Kevin Graber, MD

All Publications

• Technical validation of the Zeto wireless, dry electrode EEG system. Biomedical physics & engineering express Nadasdy, Z., Fogarty, A. S., Fisher, R. S., Primiani, C. T., Graber, K. D. 2025

  Abstract

  OBJECTIVE: Clinical adoption of innovative EEG technology is contingent on the non-inferiority of the new devices relative to conventional ones. We present the four key results from testing the signal quality of Zeto's WR19 EEG system against a conventional EEG system conducted on patients in a clinical setting. Methods: We performed 30-minute simultaneous recordings using the Zeto WR19 (zEEG) and a conventional clinical EEG system (cEEG) in a cohort of 15 patients. We compared the signal quality between the two EEG systems by computing time domain statistics, waveform correlation, spectral density, signal-to-noise ratio, and signal stability. Results: All statistical comparisons resulted in signal quality non-inferior relative to cEEG. (i) Time domain statistics, including the Hjorth parameters, showed equivalence between the two systems, except for a significant reduction of sensitivity to electric noise in zEEG relative to cEEG. (ii) The point-by-point waveform correlation between the two systems was acceptable (r>0.6; P<0.001). (iii) Each of the 15 datasets showed a high spectral correlation (r>0.99; P<0.001) and overlapping spectral density across all electrode positions, indicating no systematic signal distortion. (iv) The mean signal-to-noise ratio (SNR) of the zEEG system exceeded that of the cEEG by 4.82 dB, equivalent to a 16% improvement. (v) The signal stability was maintained through the recordings.Conclusion: In terms of signal quality, the zEEG system is non-inferior to conventional clinical EEG systems with respect to all relevant technical parameters that determine EEG readability and interpretability. Zeto's WR19 wireless dry electrode system has signal quality in the clinical EEG space at least equivalent to traditional cEEG recordings.

  View details for DOI 10.1088/2057-1976/ada4b6

  View details for PubMedID 39746217

• Multisite thalamic recordings to characterize seizure propagation in the human brain. Brain : a journal of neurology Wu, T. Q., Kaboodvand, N., McGinn, R. J., Veit, M., Davey, Z., Datta, A., Graber, K. D., Meador, K. J., Fisher, R., Buch, V., Parvizi, J. 2023

  Abstract

  Neuromodulation of the anterior nuclei of the thalamus (ANT) has shown to be efficacious in a subset of patients with refractory focal epilepsy. One important uncertainty is to what extent thalamic subregions other than the ANT could be recruited more prominently in the propagation of focal onset seizures. We designed the current study to simultaneously monitor the engagement of the ANT, mediodorsal (MD) and pulvinar (PUL) nuclei during seizures in patients who could be candidates for thalamic neuromodulation. We studied 11 patients with clinical manifestations of presumed temporal lobe epilepsy (TLE) undergoing invasive stereo-encephalography (sEEG) monitoring to confirm the source of their seizures. We extended cortical electrodes to reach the ANT, MD and PUL nuclei of the thalamus. More than one thalamic subdivision was simultaneously interrogated in nine patients. We recorded seizures with implanted electrodes across various regions of the brain and documented seizure onset zones (SOZ) in each recorded seizure. We visually identified the first thalamic subregion to be involved in seizure propagation. Additionally, in eight patients, we applied repeated single pulse electrical stimulation in each SOZ and recorded the time and prominence of evoked responses across the implanted thalamic regions. Our approach for multisite thalamic sampling was safe and caused no adverse events. Intracranial EEG recordings confirmed SOZ in medial temporal lobe, insula, orbitofrontal and temporal neocortical sites, highlighting the importance of invasive monitoring for accurate localization of SOZs. In all patients, seizures with the same propagation network and originating from the same SOZ involved the same thalamic subregion, with a stereotyped thalamic EEG signature. Qualitative visual reviews of ictal EEGs were largely consistent with the quantitative analysis of the corticothalamic evoked potentials, and both documented that thalamic nuclei other than ANT could have the earliest participation in seizure propagation. Specifically, pulvinar nuclei were involved earlier and more prominently than ANT in more than half of the patients. However, which specific thalamic subregion first demonstrated ictal activity could not be reliably predicted based on clinical semiology or lobar localization of SOZs. Our findings document the feasibility and safety of bilateral multisite sampling from the human thalamus. This may allow more personalized thalamic targets to be identified for neuromodulation. Future studies are needed to determine if a personalized thalamic neuromodulation leads to greater improvements in clinical outcome.

