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Epilepsy Benchmark IA2

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Brandy Fureman, Ph.D.
Program Director, Channels Synapses & Circuits Cluster

Deborah Hirtz, M.D.
Program Director, Division of Extramural Research

John Kehne, Ph.D.
Program Director, Anticonvulsant Screening Program

Randall Stewart, Ph.D.
Program Director, Extramural Research Program

Vicky Whittemore, Ph.D.
Program Director, Channels, Synapses & Neural Circuits Cluster

Epilepsy Benchmark IA2

Benchmark Area I: Understanding basic mechanisms of epileptogenesis

Section A: Discover the range of anatomical, physiological, and molecular substrates associated with the epilepsies; define unambiguous markers of epileptogenicity.

Specific Benchmark 2a: Create a large-scale imaging database comprised of high-resolution MRI studies of patients with epilepsy (analyzing both cross-sectional and longitudinal populations) including demographic, historical and phenotypic data, and analyze this information in light of the normative database developed by the International Consortium for Brain Mapping (ICBM).

Specific Benchmark 2b:  Use a portion of the imaging database and co-register the anatomical information with functional studies (e.g., fMRI, MEG, MRS, SPECT, PET, EEG, and cutting edge modalities) 
to identify potential structure-function relationships.

2005 Report submitted by Benchmark Steward(s):
William Theodore, M.D. (National Institute of Neurological Disorders and Stroke)
Ruben Kuzniecky, M.D. (New York University)

Background of the benchmark goal:          

Current status of field:

PET as a surrogate marker

  • Likely to be more useful to study long-term epileptogenesis than varying epileptogenicity, due to ‘physiologic time frame’ (hours) of studies, and limits on replicability due to radiation exposure. 
  • 5HT1A decreases confirmed by several studies (1-3).  Decreases are not due to cell loss (4), raises issue of relation of increased precursor (AMT) and decreased receptors, potential role in onset of MTS—seizure-related HF neurogenesis . 
  • BZP receptor studies—studies of clinical role continue
  • Other receptors—some groups working on several potential EAA-related tracers; Radioactivity uptake of intravenously administered reduced (S)-[N-methyl-11C]ketamine activity in TLE may reflect reduced NMDA-receptor density, focal atrophy, or other factors (5).


Most studies directed toward comparing clinical value of MEG and EEG, and role of the former in epilepsy surgery (6-11).  Analysis of MEG dipoles may reveal participation of additional structures in epileptogenicity, and varying modes of spread of cortical excitation.  In some cases it may be possible to obtain ictal MEG (12).  It is uncertain how much MEG adds to multichannel EEG electrical activity modeling. 

MR Spectroscopy:

Recent studies suggest that proton MRS measurements reflect neuro/glial dysfunction rather than neuronal cell loss. MRS is more sensitive than MRI to detect early changes in the epileptogenic area and thus, it may be a suitable tool to study progression in epilepsy.

MRS studies in humans have shifted to 1) High resolution combined Phosphorus/Proton studies of the temporal lobes and adjacent structures 2) editing techniques to quantify absolute neurotransmitters (Glutamate, GABA) in cortical structures. Studies demonstrate absolute reductions in Glutamate in the epileptogenic temporal lobe.

MRI Techniques

Several studies under way to evaluate sensitivity of higher field Magnets (3T Vs 1.5T) in epilepsy. DTI studies have not yielded significant findings to-date.

MRI in animal models

There has been increasing use of MRI in rodent models of epilepsy, including excitatory amino acids, febrile seizures, and other approaches ( 13-19 ).  So far, most studies have used structural imaging, although both BOLD signal and arterial spin tagging CBF measurements, and diffusion weighted imaging have been performed as well.  The short ‘time window’ of MRI allows study of fluctuating physiologic states.  EEG and MRI have been combined in animal models by some investigators, although not all the technical details have been worked out (20-1).  

Imaging cognitive / psychological / structural consequences of epilepsy

Both MEG and fMRI are being used for both preoperative cognitive mapping, and studies of functional reorganization due to epilepsy, generally confirming older data showing early onset of seizures is strongly associated with atypical language lateralization, and that Lesions in the dominant hemisphere tend to result in an intrahemispheric reorganization of linguistic function (21-27).  Studies using structural MRI or PET to follow long-term structural consequences of ‘new-onset’ epilepsy have found much less evidence of initial injury, or progression, than reported previously in populations of patients with established intractable epilepsy, due possibly to subject heterogeneity, relatively short follow-up, or the higher chance of a benign course in some patient samples  (28-30).   

