Balu Krishnan

Voxel-based morphometric magnetic resonance imaging (MRI) postprocessing in MRI-negative epilepsies.

In the presurgical workup of magnetic resonance imaging (MRI)‐negative (MRI− or “nonlesional”) pharmacoresistant focal epilepsy (PFE) patients, discovering a previously undetected lesion can drastically change the evaluation and likely improve surgical outcome. Our study utilizes a voxel‐based MRI postprocessing technique, implemented in a morphometric analysis program (MAP), to facilitate detection of subtle abnormalities in a consecutive cohort of MRI− surgical candidates.

Correlating magnetoencephalography to stereo-electroencephalography in patients undergoing epilepsy surgery

Magnetoencephalography and stereo-electroencephalography are often necessary in the course of the non-invasive and invasive presurgical evaluation of challenging patients with medically intractable focal epilepsies. In this study, we aim to examine the significance of magnetoencephalography dipole clusters and their relationship to stereo-electroencephalography findings, area of surgical resection, and seizure outcome. We also aim to define the positive and negative predictors based on magnetoencephalography dipole cluster characteristics pertaining to seizure-freedom. Included in this retrospective study were a consecutive series of 50 patients who underwent magnetoencephalography and stereo-electroencephalography at the Cleveland Clinic Epilepsy Center. Interictal magnetoencephalography localization was performed using a single equivalent current dipole model. Magnetoencephalography dipole clusters were classified based on tightness and orientation criteria. Magnetoencephalography dipole clusters, stereo-electroencephalography findings and area of resection were reconstructed and examined in the same space using the patient’s own magnetic resonance imaging scan. Seizure outcomes at 1 year post-operative were dichotomized into seizure-free or not seizure-free. We found that patients in whom the magnetoencephalography clusters were completely resected had a much higher chance of seizure-freedom compared to the partial and no resection groups ( P = 0.007). Furthermore, patients had a significantly higher chance of being seizure-free when stereo-electroencephalography completely sampled the area identified by magnetoencephalography as compared to those with incomplete or no sampling of magnetoencephalography results ( P = 0.012). Partial concordance between magnetoencephalography and interictal or ictal stereo-electroencephalography was associated with a much lower chance of seizure freedom as compared to the concordant group ( P = 0.0075). Patients with one single tight cluster on magnetoencephalography were more likely to become seizure-free compared to patients with a tight cluster plus scatter ( P = 0.0049) or patients with loose clusters ( P = 0.018). Patients whose magnetoencephalography clusters had a stable orientation perpendicular to the nearest major sulcus had a better chance of seizure-freedom as compared to other orientations ( P = 0.042). Our data demonstrate that stereo-electroencephalography exploration and subsequent resection are more likely to succeed, when guided by positive magnetoencephalography findings. As a corollary, magnetoencephalography clusters should not be ignored when planning the stereo-electroencephalography strategy. Magnetoencephalography tight cluster and stable orientation are positive predictors for a good seizure outcome after resective surgery, whereas the presence of scattered sources diminishes the probability of favourable outcomes. The concordance pattern between magnetoencephalography and stereo-electroencephalography is a strong argument in favour of incorporating localization with non-invasive tools into the process of presurgical evaluation before actual placement of electrodes. * Abbreviations : SECD : single equivalent current dipole SEEG : stereo-electroencephalography

Frequency-based Connectivity Analysis of Interictal iEEG to Localize the Epileptogenic Focus

Resective surgery of the epileptogenic focus may be the only option for selected patients with refractory epilepsy. Accurate determination of the focus is of paramount diagnostic importance, from a better selection of surgical candidates to improvement of surgery outcome. A novel localization algorithm has been developed, based on methods of measurement of information flow and its further processing. We used the measure of Generalized Partial Directed Coherence (GPDC) for analysis of long-term interictal (between seizures) intracranial electroencephalographic (iEEG) signals from 3 patients with temporal lobe epilepsy to quantify the directional information flows between brain sites, and an outlier detection statistic to identify the brain site receiving the maximum and most frequent information inflow from the other recording sites. In two out of the three patients the clinically assessed focus was detected by the algorithm as a statistically significant (p<;0.01) outlier with respect to information inflow. In the third patient, even though not statistically significant (at significance level a=0.01), the focus still had the highest inflow value. These results indicate that estimation of brains connectivity from advanced analysis of iEEG may shed light on localization of the epileptogenic focus and lead to a more accurate pre-surgical evaluation of epileptic patients.