  View details for DOI 10.1093/brain/awad121

  View details for PubMedID 37137813

• Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy. The Neurohospitalist Satyanarayan, S., Spiegel, J., Hovsepian, D., Markert, M., Thomas, R., Muffly, L., Miklos, D., Graber, K., Scott, B. J. 2023; 13 (1): 53-60

  Abstract

  Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS.Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes.Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity.Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

  View details for DOI 10.1177/19418744221128852

  View details for PubMedID 36531846

  View details for PubMedCentralID PMC9755619

• Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy NEUROHOSPITALIST Satyanarayan, S., Spiegel, J., Hovsepian, D., Markert, M., Thomas, R., Muffly, L., Miklos, D., Graber, K., Scott, B. J. 2022

  View details for DOI 10.1177/19418744221128852

  View details for Web of Science ID 000867394200001

• High-resolution hippocampal diffusion tensor imaging of mesial temporal sclerosis in refractory epilepsy. Epilepsia Chau Loo Kung, G., Chiu, A., Davey, Z., Mouchawar, N., Carlson, M., Moein Taghavi, H., Martin, D., Graber, K., Razavi, B., McNab, J., Zeineh, M. 2022

  Abstract

  OBJECTIVE: We explore the possibility of using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) to discern microstructural abnormalities in the hippocampus indicative of mesial temporal sclerosis (MTS) at the subfield level.METHODS: We analyzed data from 57 patients with refractory epilepsy who previously underwent 3.0-T magnetic resonance imaging (MRI) including DTI as a standard part of presurgical workup. We collected information about each subject's seizure semiology, conventional electroencephalography (EEG), high-density EEG, positron emission tomography reports, surgical outcome, and available histopathological findings to assign a final diagnostic category. We also reviewed the radiology MRI report to determine the radiographic category. DTI- and NODDI-based metrics were obtained in the hippocampal subfields.RESULTS: By examining diffusion characteristics among subfields in the final diagnostic categories, we found lower orientation dispersion indices and elevated axial diffusivity in the dentate gyrus in MTS compared to no MTS. By similarly examining among subfields in the different radiographic categories, we found all diffusion metrics were abnormal in the dentate gyrus and CA1. We finally examined whether diffusion imaging would better inform a radiographic diagnosis with respect to the final diagnosis, and found that dentate diffusivity suggested subtle changes that may help confirm a positive radiologic diagnosis.SIGNIFICANCE: The results suggest that diffusion metric analysis at the subfield level, especially in dentate gyrus and CA1, maybe useful for clinical confirmation of MTS.

  View details for DOI 10.1111/epi.17330

  View details for PubMedID 35751514

• Impact of high-density EEG in presurgical evaluation for refractory epilepsy patients. Clinical neurology and neurosurgery Li, Y., Fogarty, A., Razavi, B., Ardestani, P. M., Falco-Walter, J., Werbaneth, K., Graber, K., Meador, K., Fisher, R. S. 2022; 219: 107336

