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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  Seizure source imaging by means of FINE spatio-temporal dipole localization and directed transfer function in partial epilepsy patients 
Clinical Neurophysiology  2011;123(7):1275-1283.
Objective
To investigate the usage of a high-density EEG recording system and source imaging technique for localizing seizure activity in patients with medically intractable partial epilepsy.
Methods
High-density, 76-channel scalp EEG signals were recorded in ten patients with partial epilepsy. The patients underwent routine clinical pre-surgical evaluation and all had resective surgery with seizure free outcome. After applying a FINE (first principle vectors) spatial-temporal source localization and DTF (directed transfer function) connectivity analysis approach, ictal sources were imaged. Effects of number of scalp EEG electrodes on the seizure localization were also assessed using 76, 64, 48, 32, and 21 electrodes, respectively.
Results
Surgical resections were used to assess the source imaging results. Results from the 76-channel EEG in the ten patients showed high correlation with the surgically resected brain regions. The localization of seizure onset zone from 76-channel EEG showed improved source detection accuracy compared to other EEG configurations with fewer electrodes.
Conclusions
FINE together with DTF was able to localize seizure onset zones of partial epilepsy patients. High-density EEG recording can help achieve improved seizure source imaging.
Significance
The present results suggest the promise of high-density EEG and electrical source imaging for noninvasively localizing seizure onset zones.
doi:10.1016/j.clinph.2011.11.007
PMCID: PMC3327757  PMID: 22172768
High-density EEG; Ictal activities; EEG source imaging; FINE; Epilepsy; directed transfer function
11.  Spatiotemporal Neuronal Correlates of Seizure Generation in Focal Epilepsy 
Epilepsia  2012;53(5):807-816.
Summary
Purpose
Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathological brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. While in vivo recordings of single-neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long–term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure onset zone.
Methods
Microelectrode arrays recorded action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy.
Key Findings
Only 7.6% of microelectrode recordings showed increased firing rates prior to seizure onset and only 32.4% of microelectrodes showed any seizure-related activity changes. Surprisingly, firing rates on the majority of microelectrodes (67.6%) did not change throughout the seizure, including some microelectrodes located within the seizure onset zone. Furthermore, changes in firing rate prior to and at seizure onset were observed on microelectrodes located outside the seizure onset zone and even in contralateral mesial temporal lobe. These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset.
Significance
These results suggest that cellular correlates of seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure onset zone. These results further suggest that the “epileptic ensemble or network” responsible for seizure generation are more complex and heterogeneous than previously thought and that future studies may find mechanistic insights and therapeutic treatments outside the clinical seizure onset zone.
doi:10.1111/j.1528-1167.2012.03417.x
PMCID: PMC3339564  PMID: 22352423
multi-unit; ictogenesis; ensemble; microelectrode; electrophysiology; mesial temporal lobe
12.  Autoimmune Epilepsy 
Archives of neurology  2012;69(5):582-593.
Objective
To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy.
Design
Observational, retrospective case series.
Setting
Mayo Clinic Health System.
Patients
Thirty-two patients with an exclusive (n=11) or predominant (n = 21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more anti-epileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response-mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each.
Intervention
Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclo-phosphamide.
Main Outcome Measure
Seizure frequency.
Results
After a median interval of 17 months (range, 3–72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody–positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody–positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone.
Conclusion
When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.
doi:10.1001/archneurol.2011.2985
PMCID: PMC3601373  PMID: 22451162
13.  Effect of General Anesthesia in Patients With Cerebral Palsy at the Turn of the New Millennium: A Population-Based Study Evaluating Perioperative Outcome and Brief Overview of Anesthetic Implications of This Coexisting Disease 
Journal of child neurology  2011;27(7):859-866.
The severity of preoperative cerebral palsy appears to correlate directly with postoperative complications. The primary aim of this study was to characterize the frequency of perioperative morbidity and mortality in cerebral palsy patients undergoing anesthesia. This was accomplished by undertaking a systematic review of the Mayo Database. The risk for perioperative adverse events was 63.1% (95% confidence interval 59.8%–66.5%). However, it deserves clarification that hypothermia and clinically significant yet non–life-threatening hypotension represented the majority (80%) of these complications. When these 2 events are excluded, the rate of adverse perioperative events was 13.1% (95% confidence interval 10.8%–15.5%). Risk factors associated with increased risk included American Society of Anesthesiologists physical status score exceeding 2, history of seizures, upper airway hypotonia, general surgery procedures, and adults. Our findings are useful to counsel patients with cerebral palsy, their caregivers, and their guardians regarding the risk of general anesthesia.
doi:10.1177/0883073811428378
PMCID: PMC3561730  PMID: 22190505
cerebral palsy; general anesthesia; morbidity; outcome; perioperative
14.  Statistical parametric mapping demonstrates asymmetric uptake with Tc-99m ECD and Tc-99m HMPAO SPECT in normal brain 
Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.
doi:10.1038/jcbfm.2011.123
PMCID: PMC3323300  PMID: 21934696
brain asymmetry; brain imaging; SPECT
15.  Data mining neocortical high-frequency oscillations in epilepsy and controls 
Brain  2011;134(10):2948-2959.