Localization of the ictal onset zone with MEG using minimum norm estimate of a narrow band at seizure onset versus standard single current dipole modeling.

Literature on the yield of ictal magnetoencephalography (MEG) is limited to case reports and a few case series (Assaf et al., 2003; Eliashiv et al., 2002; Mohamed et al., 2007; Tang et al., 2003; Tilz et al., 2002; Yagyu et al., 2010). Most of these studies were done using single Equivalent Current Dipole (sECD) model in order to localize seizure onset zone. There are some conceptual challenges when it comes to implementing this model in localization of ictal rhythms, especially in cases of paroxysmal fast activity. Successful sECD-fitting rate appears to decrease as a function of frequency as studied by de Jongh et al. (2003). In this report, we describe a new method of analysis of ictal rhythms and implement it in an illustrative case. Although both approaches yielded concordant results at the lobar level, the rhythm-based approach provided more accurate sublobar localization. Successful surgical resection, guided by intracranial EEG, contained the area of activation delineated by the rhythm-based method leaving behind the sECD area.

Brain dynamics based automated epileptic seizure detection.

We developed and tested a seizure detection algorithm based on two measures of nonlinear and linear dynamics, that is, the adaptive short-term maximum Lyapunov exponent (ASTLmax) and the adaptive Teager energy (ATE). The algorithm was tested on long-term (0.5-11.7 days) continuous EEG recordings from five patients (3 with intracranial and 2 with scalp EEG) with a total of 56 seizures, producing a mean sensitivity of 91% and mean specificity of 0.14 false positives per hour. The developed seizure detection algorithm is data-adaptive, training-free, and patient-independent.

Feasibility of magnetoencephalography recording in an epilepsy patient with implanted responsive cortical stimulation device.

Approximately 30% of patients with medically intractable epilepsy are not candidates for surgery, and cortical stimulation is a therapeutic option for these patients. The effectiveness of responsive cortical stimulation has been shown in previous studies including a controlled clinical trial (Morrell 2011). Magnetoencephalography (MEG) is a newer noninvasive tool which can provide accurate source localization of interictal epileptiform activities. Because of its high spatiotemporal resolution and higher sensitivity, it is being increasingly employed in tertiary epilepsy centers. Since MEG is not affected by variations in conduction, and in particular the skull is transparent to magnetic fields, it is especially useful in patients with skull defects due to prior surgery or intracranial evaluation. The MEG signal is, however, easily affected by magnetic noise produced from metal devices. Our previous investigation has shown that spatial temporal filtering was necessary to remove the noise in order to obtain good estimate of dipole localization with vagus nerve stimulators (Kakisaka, et al. 2012). However, to date there is no report on the feasibility of recording MEG from patients with implanted cortical stimulation devices, e.g. the responsive neurostimulation (RNS) system (NeuroPace, Mountain View, California). Since the RNS device itself (i.e. not just the leads) is actually implanted in the skull, rather than at a distance like the vagus nerve stimulation (VNS) device, there has been an open question as to whether successful MEG recordings can be obtained in patients who have RNS implanted. A right-handed 33-year-old female presented with a history of pharmacoresistant seizures starting at the age of 9 years. Despite a previous right orbito-frontal resection, followed by right frontal lobectomy, her seizures persisted. Surgical pathology did not show any evidence of cortical dysplasia from either surgery. Seizures were axial tonic evolving to complex motor, 1-2 times per day, lasting 20-30 seconds. This patient participated in the RNS trial. The RNS® System (NeuroPace, Mountain View, CA), as shown in panel c, provided responsive cortical stimulation via a cranially implanted (right side of the head) programmable neurostimulator connected to a depth electrode inserted into the remaining tissue near the right basal frontal/diencephalon and a subdural strip near the right perislyvian region, over the right precentral gyrus near the face/arm region, where interictal spikes were seen on intraoperative ECoG previously. However, cortical stimulation failed to give improvement of the patient’s seizures, and the patient returned for further evaluation to explore possible surgical options. MEG, available in our center subsequent to her previous surgeries, was offered to the patient in an effort to refine the location of her epileptogenic zone and to consider further therapeutic strategies. Spontaneous MEG data was recorded in a magnetically shielded room using a 306-channel whole-head MEG system (Elekta Ltd, Helsinki, Finland). Signals were sampled at 1000 Hz and bandpass filtered between 0.03 and 330 Hz. We used a temporally-extended signal space separation (tSSS) algorithm, with processing performed by “Maxfilter” software provided from the vendor. Settings included a four-second time window and a subspace correlation limit of 0.9. The tSSS-filtered MEG data were analyzed after digital filtering between 5 and 45 Hz. Technical details of this processing can be found elsewhere (Song, et al. 2009). Figure 1 shows representative waveforms from the right parietal MEG sensors, before (a) and after tSSS processing (b). Only after preprocessing with tSSS filtering was it possible to perform single dipole analysis of interictal activities; one example is shown in panel d. The dipole source representing this spike was estimated on the previous resection margin (panel e), a typical finding of patients with prior surgery and recurring seizures (Mohamed, et al. 2007). Three types of interictal activities were found as shown in panel g: (1) a tight cluster with uniform horizontal orientation, located in the posterior margin of previous resection; (2) a relatively loose right temporal cluster with varying orientations, in the posterior and lateral temporal lobe and (3) another loose cluster with varying orientations, estimated in the left superior parietal lobe, posterior superior temporal and left insula. Although the first type of epileptic source just posterior to the resected area seemed to be highly consistent and focal, the existence of other active and not very focal epileptic sources in both hemispheres, consistent with video-EEG monitoring, indicated that the patient may not benefit from further surgery. Figure 1 Representative waveforms from the right parietal MEG sensors without (a) and with (b) tSSS processing, displayed on a 10-second page. Location of the implanted RNS device is in the vicinity of the right parietal MEG sensor, as can be seen on the X-ray ... In summary, we present the first clinical evidence that good-quality MEG data can be successfully recorded with the presence of a RNS device, with appropriate use of tSSS filtering. This result demonstrates that MEG can be an important component during the exploration of surgical options in patients with suboptimal results from RNS.