  Abstract

  OBJECTIVE: Electrical source localization (ESI) can help to identify the seizure onset zone or propagation zone, but it is unclear how dipole localization techniques influence surgical planning.METHODS: Patients who received a high density (HD)-EEG from 7/2014-7/2019 at Stanford were included if they met the following inclusion criteria: (1) adequate epileptiform discharges were recorded for source localization analysis, (2) underwent surgical treatment, which was at least 6 months before the survey. Interictal ESI was performed with the LORETA method on age matched MRIs. Six neurophysiologists from the Stanford Epilepsy Program independently reviewed each case through an HIPPA-protected online survey. The same cases were presented again with additional data from the HD-EEG study. Ratings of how much the HD-EEG findings added value and in what way were recorded.RESULTS: Fifty out of 202 patients met the inclusion criteria, providing a total of 276h of HDEEG recordings. All patients had video EEG recordings and at least one brain MRI, 88 % had neuropsychological testing, 78 % had either a PET or SPECT scan. Additional HD-EEG information was rated as helpful in 83.8 %, not useful in 14.4 % and misleading in 1.8 % of cases. In 20.4 % of cases the HD-EEG information altered decision-making in a major way, such as choosing a different surgical procedure, avoidance of invasive recording or suggesting placement of invasive electrodes in a lobe not previously planned. In 21.5 % of cases, HD-EEG changed the plan in a minor way, e.g., extra invasive electrodes near the previously planned sites in the same sub-lobar region. In 42.3 % cases, HD-EEG did not change their plan but provided confirmation. In cases with normal MRI, additional HD-EEG information was more likely to change physicians' decision making during presurgical process when compared to the cases with MRI-visible lesions (53.3 % vs. 34.3 %, p=0.002). Among patients achieving Engel class I/II outcome, the concordance rate of HD-EEG and resection zone was 64.7 % versus 35.3 % with class III/IV (p=0.028).CONCLUSION: HD-EEG assists presurgical planning for refractory epilepsy patients, with a higher yield in patients with non-lesional MRIs. Concordance of HD-EEG dipole analysis localization and resection site is a favorable outcome indicator.

  View details for DOI 10.1016/j.clineuro.2022.107336

  View details for PubMedID 35716454

• Contemporaneous evaluation of patient experience, surgical strategy, and seizure outcomes in patients undergoing stereoelectroencephalography or subdural electrode monitoring. Epilepsia Kim, L. H., Parker, J. J., Ho, A. L., Feng, A. Y., Kumar, K. K., Chen, K. S., Ojukwu, D. I., Shuer, L. M., Grant, G. A., Graber, K. D., Halpern, C. H. 2020

  Abstract

  Intracranial electrographic localization of the seizure onset zone (SOZ) can guide surgical approaches for medically refractory epilepsy patients, especially when the presurgical workup is discordant or functional cortical mapping is required. Minimally invasive stereotactic placement of depth electrodes, stereoelectroencephalography (SEEG), has garnered increasing use, but limited data exist to evaluate its postoperative outcomes in the context of the contemporaneous availability of both SEEG and subdural electrode (SDE) monitoring. We aimed to assess the patient experience, surgical intervention, and seizure outcomes associated with these two epileptic focus mapping techniques during a period of rapid adoption of neuromodulatory and ablative epilepsy treatments.We retrospectively reviewed 66 consecutive adult intracranial electrode monitoring cases at our institution between 2014 and 2017. Monitoring was performed with either SEEG (n = 47) or SDEs (n = 19).Both groups had high rates of SOZ identification (SEEG 91.5%, SDE 88.2%, P = .69). The majority of patients achieved Engel class I (SEEG 29.3%, SDE 35.3%) or II outcomes (SEEG 31.7%, SDE 29.4%) after epilepsy surgery, with no significant difference between groups (P = .79). SEEG patients reported lower median pain scores (P = .03) and required less narcotic pain medication (median = 94.5 vs 594.6 milligram morphine equivalents, P = .0003). Both groups had low rates of symptomatic hemorrhage (SEEG 0%, SDE 5.3%, P = .11). On multivariate logistic regression, undergoing resection or ablation (vs responsive neurostimulation/vagus nerve stimulation) was the only significant independent predictor of a favorable outcome (adjusted odds ratio = 25.4, 95% confidence interval = 3.48-185.7, P = .001).Although both SEEG and SDE monitoring result in favorable seizure control, SEEG has the advantage of superior pain control, decreased narcotic usage, and lack of routine need for intensive care unit stay. Despite a heterogenous collection of epileptic semiologies, seizure outcome was associated with the therapeutic surgical modality and not the intracranial monitoring technique. The potential for an improved postoperative experience makes SEEG a promising method for intracranial electrode monitoring.

