for identifying potential biomarkers for the prediction of these events. We present two cases of patients with focal epilepsy (occipital, insular) who had seizures during functional magnetic resonance imaging (fMRI) scans. Interictal (>30min pre-seizure) control data was available for one participant. The location and timing of pre-ictal blood oxygenation-level dependent (BOLD) signal alterations were examined along with changes in pre-ictal functional connectivity. BOLD signal increases were seen at/close to the seizure onset zone and in/near a contralateral homologous region for both patients. In one patient, BOLD signal decreases were also observed distant from the seizure onset zone. The BOLD signal changes began 11 to 3min prior to seizure onset. These findings add to a growing number of cases of pre-ictal hemodynamic alterations. The significant BOLD signal increases seen in/near the homologous region contralateral to the seizure onset zone in both patients suggests that this area may play a critical role in the pre-ictal state, perhaps functioning to inhibit the seizure onset zone, or alternatively, to be directly involved in seizure generation. Pre-ictal functional connectivity, using a seed at the presumed seizure onset zone, demonstrated increases in connectivity with regions near the contralateral homologous region prior to seizures. Alterations in connectivity were also observed and characterized in interictal data, highlighting the importance of future research in determining if the observed pre-ictal changes are specific indicators for impending seizures.

Co-localization between the BOLD response and epileptiform discharges recorded by simultaneous intracranial EEG-fMRI at 3 T.

OBJECTIVES: Simultaneous scalp EEG-fMRI can identify hemodynamic changes associated with the generation of interictal epileptiform discharges (IEDs), and it has the potential of becoming a standard, non-invasive technique for pre-surgical assessment of patients with medically intractable epilepsy. This study was designed to assess the BOLD response to focal IEDs recorded via simultaneous intracranial EEG-functional MRI (iEEG-fMRI). METHODS: Twelve consecutive patients undergoing intracranial video EEG monitoring were recruited for iEEG-fMRI studies at 3 T. Depth, subdural strip, or grid electrodes were implanted according to our standard clinical protocol. Subjects underwent 10-60 min of continuous iEEG-fMRI scanning. IEDs were marked, and the most statistically significant clusters of BOLD signal were identified (Z-score 2.3, p value < 0.05). We assessed the concordance between the locations of the BOLD response and the IED. Concordance was defined as a distance <1.0 cm between the IED and BOLD response location. Negative BOLD responses were not studied in this project. RESULTS: Nine patients (7 females) with a mean age of 31 years (range 22-56) had 11 different types of IEDs during fMR scanning. The IEDs were divided based on the location of the active electrode contact into mesial temporal, lateral temporal, and extra-temporal. Seven (5 left) mesial temporal IED types were recorded in 5 patients (110-2092 IEDs per spike location). Six of these IEDs had concordant BOLD response in the ipsilateral mesial temporal structures, <1 cm from the most active contact. One of the two subjects with left lateral temporal IEDs had BOLD responses concordant with the location of the most active contact, as well other ipsilateral and contralateral sites. Notably, the remaining two subjects with extratemporal discharges showed no BOLD signal near the active electrode contact. CONCLUSIONS: iEEG-fMRI is a feasible and low-risk method for assessment of hemodynamic changes of very focal IEDs that may not be recorded by scalp EEG. A high concordance rate between the location of the BOLD response and IEDs was seen for mesial temporal (6/7) IEDs. Significant BOLD activation was also seen in areas distant from the active electrode and these sites exhibited maximal BOLD activation in the majority of cases. This implies that iEEG-fMRI may further describe the areas involved in the generation of IEDs beyond the vicinity of the electrode(s).

The Frequency of Subarachnoid Hemorrhage from Very Small Cerebral Aneurysms (< 5 mm): A Population-Based Study.

BACKGROUND:  The prevailing view amongst neurosurgeons is that the larger the aneurysm, the higher the chance of rupture. This implies that very small aneurysms rarely rupture. To investigate this theory, we conducted a cross-sectional hospital-based study of aneurysmal subarachnoid hemorrhage, with an emphasis on aneurysm size at the time of rupture. METHODS:  We retrospectively reviewed hospital records and radiological tests of all patients admitted to Foothills Medical Center, Calgary, Alberta, with a ruptured saccular aneurysm from January 2008 to January 2012. The size of the dome and neck (in millimeters), the aspect ratio (aneurysm depth to aneurysm neck), and location of the aneurysms were determined using preoperative computed tomography angiography and digital subtraction angiography. FINDINGS:  One hundred and twenty-three patients with a ruptured saccular aneurysm were identified. The average size of the dome, neck, and the aspect ratio was 6.6±4.4 mm (range: 1.5-26 mm), 3.1 mm, and 2.6±0.9, respectively. Forty-six patients (37%) had a ruptured aneurysm with dome size < 5 mm (range: 1.5-4.9 mm). For these small aneurysms, the average size of the dome, neck, and the aspect ratio was 3.9+1.1 mm, 1.6 mm, and 2.1+0.6, respectively. The anterior communicating artery was the most common location regardless of size. CONCLUSION:  Small aneurysms (< 5 mm) are a common cause of aneurysmal subarachnoid hemorrhage. When unruptured, looking for other risk factors for rupture is highly recommended before simply leaving them alone.