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1.  Advances in Radiofrequency Ablation of the Cerebral Cortex in Primates Using the Venous System: Improvements for Treating Epilepsy with Catheter Ablation Technology 
Epilepsy research  2014;108(6):1026-1031.
Background
Pharmacology frequently fails for the treatment of epilepsy. Although surgical techniques are effective, these procedures are highly invasive. We describe feasibility and efficacy of minimally invasive mapping and ablation for the treatment of epilepsy.
Methods
Mapping and radiofrequency ablations were performed via the venous system in eleven baboons and three dogs.
Results
Mapping in deep cerebral areas was obtained in all animals. High-frequency pacing was able to induce seizure activity of local cerebral tissue in 72% of our attempts. Cerebral activity could be seen during mapping. Ablative lesions were deployed at deep brain sites without steam pops or sudden impedance rise. Histologic analysis showed necrosis at the sites of ablation in all primates.
Conclusion
Navigation through the cerebral venous system to map seizure activity is feasible. Radiofrequency energy can be delivered transvenously or transcortically to successful ablate cortical tissue in this animal model using this innovative approach.
doi:10.1016/j.eplepsyres.2014.04.002
PMCID: PMC4454459  PMID: 24836846
epilepsy; catheter ablation; venous system; radiofrequency; cerebral cortex
2.  High frequency oscillations are associated with cognitive processing in human recognition memory 
Brain  2014;137(8):2231-2244.
High frequency oscillations have been associated with focal epilepsy, but their role in human cognition is less clear. During intracranial recordings in patients undergoing seizure monitoring, Kucewicz et al. detect high gamma, ripple and fast ripple oscillations that are induced by image processing, and modulated by memory encoding and recall.
High frequency oscillations are associated with normal brain function, but also increasingly recognized as potential biomarkers of the epileptogenic brain. Their role in human cognition has been predominantly studied in classical gamma frequencies (30–100 Hz), which reflect neuronal network coordination involved in attention, learning and memory. Invasive brain recordings in animals and humans demonstrate that physiological oscillations extend beyond the gamma frequency range, but their function in human cognitive processing has not been fully elucidated. Here we investigate high frequency oscillations spanning the high gamma (50–125 Hz), ripple (125–250 Hz) and fast ripple (250–500 Hz) frequency bands using intracranial recordings from 12 patients (five males and seven females, age 21–63 years) during memory encoding and recall of a series of affectively charged images. Presentation of the images induced high frequency oscillations in all three studied bands within the primary visual, limbic and higher order cortical regions in a sequence consistent with the visual processing stream. These induced oscillations were detected on individual electrodes localized in the amygdala, hippocampus and specific neocortical areas, revealing discrete oscillations of characteristic frequency, duration and latency from image presentation. Memory encoding and recall significantly modulated the number of induced high gamma, ripple and fast ripple detections in the studied structures, which was greater in the primary sensory areas during the encoding (Wilcoxon rank sum test, P = 0.002) and in the higher-order cortical association areas during the recall (Wilcoxon rank sum test, P = 0.001) of memorized images. Furthermore, the induced high gamma, ripple and fast ripple responses discriminated the encoded and the affectively charged images. In summary, our results show that high frequency oscillations, spanning a wide range of frequencies, are associated with memory processing and generated along distributed cortical and limbic brain regions. These findings support an important role for fast network synchronization in human cognition and extend our understanding of normal physiological brain activity during memory processing.
doi:10.1093/brain/awu149
PMCID: PMC4107742  PMID: 24919972
high frequency oscillations; cognitive processing; memory; gamma oscillations; neural networks
3.  Evidence for Consolidation of Neuronal Assemblies after Seizures in Humans 
The Journal of Neuroscience  2015;35(3):999-1010.
The establishment of memories involves reactivation of waking neuronal activity patterns and strengthening of associated neural circuits during slow-wave sleep (SWS), a process known as “cellular consolidation” (Dudai and Morris, 2013). Reactivation of neural activity patterns during waking behaviors that occurs on a timescale of seconds to minutes is thought to constitute memory recall (O'Keefe and Nadel, 1978), whereas consolidation of memory traces may be revealed and served by correlated firing (reactivation) that appears during sleep under conditions suitable for synaptic modification (Buhry et al., 2011). Although reactivation has been observed in human neuronal recordings (Gelbard-Sagiv et al., 2008; Miller et al., 2013), reactivation during sleep has not, likely because data are difficult to obtain and the effect is subtle. Seizures, however, provide intense and synchronous, yet sparse activation (Bower et al., 2012) that could produce a stronger consolidation effect if seizures activate learning-related mechanisms similar to those activated by learned tasks. Continuous wide-bandwidth recordings from patients undergoing intracranial monitoring for drug-resistant epilepsy revealed reactivation of seizure-related neuronal activity during subsequent SWS, but not wakefulness. Those neuronal assemblies that were most strongly activated during seizures showed the largest correlation changes, suggesting that consolidation selectively strengthened neuronal circuits activated by seizures. These results suggest that seizures “hijack” physiological learning mechanisms and also suggest a novel epilepsy therapy targeting neuronal dynamics during post-seizure sleep.