  View details for DOI 10.1111/epi.16762

  View details for PubMedID 33236777

• Tripolar concentric EEG electrodes reduce noise. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology Aghaei-Lasboo, A. n., Inoyama, K. n., Fogarty, A. S., Kuo, J. n., Meador, K. J., Walter, J. J., Le, S. T., Graber, K. D., Razavi, B. n., Fisher, R. S. 2019; 131 (1): 193–98

  Abstract

  To assay EEG signal quality recorded with tripolar concentric ring electrodes (TCREs) compared to regular EEG electrodes.EEG segments were recorded simultaneously by TCREs and regular electrodes, low-pass filtered at 35 Hz (REG35) and 70 Hz (REG70). Clips were rated blindly by nine electroencephalographers for presence or absence of key EEG features, relative to the "gold-standard" of the clinical report.TCRE showed less EMG artifact (F = 15.4, p < 0.0001). Overall quality rankings were not significantly different. Focal slowing was better detected by TCRE and spikes were better detected by regular electrodes. Seizures (n = 85) were detected by TCRE in 64 cases (75.3%), by REG70 in 75 (88.2%) and REG35 in 69 (81.2%) electrodes. TCRE detected 9 (10.6%) seizures not detected by one of the other 2 methods. In contrast, 14 seizures (16.5%) were not detected by TCRE, but were by REG35 electrodes. Each electrode detected interictal spikes when the other did not.TCRE produced similar overall quality and confidence ratings versus regular electrodes, but less muscle artifact. TCRE recordings detected seizures in 7% of instances where regular electrodes did not.The combination of the two types increased detection of epileptiform events compared to either alone.

  View details for DOI 10.1016/j.clinph.2019.10.022

  View details for PubMedID 31809982

• Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis NEUROBIOLOGY OF DISEASE Gu, F., Parada, I., Shen, F., Li, J., Bacci, A., Graber, K., Taghavi, R., Scalise, K., Schwartzkroin, P., Wenzel, J., Prince, D. A. 2017; 108: 100–114

  Abstract

  Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition.Injury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as ~50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory interneurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy.

  View details for DOI 10.1016/j.nbd.2017.08.008

  View details for Web of Science ID 000414723000009

  View details for PubMedID 28823934

  View details for PubMedCentralID PMC5927780

• Gabapentin decreases epileptiform discharges in a chronic model of neocortical trauma NEUROBIOLOGY OF DISEASE Li, H., Graber, K. D., Jin, S., McDonald, W., Barres, B. A., Prince, D. A. 2012; 48 (3): 429-438

  Abstract

  Gabapentin (GBP) is an anticonvulsant that acts at the α2δ-1 submit of the L-type calcium channel. It is recently reported that GBP is a potent inhibitor of thrombospondin (TSP)-induced excitatory synapse formation in vitro and in vivo. Here we studied effects of chronic GBP administration on epileptogenesis in the partial cortical isolation ("undercut") model of posttraumatic epilepsy, in which abnormal axonal sprouting and aberrant synaptogenesis contribute to occurrence of epileptiform discharges. Results showed that 1) the incidence of evoked epileptiform discharges in undercut cortical slices studied 1 day or ~2 weeks after the last GBP dose, was significantly reduced by GBP treatments, beginning on the day of injury; 2) the expression of GFAP and TSP1 protein, as well as the number of FJC stained cells was decreased in GBP treated undercut animals; 3) in vivo GBP treatment of rats with undercuts for 3 or 7 days decreased the density of vGlut1-PSD95 close appositions (presumed synapses) in comparison to saline treated controls with similar lesions;4) the electrophysiological data are compatible with the above anatomical changes, showing decreases in mEPSC and sEPSC frequency in the GBP treated animals. These results indicate that chronic administration of GBP after cortical injury is antiepileptogenic in the undercut model of post-traumatic epilepsy, perhaps by both neuroprotective actions and decreases in excitatory synapse formation. The findings may suggest the potential use of GBP as an antiepileptogenic agent following traumatic brain injury.

  View details for DOI 10.1016/j.nbd.2012.06.019

  View details for Web of Science ID 000309694000017

  View details for PubMedID 22766033

  View details for PubMedCentralID PMC3461125

• Targets for preventing epilepsy following cortical injury NEUROSCIENCE LETTERS Li, H., McDonald, W., Parada, I., Faria, L., Graber, K., Takahashi, D. K., Ma, Y., Prince, D. 2011; 497 (3): 172-176

  Abstract

  Prophylaxis of posttraumatic epilepsy will require a detailed knowledge of the epileptogenic pathophysiological processes that follow brain injury. Results from studies of experimental models and human epilepsy highlight alterations in GABAergic interneurons and formation of excessive new excitatory synaptic connectivity as prominent targets for prophylactic therapies. Promising laboratory results suggest that it will be possible to experimentally modify these aberrant processes and interfere with epileptogenesis. However, a number of key issues must be addressed before these results can be used to frame clinical antiepileptogenic therapy.

