Daniel J. Pittman

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.

Feasibility of an intracranial EEG–fMRI protocol at 3 T: 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.

Tolerating Ambiguity Ambiguous Words Recruit the Left Inferior Frontal Gyrus in Absence of a Behavioral Effect

Many models of word recognition predict a lexical ambiguity disadvantage in semantic categorization tasks (SCTs). However, recent evidence suggests that an ambiguity disadvantage in SCT results from a bias in the decision-making phase of the task and not in the meaning-activation phase: Behavioral effects of ambiguity disappear when these decision biases are controlled (Pexman, Hino, & Lupker, 2004). The current study used event-related functional magnetic resonance imaging to examine the neural correlates of ambiguity in a task that produced no behavioral ambiguity effect (i.e., SCT with a well-defined decision category). Twenty healthy adults participated. Results showed that despite producing no behavioral effect of ambiguity, ambiguous words were associated with the recruitment of cortical structures implicated in top-down modulation of noisy activity (e.g., left inferior frontal gyrus) when compared to unambiguous words. These results are interpreted as evidence that multiple meanings are activated for ambiguous words in SCT.

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).

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. Hum Brain Mapp 36:5252–5264, 2015.

Gaze Behavior of Spotters During an Air-to-Ground Search

Objective: This study was designed to develop methods for evaluating the gaze behaviors of spotters during air-to-ground search and to compare field-derived measures with previous lab results. Secondary aims were to assess adherence to a prescribed scan path, evaluate search effectiveness, and determine the predictors of task success. Background: Crashed aircraft must be located quickly to minimize loss of life, often requiring visual search from the air. Method: Eye movements were measured in 10 volunteer spotters while they searched from the air for ground targets. Visual acuity, contrast levels, and performance on a lab-based search task were also measured. Results: Results were similar to those of previous lab-based studies of air-to-ground search. Task success could be predicted best from a combination of gaze and laboratory variables, and as in previous research, experience was not one of them. Conclusions: In both lab and field research, performance is poor. Improvements in air search and rescue success will depend upon improvements in training, the refinement of scan tactics, changes to the task methods or environment, or modifications to parameters of the search exercise. Application: Spotters were unable to reliably search their assigned area, which has implications for the current search training program and in-the-air protocol.

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.

Gaze behavior of spotters during an air-to-ground search

Crashed aircraft must be located quickly to minimize loss of life, often requiring visual search from the air. This study was designed to develop methods for evaluating the gaze behaviors of spotters during air-to-ground search and to compare field derived measures with similar lab measures reported in the literature. A secondary aim was to assess adherence to a prescribed scan path, evaluate search effectiveness, and determine the predictors of task success. Eye movements were measured in 10 volunteer spotters while searching from the air for ground targets. Static visual acuity at several eccentricities and contrast levels and performance on a lab-based search performance were also measured. Gaze relative to the head was transformed to gaze relative to the ground using information from the scene. Coverage and task success were similar to literature values from a lab-based study of air-to-ground search. Air search task success could be predicted best from a combination of gaze and laboratory variables and, like previous lab-based research, experience was not one of them. Results from this field study provide some support for the generalizability of lab research. In both lab and field research performance is quite poor. Future improvements in air search and rescue success will depend upon improvements in training, the refinement of scan tactics, changes to the task methods or environment, or modifications to parameters of the search exercise.

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.

Comparison of Hemodynamic Response Models in a Combined EEG-fMRI Study of an Epileptic Patient

Independent component analysis (ICA) and statistical parametric mapping (SPM) are two commonly used methods of analyzing fMRI measurements taken from a patients brain. Typically, these methods are applied separately to the measurements to produce brain maps indicating where the patients brain was active while he or she performed a task or experienced a stimulus. ICA can also be used to develop a hemodynamic response model that can be used as a regressor in SPM of fMRI measurements, a statistical analysis procedure that uses the general linear model (GLM). This may lead to a more accurate method of localizing patient brain activity because the hemodynamic response model is tailored to the patients own measurements. In this study, BOLD fMRI data and EEG data were acquired from a continuous EEG-fMRI study done on a patient suffering from refractory right temporal lobe epilepsy. Spatial ICA was performed on the subjects BOLD fMRI measurements. One hemodynamic response model signal derived from the spatial ICA (sICA) results was generated to use as a regressor in SPM of the subject data. SPM-generated brain maps of the subject data using the canonical hemodynamic response model and the sICA-derived model were compared.