Transient high-frequency (100–500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100–250 Hz) and fast ripple (250–500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100–500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.
doi:10.1093/brain/awr212
PMCID: PMC3187540  PMID: 21903727
high-frequency oscillations; epilepsy; intracranial EEG
16.  A Novel Implanted Device to Wirelessly Record and Analyze Continuous Intracranial Canine EEG 
Epilepsy research  2011;96(1-2):116-122.
We present results from continuous intracranial electroencephalographic (iEEG) monitoring in 6 dogs with naturally occurring epilepsy, a disorder similar to the human condition in its clinical presentation, epidemiology, electrophysiology and response to therapy. Recordings were obtained using a novel implantable device wirelessly linked to an external, portable real-time processing unit. We demonstrate previously uncharacterized intracranial seizure onset patterns in these animals that are strikingly similar in appearance to human partial onset epilepsy. We propose: (1) canine epilepsy as an appropriate model for testing human antiepileptic devices and new approaches to epilepsy surgery, and (2) this new technology as a versatile platform for evaluating seizures and response to therapy in the natural, ambulatory setting.
doi:10.1016/j.eplepsyres.2011.05.011
PMCID: PMC3175300  PMID: 21676591
17.  Scalp and Intracranial EEG in Medically Intractable Extratemporal Epilepsy with Normal MRI 
ISRN Neurology  2012;2012:942849.
Purpose. To investigate EEG and SPECT in the surgical outcome of patients with normal MRI (nonlesional) and extratemporal lobe epilepsy. Methods. We retrospectively identified 41 consecutive patients with nonlesional extratemporal epilepsy who underwent epilepsy surgery between 1997 and 2007. The history, noninvasive diagnostic studies (scalp EEG, MRI, and SPECT) and intracranial EEG (iEEG) monitoring was reviewed. Scalp and iEEG ictal onset patterns were defined. The association of preoperative studies and postoperative seizure freedom was analyzed using Kaplan-Meier analysis, log-rank test, and Cox proportional hazard. Results. Thirty-six of 41 patients had adequate information with a minimum of 1-year followup. Favorable surgical outcome was identified in 49% of patients at 1 year, and 35% at 4-year. On scalp EEG, an ictal onset pattern consisting of focal beta-frequency discharge (>13–125 Hz) was associated with favorable surgical outcome (P = 0.02). Similarly, a focal fast-frequency oscillation (>13–125 Hz) on iEEG at ictal onset was associated with favorable outcome (P = 0.03). Discussion. A focal fast-frequency discharge at ictal onset identifies nonlesional MRI, extratemporal epilepsy patients likely to have a favorable outcome after resective epilepsy surgery.
doi:10.5402/2012/942849
PMCID: PMC3389725  PMID: 22792484
18.  Dynamic imaging of ictal oscillations using non-invasive high-resolution EEG 
Neuroimage  2011;56(4):1908-1917.
Scalp electroencephalography (EEG) has been established as a major component of the pre-surgical evaluation for epilepsy surgery. However, its ability to localize seizure onset zones (SOZ) has been significantly restricted by its low spatial resolution and indirect correlation with underlying brain activities. Here we report a novel non-invasive dynamic seizure imaging (DSI) approach based upon high-density EEG recordings. This novel approach was particularly designed to image the dynamic changes of ictal rhythmic discharges that evolve through time, space and frequency. This method was evaluated in a group of 8 epilepsy patients and results were rigorously validated using intracranial EEG (iEEG) (n = 3) and surgical outcome (n = 7). The DSI localized the ictal activity in concordance with surgically resected zones and ictal iEEG recordings in the cohort of patients. The present promising results support the ability to precisely and accurately image dynamic seizure activity from non-invasive measurements. The successful establishment of such a non-invasive seizure imaging modality for surgical evaluation will have a significant impact in the management of medically intractable epilepsy.
doi:10.1016/j.neuroimage.2011.03.043
PMCID: PMC3359824  PMID: 21453776
High-resolution EEG; Dynamic seizure imaging; Pre-surgical planning
19.  Swine Model for Translational Research of Invasive Intracranial Monitoring 
Epilepsia  2011;52(6):e49-e53.