  View details for DOI 10.1016/j.neulet.2011.02.042

  View details for Web of Science ID 000292411600004

  View details for PubMedID 21354270

  View details for PubMedCentralID PMC3409878

• Neocortical posttraumatic epileptogenesis EPILEPSIA Prince, D. A., Parada, I., Li, H., McDonald, W., Graber, K. 2010; 51: 30-30

  Abstract

  Development of new excitatory connectivity and decreases in GABAergic inhibition are mechanisms underlying posttraumatic epileptogenesis in animal models. Experimental strategies that interfere with these processes, applied between the trauma andseizure onset, are antiepileptogenic in the laboratory, and have promise for prophylaxis of epileptogenesis after cortical injury in man. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press. Available on NCBI Bookshelf.

  View details for DOI 10.1111/j.1528-1167.2010.02816.x

  View details for Web of Science ID 000285388600025

  View details for PubMedCentralID PMC3082392

• Neocortical Posttraumatic Epileptogenesis. Epilepsia Prince, D. A., Parada, I., Li, H., McDonald, W., Graber, K. 2010; 51 Suppl 5: 30

  Abstract

  Development of new excitatory connectivity and decreases in GABAergic inhibition are mechanisms underlying posttraumatic epileptogenesis in animal models. Experimental strategies that interfere with these processes, applied between the trauma andseizure onset, are antiepileptogenic in the laboratory, and have promise for prophylaxis of epileptogenesis after cortical injury in man. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press. Available on NCBI Bookshelf.

  View details for DOI 10.1111/j.1528-1167.2010.02816.x

  View details for PubMedID 22056919

  View details for PubMedCentralID PMC3082392

• Neocortical posttraumatic epileptogenesis. Epilepsia Prince, D. A., Parada, I., Li, H., McDonald, W., Graber, K. 2010; 51 Suppl s5: 30

  Abstract

  Development of new excitatory connectivity and decreases in γ-aminobutyric acid (GABA)ergic inhibition are mechanisms underlying posttraumatic epileptogenesis in animal models. Experimental strategies that interfere with these processes, applied between the trauma and seizure onset, are antiepileptogenic in the laboratory, and have promise for prophylaxis of epileptogenesis after cortical injury in humans. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) National Library of Medicine Bookshelf [NCBI] at http://www.ncbi.nlm.nih.gov/books).

  View details for DOI 10.1111/j.1528-1167.2010.02816.x

  View details for PubMedID 21158780

• Direct electrical stimulation for epilepsy: The laboratory evidence EPILEPSIA Graber, K. D., Fisher, R. S. 2010; 51: 86-86

  View details for DOI 10.1111/j.1528-1167.2010.02872.x

  View details for Web of Science ID 000285388600081

• Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy EPILEPSIA Fisher, R., Salanova, V., Witt, T., Worth, R., Henry, T., Gross, R., Oommen, K., Osorio, I., Nazzaro, J., Labar, D., Kaplitt, M., Sperling, M., Sandok, E., Neal, J., Handforth, A., Stern, J., DeSalles, A., Chung, S., Shetter, A., Bergen, D., Bakay, R., Henderson, J., French, J., Baltuch, G., Rosenfeld, W., Youkilis, A., Marks, W., Garcia, P., Barbaro, N., Fountain, N., Bazil, C., Goodman, R., McKhann, G., Krishnamurthy, K. B., Papavassiliou, S., Epstein, C., Pollard, J., Tonder, L., Grebin, J., Coffey, R., Graves, N. 2010; 51 (5): 899-908

  Abstract

  We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy.Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation.One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and "most severe" seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events.Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures.