Advanced MEG Source Analysis for Epileptogenic Focus Localization in Patients with Non-Lesional MRI

Accurate determination of the epileptogenic focus can be challenging, especially when electroencephalography (EEG) and/or imaging studies (e.g. MRI) are inconclusive. A significant number of patients who undergo presurgical MEG testing have neocortical epilepsy with normal (non-lesional) MRI. The methodology we developed first identifies potential current sources in the brain that could account for the spontaneous MEG signals that are recorded in the sensor space, and subsequently measures directional information flow in the space of the identified current dipole sources. Applying this methodology to the interictal MEG recordings from two patients with neocortical epilepsy and non-lesional MRIs, who were seizure-free at least 6 months after surgery and resection of their epileptogenic focus, we were able to correctly localize the focus irrespectively of the presence or absence of interictal epileptic spikes in the data. It is anticipated that the promise of the proposed methodology to noninvasively identify the location of obscure neocortical epileptogenic foci, a yet unfulfilled goal for many patients with focal epilepsy and normal MRIs, could lead to a paradigm shift in the diagnosis and treatment of epilepsy by decreasing the need for prolonged hospitalization, improving selection of surgical candidates, and guiding the placement of intracranial electrodes when needed.

The Concept of Effective Inflow: Application to Interictal Localization of the Epileptogenic Focus From iEEG

GOAL Accurate determination of the epileptogenic focus is of paramount diagnostic and therapeutic importance in epilepsy. The current gold standard for focus localization is from ictal (seizure) onset and thus requires the occurrence and recording of multiple typical seizures of a patient. Localization of the focus from seizure-free (interictal) periods remains a challenging problem, especially in the absence of interictal epileptiform activity. METHODS By exploring the concept of effective inflow, we developed a focus localization algorithm (FLA) based on directed connectivity between brain sites. Subsequently, using the measure of generalized partial directed coherence (GPDC) over a broad frequency band in FLA for the analysis of interictal periods from long-term (days) intracranial electroencephalographic (iEEG) signals, we identified the brain region that is the most frequent receiver of maximal effective inflow from other brain regions. RESULTS In six out of nine patients with temporal lobe epilepsy, the thus identified brain region was a statistically significant outlier (p<0.01) and coincided with the clinically assessed epileptogenic focus. In the remaining three patients, the clinically assessed focus still exhibited the highest inflow, but it was not deemed an outlier (p>0.01). CONCLUSIONS These findings suggest that the epileptogenic focus is a region of intense influence from other regions interictally, possibly as a mechanism to keep it under control in seizure-free periods. SIGNIFICANCE The developed framework is expected to assist with the accurate epileptogenic focus localization, reduce hospital stay and healthcare cost, and provide guidance to treatment of epilepsy via resective surgery or neuromodulation.Goal: Accurate determination of the epileptogenic focus is of paramount diagnostic and therapeutic importance in epilepsy. The current gold standard for focus localization is from ictal (seizure) onset and thus requires the occurrence and recording of multiple typical seizures of a patient. Localization of the focus from seizure-free (interictal) periods remains a challenging problem, especially in the absence of interictal epileptiform activity. Methods: By exploring the concept of effective inflow, we developed a focus localization algorithm (FLA) based on directed connectivity between brain sites. Subsequently, using the measure of generalized partial directed coherence over a broad frequency band in FLA for the analysis of interictal periods from long-term (days) intracranial electroencephalographic signals, we identified the brain region that is the most frequent receiver of maximal effective inflow from other brain regions. Results: In six out of nine patients with temporal lobe epilepsy, the thus identified brain region was a statistically significant outlier (p < 0.01) and coincided with the clinically assessed epileptogenic focus. In the remaining three patients, the clinically assessed focus still exhibited the highest inflow, but it was not deemed an outlier (p > 0.01). Conclusions: These findings suggest that the epileptogenic focus is a region of intense influence from other regions interictally, possibly as a mechanism to keep it under control in seizure-free periods. Significance: The developed framework is expected to assist with the accurate epileptogenic focus localization, reduce hospital stay and healthcare cost, and provide guidance to treatment of epilepsy via resective surgery or neuromodulation.