doi:10.1523/JNEUROSCI.3019-14.2015
PMCID: PMC4300336  PMID: 25609617
consolidation; epilepsy; learning; memory; neural assemblies; seizures
4.  Pathologic brain network activity 
Neurology  2013;81(1):12-13.
doi:10.1212/WNL.0b013e318297ef3c
PMCID: PMC4490898  PMID: 23685930 CAMSID: cams4872
5.  Noninvasive Imaging of the High Frequency Brain Activity in Focal Epilepsy Patients 
High frequency (HF) activity represents a potential biomarker of the epileptogenic zone in epilepsy patients, the removal of which is considered to be crucial for seizure-free surgical outcome. We proposed a high frequency source imaging (HFSI) approach to noninvasively image the brain sources of scalp recorded high frequency EEG activity. Both computer simulation and clinical patient data analysis were performed to investigate the feasibility of using the HFSI approach to image the sources of HF activity from noninvasive scalp EEG recordings. The HF activity was identified from high-density scalp recordings after high-pass filtering the EEG data and the EEG segments with HF activity were concatenated together to form repetitive HF activity. Independent component analysis was utilized to extract the components corresponding to the HF activity. Noninvasive EEG source imaging using realistic geometric boundary element head modeling was then applied to image the sources of the pathological HF brain activity. Five medically intractable focal epilepsy patients were studied and the estimated sources were found to be concordant with the surgical resection or intracranial recordings of the patients. The present study demonstrates, for the first time, that source imaging from the scalp HF activity could help to localize the seizure onset zone (SOZ) and provide a novel noninvasive way of studying the epileptic brain in humans. This study also indicates the potential application of studying HF activity in the pre-surgical planning of medically intractable epilepsy patients.
doi:10.1109/TBME.2013.2297332
PMCID: PMC4123538  PMID: 24845275
Source imaging; High frequency activity; Epileptogenic zone; Scalp EEG; Epilepsy
6.  Diagnostic Outcome of Surgical Revision of Intracranial Electrode Placements for Seizure Localization 
Purpose
We aimed to determine the yield of revising intracranially implanted electrodes and the factors contributing to the yield.
Methods
Patients were identified from the Mayo Clinic Epilepsy Surgery Database between 1997 and 2010. Twenty patients had revision of intracranial electrode placements because initial implantation did not localize seizure onset adequately.
Results
Seizures were captured in 18 of 20 patients who underwent intracranial electrode revision, of which 10 (55.6%) showed localized seizure onset that led to a surgical resection. Seizures were improved in 9 of 10 patients who underwent resection; of these, 5were seizure free. The only factors found to be statistically significant in localizing ictal onset zone after revised implantation were prior focal scalp interictal discharges and an initial intracranial EEG showing ictal onset at the edge of the electrode grid. No permanent complication was associated with revised implantation, but 1 patient had transient apraxia of the right foot.
Conclusion
Revised implantation could be useful in selected patients with inadequate seizure localization on initial intracranial EEG. Resective surgery was performed in 50% of patients who underwent revision of intracranial electrodes, with the majority of these patients experiencing an improvement in seizure control.
doi:10.1097/WNP.0000000000000047
PMCID: PMC4049195  PMID: 24887601
epilepsy surgery; intracranial EEG monitoring; seizure
7.  Electrophysiological Biomarkers of Epilepsy 
Neurotherapeutics  2014;11(2):334-346.
In patients being evaluated for epilepsy and in animal models of epilepsy, electrophysiological recordings are carried to capture seizures to determine the existence of epilepsy. Electroencephalography recordings from the scalp, or sometimes directly from the brain, are also used to locate brain areas where seizure begins, and in surgical treatment help plan the area for resection. As seizures are unpredictable and can occur infrequently, ictal recordings are not ideal in terms of time, cost, or risk when, for example, determining the efficacy of existing or new anti-seizure drugs, evaluating potential anti-epileptogenic interventions, or for prolonged intracerebral electrode studies. Thus, there is a need to identify and validate other electrophysiological biomarkers of epilepsy that could be used to diagnose, treat, cure, and prevent epilepsy. Electroencephalography recordings in the epileptic brain contain other interictal electrophysiological disturbances that can occur more frequently than seizures, such as interictal spikes (IIS) and sharp waves, and from invasive studies using wide bandwidth recording and small diameter electrodes, the discovery of pathological high-frequency oscillations (HFOs) and microseizures. Of IIS, HFOs, and microseizures, a significant amount of recent research has focused on HFOs in the pathophysiology of epilepsy. Results from studies in animals with epilepsy and presurgical patients have consistently found a strong association between HFOs and epileptogenic brain tissue that suggest HFOs could be a potential biomarker of epileptogenicity and epileptogenesis. Here, we discuss several aspects of HFOs, as well as IIS and microseizures, and the evidence that supports their role as biomarkers of epilepsy.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-014-0259-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-014-0259-0
PMCID: PMC3996122  PMID: 24519238
High frequency oscillation; Interictal spike; Microseizure; Epileptogenicity; Epileptogenesis; Ictogenesis
8.  Statistical SPECT processing in MRI-negative epilepsy surgery 
Neurology  2014;82(11):932-939.