  View details for DOI 10.1111/j.1528-1167.2010.02536.x

  View details for PubMedID 20331461

• The microtubule interacting drug candidate NAP protects against kainic acid toxicity in a rat model of epilepsy JOURNAL OF NEUROCHEMISTRY Zemlyak, I., Manley, N., Vulih-Shultzman, I., Cutler, A. B., Graber, K., Sapolsky, R. M., Gozes, I. 2009; 111 (5): 1252-1263

  Abstract

  NAP (NAPVSIPQ, generic name, davunetide), a neuroprotective peptide in clinical development for neuroprotection against Alzheimer's disease and other neurodegenerative indications, has been recently shown to provide protection against kainic acid excitotoxicity in hippocampal neuronal cultures. In vivo, kainic acid toxicity models status epilepticus that is associated with hippocampal cell death. Kainic acid toxicity has been previously suggested to involve the microtubule cytoskeleton and NAP is a microtubule-interacting drug candidate. In the current study, kainic acid-treated rats showed epileptic seizures and neuronal death. Injection of NAP into the dentate gyrus partially protected against kainic acid-induced CA3 neuron death. Microarray analysis (composed of > 31 000 probe sets, analyzing over 30 000 transcripts and variants from over 25 000 well-substantiated rat genes) in the kainic acid-injured rat brain revealed multiple changes in gene expression, which were prevented, in part, by NAP treatment. Selected transcripts were further verified by reverse transcription coupled with quantitative real-time polymerase chain reaction. Importantly, among the transcripts regulated by NAP were key genes associated with proconvulsant properties and with long-lasting changes that underlie the epileptic state, including activin A receptor (associated with apoptosis), neurotensin (associated with proper neurotransmission) and the Wolfram syndrome 1 homolog (human, associated with neurodegeneration). These data suggest that NAP may provide neuroprotection in one of the most serious neurological conditions, epilepsy.

  View details for DOI 10.1111/j.1471-4159.2009.06415.x

  View details for Web of Science ID 000271496500016

  View details for PubMedID 19799711

• Epilepsy following cortical injury: Cellular and molecular mechanisms as targets for potential prophylaxis EPILEPSIA Prince, D. A., Parada, I., Scalise, K., Graber, K., Jin, X., Shen, F. 2009; 50: 30-40

  Abstract

  The sequelae of traumatic brain injury, including posttraumatic epilepsy, represent a major societal problem. Significant resources are required to develop a better understanding of the underlying pathophysiologic mechanisms as targets for potential prophylactic therapies. Posttraumatic epilepsy undoubtedly involves numerous pathogenic factors that develop more or less in parallel. We have highlighted two potential "prime movers": disinhibition and development of new functional excitatory connectivity, which occur in a number of animal models and some forms of epilepsy in humans. Previous experiments have shown that tetrodotoxin (TTX) applied to injured cortex during a critical period early after lesion placement can prevent epileptogenesis in the partial cortical ("undercut") model of posttraumatic epilepsy. Here we show that such treatment markedly attenuates histologic indices of axonal and terminal sprouting and presumably associated aberrant excitatory connectivity. A second finding in the undercut model is a decrease in spontaneous inhibitory events. Current experiments show that this is accompanied by regressive alterations in fast-spiking gamma-aminobutyric acid (GABA)ergic interneurons, including shrinkage of dendrites, marked decreases in axonal length, structural changes in inhibitory boutons, and loss of inhibitory synapses on pyramidal cells. Other data support the hypothesis that these anatomic abnormalities may result from loss of trophic support normally provided to interneurons by brain-derived neurotrophic factor (BDNF). Approaches that prevent these two pathophysiologic mechanisms may offer avenues for prophylaxis for posttraumatic epilepsy. However, major issues such as the role of these processes in functional recovery from injury and the timing of the critical period(s) for application of potential therapies in humans need to be resolved.