Activities update:

A conference on Imaging Markers of Epileptogenesis: New Research Directions was held April 10-11, 2003

The conclusions / recommendations were:

  • A need for preclinical imaging studies to develop and evaluate methods in animal models
  • need to use animal models to develop imaging markers that could be linked to electrophysiological abnormalities
  • new ictal mapping methods to detect structures participating in seizure spread
  • Prospective collaborative clinical investigations with event-related (such as first febrile or afebrile seizure or traumatic brain injury) entry
  • need for technical and infrastructure development

Top priorities for next 5-10 years:

  • Establish validity of imaging markers of both epileptogenicity and epileptogenesis, followed by intervention trials in animal models.
  • Refinement of fMRI-EEG techniques for both animal and human studies.
  • Additional human collaborative imaging studies such as current consequences of prolonged febrile seizures
  • Develop additional PET ligands, and refine techniques to allow more studies in children with new onset epilepsy.
  • Validation of new MRS editing techniques to quantify neurotransmitters in humans
  • Encourage / support more widespread use of ICBM database   (

Roadblocks to progress:

  • Lack of knowledge of complementary techniques
  • Insufficient interaction of ‘imagers’ and ‘epileptologists’. 


  1. Toczek MT, Carson RE, Lang L, et al. PET imaging of 5-HT1A receptor binding in patients with temporal lobe epilepsy. Neurology. 2003;60:749-756. 
  2. Merlet I, Ryvlin P, Costes N, et al. Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG. Neuroimage. 2004;22:886-896. 
  3. Savic I, Lindstrom P, Gulyas B, Halldin C, Andree B, Farde L. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology. 2004;62:1343-1351. 
  4. Giovacchini G, Toczek MT, MD Bonwetsch R, Bagic A, Lang L, Fraser F, Reeves-Tyer P, Herscovitch P, Eckelman WC, Carson RE, Theodore WH. 5-hT1a receptors  are Reduced in temporal lobe  epilepsy after partial volume correction.  J Nucl Med, in press 
  5. Kumlien E, Hartvig P, Valind S, Oye I, Tedroff J, Langstrom B.NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy. Epilepsia. 1999 Jan;40(1):30-7.  
  6. Pataraia E, Lindinger G, Deecke L, Mayer D, Baumgartner C.Combined MEG/EEG analysis of the interictal spike complex in mesial temporal lobe epilepsy.Neuroimage. 2005 Feb 1;24(3):607-14 
  7. Fischer MJ, Scheler G, Stefan H. Utilization of magnetoencephalography results to obtain favourable outcomes in epilepsy surgery. Brain. 2005 Jan;128(Pt 1):153-7. 
  8. Fernandez A, de Sola RG, Amo C, Turrero A, Zuluaga P, Maestu F, Campo P, Ortiz T. Dipole density of low-frequency and spike magnetic activity: a reliable procedure in presurgical evaluation of temporal lobe epilepsy. J Clin Neurophysiol. 2004 Jul-Aug;21(4):254-66. 
  9. Pataraia E, Simos PG, Castillo EM, Billingsley RL, Sarkari S, Wheless JW, Maggio V, Maggio W, Baumgartner JE, Swank PR, Breier JI, Papanicolaou AC.Does magnetoencephalography add to scalp video-EEG as a diagnostic tool in epilepsy surgery?  Neurology. 2004 Mar 23;62(6):943-8. 
  10. Genow A, Hummel C, Scheler G, Hopfengartner R, Kaltenhauser M, Buchfelder M, Romstock J, Stefan H. Epilepsy surgery, resection volume and MSI localization in lesional frontal lobe epilepsy. Neuroimage. 2004 Jan;21(1):444-9. 
  11. Stefan H, Hummel C, Scheler G, Genow A, Druschky K, Tilz C, Kaltenhauser M, Hopfengartner R, Buchfelder M, Romstock J. Magnetic brain source imaging of focal epileptic activity: a synopsis of 455 cases. Brain. 2003 Nov;126(Pt 11):2396-405. 