Summary
Focal cortical epilepsy is currently most effectively studied in humans. However, improvement in cortical monitoring and investigational device development is limited by lack of an animal model mimicking human acute focal cortical epileptiform activity under epilepsy surgery conditions. Therefore, we assessed the swine model for translational epilepsy research. Swine were used due to their cost effectiveness, convoluted cortex, and comparative anatomy similar to humans. Focal subcortical injection of benzyl-penicillin produced clinical seizures correlating with epileptiform activity demonstrating temporal and spatial progression. Swine were evaluated under 5 different anesthesia regimens. Of the 5 regimens, conditions similar to human intraoperative anesthesia, including continuous fentanyl with low dose isoflorane, was the most effective for eliciting complex, epileptiform activity after benzyl-penicillin injection. The most complex epileptiform activity (spikes, and high frequency activity) was then repeated reliably in 9 animals, utilizing 14 swine total. There were 20.1 ± 10.8 (95% CI: 11.8–28.4) epileptiform events with greater than 3.5 hertz activity occurring per animal. Average duration of each event was 46.3 ± 15.6 (95% CI: 44.0 to 48.6) seconds, ranging from 20 to 100 seconds. In conclusion, the acute swine model of focal cortical epilepsy surgery provides an animal model mimicking human surgical conditions with a large brain, gyrated cortex, and is relatively cheap among animal models. Therefore, we feel this model provides a valuable, reliable, and novel platform for translational studies of implantable hardware for intracranial monitoring.
doi:10.1111/j.1528-1167.2011.03096.x
PMCID: PMC3116097  PMID: 21627648
Epilepsy; Animal Model; Electroencephalography; Swine; Pig; Translational Research
20.  Interictal spike analysis of high density EEG in patients with partial epilepsy 
Objective
The aim of this study is to investigate the use of interictal spikes to localize epileptogenic brain from noninvasive scalp EEG recordings in patients with medically intractable epilepsy.
Methods
Source reconstructions were performed using a high density electrode montage and a low density electrode montage by means of a distributed source modeling method. The source of interictal spike activity was localized using both realistic geometry boundary element method (BEM) head models and the 3-shell spherical head model.
Results
In the analysis of 7 patients, the high density electrode montage was found to provide results more consistent with the suspected region of epileptogenic brain identified for surgical resection using intracranial EEG recordings and structural MRI lesions, as compared to the spatial low density electrode montage used in routine clinical practice. Furthermore, the realistic geometry BEM head model provided better source localization.
Conclusions
Our results indicate the merits of using high density scalp EEG recordings and realistic geometry head modeling for source localization of interictal spikes in patients with partial epilepsy.
Significance
The present results suggest further improvement of source localization accuracy of epileptogenic brain from interictal EEG recorded using high density scalp electrode montage and realistic geometry head models.
doi:10.1016/j.clinph.2010.10.043
PMCID: PMC3232053  PMID: 21126908
EEG source localization; Partial epilepsy; Localization error; Boundary element method; Interictal spike
21.  High-Frequency Oscillations Recorded on Scalp EEG 
Epilepsy Currents  2012;12(2):57-58.
doi:10.5698/1535-7511-12.2.57
PMCID: PMC3316367  PMID: 22473542
22.  Causality Analysis of Neural Connectivity: Critical Examination of Existing Methods and Advances of New Methods 
Granger causality (GC) is one of the most popular measures to reveal causality influence of time series and has been widely applied in economics and neuroscience. Especially, its counterpart in frequency domain, spectral GC, as well as other Granger-like causality measures have recently been applied to study causal interactions between brain areas in different frequency ranges during cognitive and perceptual tasks. In this paper, we show that: 1) GC in time domain cannot correctly determine how strongly one time series influences the other when there is directional causality between two time series, and 2) spectral GC and other Granger-like causality measures have inherent shortcomings and/or limitations because of the use of the transfer function (or its inverse matrix) and partial information of the linear regression model. On the other hand, we propose two novel causality measures (in time and frequency domains) for the linear regression model, called new causality and new spectral causality, respectively, which are more reasonable and understandable than GC or Granger-like measures. Especially, from one simple example, we point out that, in time domain, both new causality and GC adopt the concept of proportion, but they are defined on two different equations where one equation (for GC) is only part of the other (for new causality), thus the new causality is a natural extension of GC and has a sound conceptual/theoretical basis, and GC is not the desired causal influence at all. By several examples, we confirm that new causality measures have distinct advantages over GC or Granger-like measures. Finally, we conduct event-related potential causality analysis for a subject with intracranial depth electrodes undergoing evaluation for epilepsy surgery, and show that, in the frequency domain, all measures reveal significant directional event-related causality, but the result from new spectral causality is consistent with event-related time–frequency power spectrum activity. The spectral GC as well as other Granger-like measures are shown to generate misleading results. The proposed new causality measures may have wide potential applications in economics and neuroscience.
doi:10.1109/TNN.2011.2123917
PMCID: PMC3281296  PMID: 21511564
Event-related potential; Granger or Granger-like causality; linear regression model; new causality; power spectrum
23.  Cortical ependymoma: an unusual epileptogenic lesion 
Journal of Neurosurgery  2011;114(4):1187-1194.