  View details for DOI 10.1111/j.1528-1167.2008.02008.x

  View details for Web of Science ID 000262827500006

  View details for PubMedID 19187292

  View details for PubMedCentralID PMC2710960

• Sensitivity and specificity of video alone versus electroencephalography alone for the diagnosis of partial seizures EPILEPSY & BEHAVIOR Chen, D. K., Graber, K. D., Anderson, C. T., Fisher, R. S. 2008; 13 (1): 115-118

  Abstract

  We examined the usefulness of video versus EEG in isolation for the differentiation of epileptic seizures (ES) from psychogenic nonepileptic events (PNEE). Video-EEG recordings of 43 events in 43 patients (27 with ES and 16 with PNEE) were analyzed by experienced clinical epileptologists/electroencephalographers blinded to the patients' clinical histories. Both the video and EEG were scored independently by the same reader for each event. Relying on video recordings alone, the readers correctly identified ES with a sensitivity of 93% and specificity of 94%. Based on EEG data alone, the readers correctly identified ES with a sensitivity of 89% and specificity of 94%. Semiologically, a gradual evolving buildup of visible symptoms, reaching maximal behavioral intensity within 70 seconds of event onset, was a reliable indicator of ES. No patient with ES demonstrated eye closure at the time of peak behavioral manifestations. Although several additional semiologic features were statistically associated with either ES or PNEE, they were less reliably present and, hence, less clinically useful. Correct categorization of some neurobehavioral events can be made by experienced epileptologists on the basis of video or EEG recordings during an event, without simultaneous review of both provided that the full event is recorded. Home video recordings may represent a useful screening tool for a subset of patients with neurobehavioral events of unclear etiology.

  View details for DOI 10.1016/j.yebeh.2008.02.018

  View details for Web of Science ID 000257009400020

  View details for PubMedID 18396110

• Homeostatic Plasticity Studied Using In Vivo Hippocampal Activity-Blockade: Synaptic Scaling, Intrinsic Plasticity and Age-Dependence PLOS ONE Echegoyen, J., Neu, A., Graber, K. D., Soltesz, I. 2007; 2 (8)

  Abstract

  Homeostatic plasticity is thought to be important in preventing neuronal circuits from becoming hyper- or hypoactive. However, there is little information concerning homeostatic mechanisms following in vivo manipulations of activity levels. We investigated synaptic scaling and intrinsic plasticity in CA1 pyramidal cells following 2 days of activity-blockade in vivo in adult (postnatal day 30; P30) and juvenile (P15) rats. Chronic activity-blockade in vivo was achieved using the sustained release of the sodium channel blocker tetrodotoxin (TTX) from the plastic polymer Elvax 40W implanted directly above the hippocampus, followed by electrophysiological assessment in slices in vitro. Three sets of results were in general agreement with previous studies on homeostatic responses to in vitro manipulations of activity. First, Schaffer collateral stimulation-evoked field responses were enhanced after 2 days of in vivo TTX application. Second, miniature excitatory postsynaptic current (mEPSC) amplitudes were potentiated. However, the increase in mEPSC amplitudes occurred only in juveniles, and not in adults, indicating age-dependent effects. Third, intrinsic neuronal excitability increased. In contrast, three sets of results sharply differed from previous reports on homeostatic responses to in vitro manipulations of activity. First, miniature inhibitory postsynaptic current (mIPSC) amplitudes were invariably enhanced. Second, multiplicative scaling of mEPSC and mIPSC amplitudes was absent. Third, the frequencies of adult and juvenile mEPSCs and adult mIPSCs were increased, indicating presynaptic alterations. These results provide new insights into in vivo homeostatic plasticity mechanisms with relevance to memory storage, activity-dependent development and neurological diseases.

  View details for DOI 10.1371/journal.pone.0000700

  View details for Web of Science ID 000207452400004

  View details for PubMedID 17684547

  View details for PubMedCentralID PMC1933594

• Chronic Partial Cortical Isolation MODELS OF SEIZURES AND EPILEPSY Graber, K. D., Prince, D. A., Pitkanen, A., Schwartzkroin, P. A., Moshe, S. L. 2006: 477-493

  View details for DOI 10.1016/B978-012088554-1/50040-2

  View details for Web of Science ID 000311355400040

• A critical period for prevention of posttraumatic neocortical hyperexcitability in rats ANNALS OF NEUROLOGY Graber, K. D., Prince, D. A. 2004; 55 (6): 860-870