Interictal Infraslow Activity in Stereoelectroencephalography: From Focus to Network.

Purpose: Infraslow activity (ISA) occurring during the interictal state in focal epilepsy is largely unstudied. In this exploratory analysis, the authors aimed to characterize features of interictal ISA in a cohort of patients studied by stereoelectroencephography. Methods: The interictal stereoelectroencephography records for 15 consecutive adult patients were retrospectively analyzed, after application of both conventional (1.6–70 Hz) and infraslow (0.01–0.1 Hz) bandpass filters. Visual analysis was complemented by time–frequency analysis to quantify the change in ISA power over hours. Linear correlation coefficient (R) calculations were used to map interictal connectivity in the infraslow band. Results: Interictal ISA background fluctuations were present throughout the interictal state in all patients, manifesting as recurrent and stereotyped oscillations. These oscillations had an apparent modulatory effect on conventional-band activities and spikes (“spike-crested oscillations”). In the infraslow band, the correlations between electrode contacts were shown to have a stable structure over time. Conclusions: Infraslow activity exists as a fundamental component of wideband cortical dynamics in focal epilepsy, with features suggestive of scale-free (1/f) dynamics: evidence of phase-amplitude coupling and functional connectivity in the infraslow band. Rather than viewed as a focal paroxysmal activity, interictal ISA may be better understood as a network process, although this requires further study.

Connectivity in ictal single photon emission computed tomography perfusion: a cortico-cortical evoked potential study

Subtraction ictal and interictal single photon emission computed tomography can demonstrate complex ictal perfusion patterns. Regions with ictal hyperperfusion are suggested to reflect seizure onset and propagation pathways. The significance of ictal hypoperfusion is not well understood. The aim of this study was to verify whether ictal perfusion changes, both hyper- and hypoperfusion, correspond to electrically connected brain networks. A total of 36 subtraction ictal and interictal perfusion studies were analysed in 31 consecutive medically refractory focal epilepsy patients, evaluated by stereo-electroencephalography that demonstrated a single focal onset. Cortico-cortical evoked potential studies were performed after repetitive electrical stimulation of the ictal onset zone. Evoked responses at electrode contacts outside the stimulation site were used as a measure of connectivity. The evoked responses at these electrodes were compared to ictal perfusion values noted at these locations. In 67% of studies, evoked responses were significantly larger in hyperperfused compared to baseline-perfused areas. The majority of hyperperfused contacts also had significantly increased evoked responses relative to pre-stimulus electroencephalogram. In contrast, baseline-perfused and hypoperfused contacts mainly demonstrated non-significant evoked responses. Finally, positive significant correlations (P < 0.05) were found between perfusion scores and evoked responses in 61% of studies. When the stimulated ictal onset area was hyperperfused, 82% of studies demonstrated positive significant correlations. Following stimulation of hyperperfused areas outside seizure onset, positive significant correlations between perfusion changes and evoked responses could be seen, suggesting bidirectional connectivity. We conclude that strong connectivity was demonstrated between the ictal onset zone and hyperperfused regions, while connectivity was weaker in the direction of baseline-perfused or hypoperfused areas. In trying to understand a patients epilepsy, one should consider the contribution of all hyperperfused regions, as these are likely not random, but represent an electrically connected epileptic network.