Object
Supratentorial cortical ependymomas (CE) are rare, with 7 cases reported. The lesions, typically occurring in the superficial cortex in young adults and associated with a history of seizures, are not fully characterized. Furthermore, their relationship with the recently described angiocentric glioma (AG) is still being debated. This study was undertaken to summarize the authors’ experience with CEs.
Methods
Between 1997 and 2009, 202 cases of ependymoma were surgically treated at the Mayo Clinic, 49 of which were supratentorial. Among these, 9 CE cases were retrospectively identified. Clinical, imaging, and pathological features of each case were reviewed.
Results
Tumors arose from the frontal (5 cases), parietal (3), and occipital (1) lobes. No tumor occurred in the temporal lobe, despite its reported association with seizures. The mean age at presentation was 27 ± 19 years (± SD) and age at resection was 36 ± 16 years. The mean size of the lesion was 16 ± 14 cm3. Seizures were the presenting symptom in 78%. Cross-sectional imaging in 8 cases was characterized by a heterogeneous mass with multiple cystlike areas and enhancement of the soft-tissue component. Gross-total resection was achieved in 8 of 9 tumors. Pathologically, 6 were low-grade (WHO Grade II) and 3 were anaplastic (WHO Grade III) ependymomas. All tumors exhibited the focal presence of perivascular pseudorosettes, but only 1 (11 %) exhibited the focal presence of a true rosette. A bipolar spindle cell component resembling AG was present in 3 (33%) and “Schwannian-like” nodules in 2 (22%). Subpial aggregation and peripheral infiltration were present in 4 cases (44%}. With a mean postsurgery follow-up of 62 ± 38 months, only 2 lesions recurred locally after imaging-confirmed gross-total resection, both being Grade III. In 5 (71 %) of 7 patients presenting with seizures an Engel Class I outcome was achieved.
Conclusions
Cortical ependymomas represent a rare type of ependymoma occurring superficially in the cortex. Morphologically, these tumors are protean, varying from classic to epithelioid, clear cell, and tanycytic. Some also exhibited features typical of AG. Most tumors were low grade and cured with resection. Anaplastic tumors occur and may recur locally despite provision of radiation therapy. Cortical ependymomas frequently, but not always, present with seizures, but despite their high association with epilepsy, none occurred in the temporal lobe in any of the authors’ 9 patients. Overall, CEs appear to have a relatively favorable prognosis compared with other supratentorial ependymomas.
doi:10.3171/2010.12.JNS10846
PMCID: PMC3271434  PMID: 21235315
ependymoma; epilepsy; cortical ependymoma; outcome
24.  Imaging Focal Cortical Dysplasia in Refractory Epilepsy 
Epilepsy Currents  2012;12(1):35-36.
doi:10.5698/1535-7511-12.1.35
PMCID: PMC3280475  PMID: 22368528
25.  Time-frequency analysis using damped-oscillator pseudo-wavelets: application to electrophysiological recordings 
Journal of neuroscience methods  2010;194(1):179-192.
The damped-oscillator pseudo-wavelet is presented as a method of time-frequency analysis along with a new spectral density measure, the data power. An instantaneous phase can be defined for this pseudo-wavelet, and it is easily inverted. The data power measure is tested on both computer generated data and in vivo intrahippocampal electrophysiological recordings from a rat. The data power spectral density is found to give better time and frequency resolution than the more conventional total energy measure, and additionally shows intricate time-frequency structure in the rat that is altered in association with the emergence of epilepsy. With epileptogenesis, the baseline theta oscillation is severely degraded and is absorbed into a broader gamma band. There are also broad 600 Hz and 2000 Hz bands which localize to hippocampal layers that are distinct from those of the theta and gamma bands. The 600 Hz band decreases in prominence with epileptogenesis while the 2000 Hz band increases in prominence. The origins of these high frequency bands await further study. In general, we find that the damped-oscillator pseudo-wavelet is easy to use and is particularly suitable for problems where a wide range of oscillator frequencies is expected.
doi:10.1016/j.jneumeth.2010.09.019
PMCID: PMC2993774  PMID: 20933002
time-frequency analysis; wavelet analysis; high frequency oscillations; epileptogenesis

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