  Abstract

  Penetrating cortical trauma frequently results in delayed development of epilepsy. In the rat undercut model of neocortical posttraumatic hyperexcitability, suppression of neuronal activity by exposing the injured cortex to tetrodotoxin (TTX) in vivo for approximately 2 weeks prevents the expression of abnormal hypersynchronous discharges in neocortical slices. We examined the relationship between neuronal activity during the latent period after trauma and subsequent expression of hyperexcitability by varying the timing of TTX treatment. Partially isolated islands of rat sensorimotor cortex were treated with Elvax polymer containing TTX to suppress cortical activity and slices obtained for in vitro experiments 10 to 15 days later. TTX treatment was either started immediately after injury and discontinued after a variable number of days or delayed for a variable time after the lesion was placed. Immediate treatment lasting only 2 to 3 days and treatment delayed up to 3 days prevented hyperexcitability. Thus, there is a critical period for development of hyperexcitability in this model that depends on cortical activity. We propose that the hyperexcitability caused by partial cortical isolation may represent an early stage of posttraumatic epileptogenesis. A hypothetical cascade of events leading to subsequent pathophysiological activity is likely initiated at the time of injury but remains plastic during this critical period.

  View details for DOI 10.1002/ana.20124

  View details for Web of Science ID 000221716300013

  View details for PubMedID 15174021

• Postlesional epilepsy: The ultimate brain plasticity 5th Workshop on the Neurobiology of Epilepsy (WONOEP V) Jacobs, K. M., Graber, K. D., Kharazia, V. N., Parada, I., Prince, D. A. WILEY-BLACKWELL. 2000: S153–S161

  Abstract

  Lesions that occur either during fetal development or after postnatal brain trauma often result in seizures that are difficult to treat. We used two animal models to examine epileptogenic mechanisms associated with lesions that occur either during cortical development or in young adults. Results from these experiments suggest that there are three general ways that injury may induce hyperexcitability. Direct injury to cortical pyramidal neurons causes changes in membrane ion channels that make these cells more responsive to excitatory inputs, including increases in input resistance and a reduction in calcium-activated potassium conductances that regulate the rate of action potential discharge. The connectivity of cortical circuits is also altered after injury, as shown by axonal sprouting within pyramidal cell intracortical arbors. Enhanced excitatory connections may increase recurrent excitatory loops within the epileptogenic zone. Hyperinnervation attributable to reorganization of thalamocortical, callosal, and intracortical circuitry, and failure to prune immature connections, may be prominent when lesions affect the developing neocortex. Finally, focal injury can produce widespread changes in gamma-aminobutyric acid and glutamate receptors, particularly in the developing brain. All of these factors may contribute to epileptogenesis.

  View details for Web of Science ID 000089156500028

  View details for PubMedID 10999537

• Tetrodotoxin prevents posttraumatic epileptogenesis in rats ANNALS OF NEUROLOGY Graber, K. D., Prince, D. A. 1999; 46 (2): 234-242

  Abstract

  Severe cortical trauma frequently causes epilepsy that develops after a long latency. We hypothesized that plastic changes in excitability during this latent period might be initiated or sustained by the level of neuronal activity in the injured cortex. We therefore studied effects of action potential blockade by application of tetrodotoxin (TTX) to areas of cortical injury in a model of chronic epileptogenesis. Partially isolated islands of sensorimotor cortex were made in 28- to 30-day-old male Sprague-Dawley rats and thin sheets of Elvax polymer containing TTX or control vehicle were implanted over lesions. Ten to 15 days later neocortical slices were obtained through isolates for electrophysiological studies. Slices from all animals (n = 12) with lesions contacted by control-Elvax (58% of 36 slices) exhibited evoked epileptiform field potentials, and those from 4 rats had spontaneous epileptiform events. Only 2 of 11 lesioned animals and 6% of slices from cortex exposed to TTX in vivo exhibited evoked epileptiform potentials, and no spontaneous epileptiform events were observed. There was no evidence of residual TTX during recordings. TTX-Elvax was ineffective in reversing epileptogenesis when implanted 11 days after cortical injury. These data suggest that development of antiepileptogenic drugs for humans may be possible.

  View details for Web of Science ID 000081876900013

  View details for PubMedID 10443889

• Tetrodotoxin (TTX) prevents epileptogenesis and attenuates neuronal structural alterations following neocortical injury in rats Graber, K. D., Parada, Prince, D. A. LIPPINCOTT WILLIAMS & WILKINS. 1998: A140-A141

  View details for Web of Science ID 000073240900402