Objective:
To evaluate the benefit of statistical SPECT processing over traditional subtraction methods, we compared ictal–interictal SPECT analyzed by statistical parametric mapping (SPM) (ISAS), statistical ictal SPECT coregistered to MRI (STATISCOM), and subtraction ictal–interictal SPECT coregistered with MRI (SISCOM) in patients with MRI-negative focal temporal lobe epilepsy (nTLE) and extratemporal lobe epilepsy (nETLE).
Methods:
We retrospectively identified 49 consecutive cases of drug-resistant focal epilepsy that had a negative preoperative MRI and underwent interictal and ictal SPECT prior to resective epilepsy surgery. Interictal and ictal SPECT scans were analyzed using SISCOM, ISAS, and STATISCOM to create hyperperfusion and hypoperfusion maps for each patient. Reviewers blinded to clinical data and the SPECT analysis method marked the site of probable seizure origin and indicated their confidence in the localization.
Results:
In nTLE and nETLE, the hyperperfusions detected by STATISCOM (71% nTLE, 57% nETLE) and ISAS (67% nTLE, 53% nETLE) were more often colocalized with surgery resection site compared to SISCOM (38% nTLE, 36% nETLE). In nTLE, localization of the hyperperfusion to the region of surgery was associated with an excellent outcome for STATISCOM (p = 0.005) and ISAS (p = 0.027), but not in SISCOM (p = 0.071). This association was not present in nETLE for any method.
Conclusion:
In an unselected group of patients with normal MRI and focal epilepsy, SPM-based methods of SPECT processing showed better localization of SPECT hyperperfusion to surgical resection site and higher interobserver agreement compared to SISCOM. These results show the benefit of statistical SPECT processing methods and further highlight the challenge of nETLE.
doi:10.1212/WNL.0000000000000209
PMCID: PMC3963002  PMID: 24532274
9.  Long-term treatment with responsive brain stimulation in adults with refractory partial seizures 
Neurology  2015;84(8):810-817.
Objective:
The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures.
Methods:
All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy.
Results:
The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%).
Conclusions:
The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures.
Classification of evidence:
This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.
doi:10.1212/WNL.0000000000001280
PMCID: PMC4339127  PMID: 25616485
10.  What is the importance of abnormal “background” activity in seizure generation? 
Investigations of interictal epileptiform spikes and seizures have played a central role in the study of epilepsy. The background EEG activity, however, has received less attention. In this chapter we discuss the characteristic features of the background activity of the brain when individuals are at rest and awake (resting wake) and during sleep. The characteristic rhythms of the background EEG are presented, and the presence of 1/f β behavior of the EEG power spectral density is discussed and its possible origin and functional significance. The interictal EEG findings of focal epilepsy and the impact of interictal epileptiform spikes on cognition are also discussed.
doi:10.1007/978-94-017-8914-1_3
PMCID: PMC4276130  PMID: 25012365
Electroencephalogram; Epilepsy; Local Field Potential Oscillations; High Frequency Oscillations; Sleep
11.  Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial 
Epilepsia  2014;55(3):432-441.
Objective
To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.
Methods
Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.
Results
All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.
Significance
Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.
doi:10.1111/epi.12534
PMCID: PMC4233950  PMID: 24621228
Cortical stimulation; Partial seizures; Focal seizures; Responsive stimulation; Neurostimulator
12.  Interictal Scalp Electroencephalography and Intraoperative Electrocorticography in Magnetic Resonance Imaging–Negative Temporal Lobe Epilepsy Surgery 
JAMA neurology  2014;71(6):702-709.
IMPORTANCE
Scalp electroencephalography (EEG) and intraoperative electrocorticography (ECoG) are routinely used in the evaluation of magnetic resonance imaging–negative temporal lobe epilepsy (TLE) undergoing standard anterior temporal lobectomy with amygdalohippocampectomy (ATL), but the utility of interictal epileptiform discharge (IED) identification and its role in outcome are poorly defined.
OBJECTIVES
To determine whether the following are associated with surgical outcomes in patients with magnetic resonance imaging–negative TLE who underwent standard ATL: (1) unilateral-only IEDs on preoperative scalp EEG; (2) complete resection of tissue generating IEDs on ECoG; (3) complete resection of opioid-induced IEDs recorded on ECoG; and (4) location of IEDs recorded on ECoG.
DESIGN, SETTING, AND PARTICIPANTS
Data were gathered through retrospective medical record review at a tertiary referral center. Adult and pediatric patients with TLE who underwent standard ATL between January 1, 1990, and October 15, 2010, were considered for inclusion. Inclusion criteria were magnetic resonance imaging–negative TLE, standard ECoG performed at the time of surgery, and a minimum follow-up of 12 months. Univariate analysis was performed using log-rank time-to-event analysis. Variables reaching significance with log-rank testing were further analyzed using Cox proportional hazards.
MAIN OUTCOMES AND MEASURES
Excellent or nonexcellent outcome at time of last follow-up. An excellent outcome was defined as Engel class I and a nonexcellent outcome as Engel classes II through IV.
RESULTS
Eighty-seven patients met inclusion criteria, with 48 (55%) achieving an excellent outcome following ATL. Unilateral IEDs on scalp EEG (P = .001) and complete resection of brain regions generating IEDs on baseline intraoperative ECoG (P = .02) were associated with excellent outcomes in univariate analysis. Both were associated with excellent outcomes when analyzed with Cox proportional hazards (unilateral-only IEDs, relative risk = 0.31 [95% CI, 0.16-0.64]; complete resection of IEDs on baseline ECoG, relative risk = 0.39 [95% CI, 0.20-0.76]). Overall, 25 of 35 patients (71%) with both unilateral-only IEDs and complete resection of baseline ECoG IEDs had an excellent outcome.
CONCLUSIONS AND RELEVANCE
Unilateral-only IEDs on preoperative scalp EEG and complete resection of IEDs on baseline ECoG are associated with better outcomes following standard ATL in magnetic resonance imaging–negative TLE. Prospective evaluation is needed to clarify the use of ECoG in tailoring temporal lobectomy.
doi:10.1001/jamaneurol.2014.585
PMCID: PMC4183227  PMID: 24781216
13.  Feasibility Study of a Caregiver Seizure Alert System in Canine Epilepsy 
Epilepsy research  2013;106(3):456-460.
Summary
A device capable of detecting seizures and alerting caregivers would be a major advance for epilepsy management, and could be used to guide early intervention and prevent seizure-related injuries. The objective of this work was to evaluate a seizure advisory system (SAS) that alerts caregivers of seizures in canines with naturally occurring epilepsy. Four dogs with epilepsy were implanted with a SAS that wirelessly transmits continuous intracranial EEG (iEEG) to an external device embedded with a seizure detection algorithm and the capability to alert caregivers. In this study a veterinarian was alerted by automated text message if prolonged or repetitive seizures occurred, and a rescue therapy protocol was implemented. The performance of the SAS caregiver alert was evaluated over the course of 8 weeks. Following discontinuation of antiepileptic drugs, the dogs experienced spontaneous unprovoked partial seizures that secondarily generalized. Three prolonged or repetitive seizure episodes occurred in 2 of the dogs. On each occasion, the SAS caregiver alert successfully alerted an on call veterinarian who confirmed the seizure activity via remote video-monitoring. A rescue medication was then administered and the seizures were aborted. This study demonstrates the feasibility of a SAS caregiver alert for prolonged or repetitive seizures, and enabling rescue medications to be delivered in a timely manner. The SAS may improve the management of human epilepsy by alerting caregivers of seizures, enabling early interventions, and potentially improving outcomes and quality of life of patients and caregivers.
doi:10.1016/j.eplepsyres.2013.06.007
PMCID: PMC3903427  PMID: 23962794
epilepsy; seizure management; seizure advisory; caregiver alert; EEG; device
14.  Electrocortical source imaging of intracranial EEG data in epilepsy 
Here we report first results of numerical methods for modeling the dynamic structure and evolution of epileptic seizure activity in an intracranial subdural electrode (iEEG, ECoG) recording from a patient with partial refractory epilepsy. A 15-min dataset containing two seizures was decomposed using up to five competing adaptive mixture ICA (AMICA) models. Multiple models modeled early or late ictal, or pre-or post-ictal periods in the data, respectively. To localize sources, a realistic Boundary Element Method (BEM) head model was constructed for the patient with custom open skull and plastic (non-conductive) electrode holder features. Source localization was performed using Sparse Bayesian Learning (SBL) on a dictionary of overlapping multi-scale cortical patches constructed from 80,130 dipoles in gray matter perpendicular to the cortical surface. Remaining mutual information among seizure-model AMICA components was dominated by two dependent component subspaces with largely contiguous source domains localized to superior frontal gyrus and precentral gyrus; these accounted for most of the ictal activity. Similar though much weaker dependent subspaces were also revealed in pre-ictal data by the associated AMICA model. Electrocortical source imaging appears promising both for clinical epilepsy research and for basic cognitive neuroscience research using volunteer patients who must undergo invasive monitoring for medical purposes.
doi:10.1109/IEMBS.2011.6090971
PMCID: PMC4135517  PMID: 22255194
15.  Modeling Cortical Source Dynamics and Interactions During Seizure 
Mapping the dynamics and spatial topography of brain source processes critically involved in initiating and propagating seizure activity is critical for effective epilepsy diagnosis, intervention, and treatment. In this report we analyze neuronal dynamics before and during epileptic seizures using adaptive multivariate autoregressive (VAR) models applied to maximally-independent (ICA) sources of intracranial EEG (iEEG, ECoG) data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. We visualize the spatial distribution of causal sources and sinks of ictal activity on the cortical surface (gyral and sulcal) using a novel combination of multivariate Granger-causal and graph-theoretic metrics combined with distributed source localization by Sparse Bayesian Learning applied to a multi-scale patch basis. This analysis reveals and visualizes distinct, seizure stage-dependent shifts in inter-component spatiotemporal dynamics and connectivity including the clinically-identified epileptic foci.
doi:10.1109/IEMBS.2011.6090332
PMCID: PMC4136461  PMID: 22254582
16.  Network oscillations modulate interictal epileptiform spike rate during human memory 
Brain  2013;136(8):2444-2456.
Eleven patients being evaluated with intracranial electroencephalography for medically resistant temporal lobe epilepsy participated in a visual recognition memory task. Interictal epileptiform spikes were manually marked and their rate of occurrence compared between baseline and three 2 s periods spanning a 6 s viewing period. During successful, but not unsuccessful, encoding of the images there was a significant reduction in interictal epileptiform spike rate in the amygdala, hippocampus, and temporal cortex. During the earliest encoding period (0–2000 ms after image presentation) in these trials there was a widespread decrease in the power of theta, alpha and beta band local field potential oscillations that coincided with emergent focal gamma frequency activity. Interictal epileptiform spike rate correlated with spectral band power changes and broadband (4–150 Hz) desynchronization, which predicted significant reduction in interictal epileptiform spike rate. Spike-triggered averaging of the field potential power spectrum detected a burst of low frequency synchronization 200 ms before the interictal epileptiform spikes that arose during this period of encoding. We conclude that interictal epileptiform spikes are modulated by the patterns of network oscillatory activity that accompany human memory offering a new mechanistic insight into the interplay of cognitive processing, local field potential dynamics and interictal epileptiform spike generation.
doi:10.1093/brain/awt159
PMCID: PMC3722348  PMID: 23803305
interictal epileptiform spikes; epilepsy; memory
17.  Intravenous Recording of Intracranial, Broadband EEG 
Journal of neuroscience methods  2013;214(1):21-26.
The most direct evaluation of human brain activity has been obtained from intracranial electrodes placed either on the surface of the brain or inserted into the brain to record from deep brain structures. Currently, the placement of intracranial electrodes implies transcranial surgery, either through a burr hole or a craniotomy, but the high degree of invasiveness and potential for morbidity of such major surgical procedures limits the applicability of intracranial recording. The vascular system provides a natural avenue to reach many brain regions that currently are reached by transcranial approaches, along with deep brain structures that cannot be reached via a transcranial approach without significant risk. To determine the applicability of intravascular approaches to high-frequency intracranial monitoring, a catheter containing multiple macro- and micro-electrodes was placed into the superior sagittal sinus of anesthetized pigs in parallel with clinical, subdural electrode grids to record epileptiform activity induced by direct, cortical injection of penicillin and to record responses to electrical stimulation. Intravascular electrodes recorded epileptiform spikes with similar magnitudes and waveshapes to those obtained by surface electrodes, both for macroelectrodes and microelectrodes, including the spatiotemporal evolution of epileptiform activity, suggesting that intravascular electrodes might provide localizing information regarding seizure foci. Sinusoidal electrical stimulation showed that intravascular electrodes provide sufficient broadband fidelity to record high-frequency, physiological events that may also prove useful in localizing seizure onset zones. As intravascular techniques have transformed cardiology, so intravascular neurophysiology may transform intracranial monitoring, in general, and the treatment of epilepsy, in particular.
doi:10.1016/j.jneumeth.2012.12.027
PMCID: PMC3593671  PMID: 23313850
18.  Multivariate Principal Oscillation Pattern Analysis of ICA Sources During Seizure 
Mapping the dynamics of neural source processes critically involved in initiating and propagating seizure activity is important for effective epilepsy diagnosis, intervention, and treatment. Tracking time-varying shifts in the oscillation modes of an evolving seizure may be useful for both seizure onset detection as well as for improved non-surgical interventions such as microstimulation. In this report we apply a multivariate eigendecomposition method to analyze the time-varying principal oscillation patterns (POPs, or eigenmodes) of maximally-independent (ICA) sources of intracranial EEG data recorded from subdural electrodes implanted in a human patient for evaluation of surgery for epilepsy. Our analysis of a subset of the most dynamically important eigenmodes reveals distinct shifts in characteristic frequency and damping time before, throughout, and following seizures providing insight into the dynamical structure of the system throughout seizure evolution.
doi:10.1109/EMBC.2012.6346575
PMCID: PMC3920590  PMID: 23366536
19.  Long-term Outcomes After Nonlesional Extratemporal Lobe Epilepsy Surgery 
JAMA neurology  2013;70(8):1003-1008.
Importance
A focal lesion detected by use of magnetic resonance imaging (MRI) is a favorable prognostic finding for epilepsy surgery. Patients with normal MRI findings and extratemporal lobe epilepsy have less favorable outcomes. Most studies investigating the outcomes of patients with normal MRI findings who underwent (nonlesional) extratemporal epilepsy surgery are confined to a highly select group of patients with limited follow-up.
Objective
To evaluate noninvasive diagnostic test results and their association with excellent surgical outcomes (defined using Engel classes I–IIA of surgical outcomes) in a group of patients with medically resistant nonlesional extratemporal epilepsy.
Design
A retrospective study.
Setting
Mayo Clinic, Rochester, Minnesota.
Participants
From 1997 through 2002, we identified 85 patients with medically resistant extratemporal lobe epilepsy who had normal MRI findings. Based on a standardized presurgical evaluation and review at a multi-disciplinary epilepsy surgery conference, some of these patients were selected for intracranial electroencephalographic (EEG) monitoring and epilepsy surgery.
Exposure
Nonlesional extratemporal lobe epilepsy surgery.
Main Outcomes and Measures
The results of non-invasive diagnostic tests and the clinical variables potentially associated with excellent surgical outcome were examined in patients with a minimum follow-up of 1 year (mean follow-up, 9 years).
Results
Based on the noninvasive diagnostic test results, a clear hypothesis for seizure origin was possible for 47 of the 85 patients (55%), and 31 of these 47 patients (66%) proceeded to intracranial EEG monitoring. For 24 of these 31 patients undergoing long-term intracranial EEG (77%), a seizure focus was identified and surgically resected. Of these 24 patients, 9 (38%) had an excellent outcome after resective epilepsy surgery. All patients with an excellent surgical outcome had at least 10 years of follow-up. Univariate analysis showed that localized interictal epileptiform discharges on scalp EEGs were associated with an excellent surgical outcome.
Conclusions and Relevance
Scalp EEG was the most useful test for identifying patients with normal MRI findings and extratemporal lobe epilepsy who were likely to have excellent outcomes after epilepsy surgery. Extending outcome analysis beyond the resective surgery group to the entire group of patients who were evaluated further highlights the challenge that these patients pose. Although 9 of 24 patients undergoing resective surgery (38%) had excellent outcomes, only 9 of 31 patients undergoing intracranial EEG (29%) and only 9 of 85 patient with nonlesional extratemporal lobe epilepsy (11%) had long-term excellent outcomes.
doi:10.1001/jamaneurol.2013.209
PMCID: PMC3920594  PMID: 23732844
20.  Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy 
Neurosurgical focus  2010;29(3):E16.
Object
Microsurgical resection of supratentorial cavernomas associated with intractable epilepsy is performed frequently. Despite its common occurrence, little is known about patient perceptions of microsurgical resection for cavernomas. This survey study was performed to investigate patient perceived outcome after surgery for cavernomas associated with intractable epilepsy.
Methods
The authors’ surgical database was searched for cavernoma resection performed between 1971 and July of 2006. Of the initial 173 patients identified, 102 met criteria for medically intractable seizures. These 102 patients were then mailed a survey to determine follow-up and patient satisfaction. Thirty-nine surveys were returned as undeliverable, and 30 (48%) of the remaining 63 patients responded.
Results
The average age at surgery for patients responding to this survey was 40 ± 16 years compared with 35 ± 15 years for all 102 patients. At prolonged follow-up, 87% of patients reported being seizure-free. Of those with seizures, 2 (7%) reported being nearly seizure-free (rare disabling seizures), 2 (7%) believed they had a worthwhile improvement in seizure frequency, and no patient (0%) in this series believed they did not have a worthwhile improvement in seizure frequency. Ninety percent of responders stated they definitely, and 10% probably, would have surgery again. No patient responded that they probably or definitely would not have epilepsy surgery. Mean clinical follow-up was 36 ± 8 months and survey follow-up was 97 ± 13 months for these 30 patients. Use of the mail-in survey increased follow-up length 2.7 times longer compared with clinical follow-up.
Conclusions
It is clear from this select group of survey responders that patients undergoing surgery for cavernomas associated with medically intractable epilepsy are happy they underwent surgery (100%) and had excellent surgical outcomes (87% seizure-free) at prolonged follow-up of 97 ± 13 months. These survey results support that microsurgical resection for cavernomas is highly effective and significantly improves these patients’ quality of life.
doi:10.3171/2010.6.FOCUS10127
PMCID: PMC3920597  PMID: 20809757
cavernoma; epilepsy; survey; patient outcome; postal questionnaire
21.  Forecasting Seizures in Dogs with Naturally Occurring Epilepsy 
PLoS ONE  2014;9(1):e81920.
Seizure forecasting has the potential to create new therapeutic strategies for epilepsy, such as providing patient warnings and delivering preemptive therapy. Progress on seizure forecasting, however, has been hindered by lack of sufficient data to rigorously evaluate the hypothesis that seizures are preceded by physiological changes, and are not simply random events. We investigated seizure forecasting in three dogs with naturally occurring focal epilepsy implanted with a device recording continuous intracranial EEG (iEEG). The iEEG spectral power in six frequency bands: delta (0.1–4 Hz), theta (4–8 Hz), alpha (8–12 Hz), beta (12–30 Hz), low-gamma (30–70 Hz), and high-gamma (70–180 Hz), were used as features. Logistic regression classifiers were trained to discriminate labeled pre-ictal and inter-ictal data segments using combinations of the band spectral power features. Performance was assessed on separate test data sets via 10-fold cross-validation. A total of 125 spontaneous seizures were detected in continuous iEEG recordings spanning 6.5 to 15 months from 3 dogs. When considering all seizures, the seizure forecasting algorithm performed significantly better than a Poisson-model chance predictor constrained to have the same time in warning for all 3 dogs over a range of total warning times. Seizure clusters were observed in all 3 dogs, and when the effect of seizure clusters was decreased by considering the subset of seizures separated by at least 4 hours, the forecasting performance remained better than chance for a subset of algorithm parameters. These results demonstrate that seizures in canine epilepsy are not randomly occurring events, and highlight the feasibility of long-term seizure forecasting using iEEG monitoring.
doi:10.1371/journal.pone.0081920
PMCID: PMC3885383  PMID: 24416133
22.  Efficacy of a Reduced Electroencephalography Electrode Array for Detection of Seizures 
The Neurohospitalist  2014;4(1):6-8.
Background:
The expertise required for proper electroencephalography (EEG) setup can make the 10-20 array unwieldy in the hospital setting. There may be a role for an EEG array with reduced leads to improve the efficiency of inpatient practice.
Methods:
Clips from 100 EEG records, 50 ictal and 50 non-ictal, in adult inpatients from January 1, 2007, to January 1, 2012, were retrospectively reviewed and selected for digital lead reduction and blind review. Two epileptologists reviewed these tracings and documented the presence of seizures and severe disturbance of background. The reduced array included 7 leads spanning the scalp. Three different montages were available. Sensitivity and specificity of the reduced array were calculated using the formal EEG report as the comparison standard.
Results:
For the detection of any seizure, the reduced array EEG had a sensitivity of 70% and specificity of 96%. Sensitivity for identifying encephalopathic patterns was 62% and specificity was 86%. Focal seizures were more readily identified by the reduced array (20 of 25) than were generalized ictal patterns (13 of 25).
Conclusion:
The reduced electrode array was insufficiently sensitive to seizure detection. Reducing EEG leads might not be a preferred means of optimizing hospital EEG efficiency.
doi:10.1177/1941874413507930
PMCID: PMC3869310  PMID: 24381704
EEG; montage; seizure; hospital; reduced; array
23.  Dynamic imaging of seizure activity in pediatric epilepsy patients 
Objective
To investigate the feasibility of using noninvasive EEG source imaging approach to image continuous seizure activity in pediatric epilepsy patients.
Methods
Nine pediatric patients with medically intractable epilepsy were included in this study. Eight of the patients had extratemporal lobe epilepsy and one had temporal lobe epilepsy. All of the patients underwent resective surgery and seven of them underwent intracranial EEG (iEEG) monitoring. The ictal EEG was analyzed using a noninvasive dynamic seizure imaging (DSI) approach. The DSI approach separates scalp EEGs into independent components and extracts the spatio-temporal ictal features to achieve dynamic imaging of seizure sources. Surgical resection and intracranial recordings were used to validate the noninvasive imaging results.
Results
The DSI determined seizure onset zones (SOZs) in these patients were localized within or in close vicinity to the surgically resected region. In the seven patients with intracranial monitoring, the estimated seizure onset sources were concordant with the seizure onset zones of iEEG. The DSI also localized the multiple foci involved in the later seizure propagation, which were confirmed by the iEEG recordings.
Conclusions
Dynamic seizure imaging can noninvasively image the seizure activations in pediatric patients with both temporal and extratemporal lobe epilepsy.
Significance
EEG seizure imaging can potentially be used to noninvasively image the SOZs and aid the pre-surgical planning in pediatric epilepsy patients.
doi:10.1016/j.clinph.2012.04.021
PMCID: PMC3438337  PMID: 22608485
Pediatric patients; Epilepsy; EEG; Dynamic seizure imaging; Intracranial recording; Surgical resection
24.  Use of Anterior Temporal Lobectomy for Epilepsy in a Community-Based Population 
Archives of neurology  2012;69(11):1476-1481.
Objective
To assess the hypothesis that use of anterior temporal lobectomy (ATL) for temporal epilepsy has diminished over time.
Design
Population-based cohort study.
Setting
The Rochester Epidemiology Project based in Olmsted County, Minnesota.
Participants
Residents of Olmsted County.
Main Outcome Measures
Poisson regression was used to evaluate changes in ATL use over time by sex.
Results
Over a 17-year period, from 1993 to 2009, 847 ATLs were performed with the primary indication of epilepsy (average, 50 procedures/y). Of these, 26 occurred among Olmsted County residents. The use rates de clined significantly between 1993 and 2000 (8 years) and 2001 and 2009 (9 years) according to Poisson regression analysis, from 1.9 to 0.7 per 100 000 person-years (P=.01). The rate of ATL use among Olmsted County residents was 1.2 (95% CI, 0.9 to 2.4) per 100 000 person-years of follow-up over this 17-year period. The sex-specific rates were 1.6 (95% CI, 0.9 to 2.4) and 0.7 (95% CI, 0.2 to 1.3) per 100 000 person-years for females and males, respectively.
Conclusions
In this community-based cohort, the rate of ATL use was 1.2 per 100 000 person-years of follow-up. Use of this procedure has declined over time; the reasons for this are unknown but do not include referral pattern changes.
doi:10.1001/archneurol.2012.1200
PMCID: PMC3526693  PMID: 22911042
25.  Spectral and spatial shifts of post-ictal slow waves in temporal lobe seizures 
Brain  2012;135(10):3134-3143.
Temporal lobe seizures have a significant chance to induce impairment of normal brain functions. Even after the termination of ictal discharges, during the post-ictal period, loss of consciousness, decreased responsiveness or other cognitive dysfunctions can persist. Previous studies have found various anatomical and functional abnormalities accompanying temporal lobe seizures, including an abnormal elevation of cortical slow waves. Intracranial electroencephalography studies have shown a prominent increase of lower frequency components during and following seizures that impair (complex partial seizures) but not those that preserve (simple partial seizures) normal consciousness and responsiveness. However, due to the limited spatial coverage of intracranial electroencephalography, the investigation of cortical slow waves cannot be easily extended to the whole brain. In this study, we used scalp electroencephalography to study the spectral features and spatial distribution of post-ictal slow waves with comprehensive spatial coverage. We studied simple partial, complex partial and secondarily generalized seizures in 28 patients with temporal lobe seizures. We used dense-array electroencephalography and source imaging to reconstruct the post-ictal slow-wave distribution. In the studied cohort, we found that a ‘global’ spectral power shift to lower frequencies accompanied the increased severity of seizures. The delta spectral power relative to higher frequency bands was highest for secondarily generalized seizures, followed by complex partial seizures and lastly simple partial seizures. In addition to this ‘global’ spectral shift, we found a ‘regional’ spatial shift in slow-wave activity. Secondarily generalized seizures and complex partial seizures exhibited increased slow waves distributed to frontal areas with spread to contralateral temporal and parietal regions than in simple partial seizures. These results revealed that a widespread cortical network including temporal and fronto-parietal cortex is involved in abnormal slow-wave activity following temporal lobe seizures. The differential spectral and spatial shifts of post-ictal electroencephalography activity in simple partial, complex partial and secondarily generalized seizures suggest a possible connection between cortical slow waves and behavioural and cognitive changes in a human epilepsy model.
doi:10.1093/brain/aws221
PMCID: PMC3470709  PMID: 22923634
cortical slowing; temporal lobe seizure; post-ictal state; consciousness; responsiveness

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