  12. Assaf BA, Karkar KM, Laxer KD, Garcia PA, Austin EJ, Barbaro NM, Aminoff MJ.  Ictal magnetoencephalography in temporal and extratemporal lobe epilepsy. Epilepsia. 2003 Oct;44(10):1320-7. 
  13. Wolf O.T.,. Dyakin V,. Patel A,. Vadasz C,. de Leon M.J, ,. McEwen B.S,. Bulloch K Volumetric structural magnetic resonance imaging (MRI) of the rathippocampus following kainic acid (KA) treatment Brain Research 934 (2002) 87–96 
  14. Eidt S, Kendall EJ, Obenaus A  Neuronal and Glial Cell Populations in the Piriform Cortex Distinguished by Using an Approximation of q-Space Imaging after Status Epilepticus AJNR Am J Neuroradiol 25:1225–1233, August 2004 
  15. . Ludwig R. Bodgdanov G,. King J,. Allard A,. Ferris C.F.  A dual RF resonator system for high-field functional magnetic resonance imaging of small animals Journal of Neuroscience Methods 132 (2004) 125–135 
  16. Dube C, Yu H, Nalcioglu O, Baram TZ.  Serial MRI after experimental febrile seizures: altered T2 signal without neuronal death.  Ann Neurol. 2004 Nov;56(5):709-14 
  17. Nairismagi J, Grohn OH, Kettunen MI, Nissinen J, Kauppinen RA, Pitkanen A. Progression of brain damage after status epilepticus and its association with epileptogenesis: a quantitative MRI study in a rat model of temporal lobe epilepsy. Epilepsia. 2004 Sep;45(9):1024-34. 
  18. Roch C, Leroy C, Nehlig A, Namer IJ.  Predictive Value of Cortical Injury for the Development of Temporal Lobe Epilepsy in 21-day-old Rats: An MRI Approach Using the Lithium-pilocarpine Model Epilepsia, 43(10):1129–1136, 2002 
  19. Fabene P.F.. Marzola, P. Sbarbati, A. Bentivoglio M.  Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage NeuroImage 18 (2003) 375–389 
  20. Nersesyan H, Hyder F, Rothman DL, Blumenfeld H.Dynamic fMRI and EEG recordings during spike-wave seizures and generalized tonic-clonic seizures in WAG/Rij rats.  J Cereb Blood Flow Metab. 2004 Jun;24(6):589-99. 
  21. Tenney JR, Duong TQ, King JA, Ferris CF.Epilepsia. 2004 Jun;45(6):576-82.  FMRI of brain activation in a genetic rat model of absence seizures.
  22. Bowyer SM, Moran JE, Mason KM, Constantinou JE, Smith BJ, Barkley GL, Tepley N. MEG localization of language-specific cortex utilizing MR-FOCUSS.  Neurology. 2004 Nov 23;63(10):1825-32 
  23. Pataraia E, Simos PG, Castillo EM, Billingsley-Marshall RL, McGregor AL, Breier JI, Sarkari S, Papanicolaou AC. Reorganization of language-specific cortex in patients with lesions or mesial temporal epilepsy.  Neurology. 2004 Jun 22;62(12):2247-55) 
  24. Janszky J, Jokeit H, Kontopoulou K, Mertens M, Ebner A, Pohlmann-Eden B, Woermann FG. Functional MRI predicts memory performance after right mesiotemporal epilepsy surgery.  Epilepsia. 2005 Feb;46(2):244-50. 
  25. Thivard L, Hombrouck J, Tezenas du Montcel S, Delmaire C, Cohen L, Samson S, Dupont S, Chiras J, Baulac M, Lehericy S. Productive and perceptive language reorganization in temporal lobe epilepsy. Neuroimage. 2005 Feb 1;24(3):841-51. Epub 2004 Nov 11. 
  26. Gaillard WD, Balsamo L, Xu B, McKinney C, Papero PH, Weinstein S, Conry J, Pearl PL, Sachs B, Sato S, Vezina LG, Frattali C, Theodore WH. fMRI language task panel improves determination of language dominance. Neurology. 2004 Oct 26;63(8):1403-8. 
  27. Richardson MP, Strange BA, Thompson PJ, Baxendale SA, Duncan JS, Dolan RJ. Pre-operative verbal memory fMRI predicts post-operative memory decline after left temporal lobe resection. Brain. 2004 Nov;127(Pt 11):2419-26. Epub 2004 Sep 30. 
  28. Rabin ML, Narayan VM, Kimberg DY, Casasanto DJ, Glosser G, Tracy JI, French JA, Sperling MR, Detre JA. Functional MRI predicts post-surgical memory following temporal lobectomy. Brain. 2004 Oct;127(Pt 10):2286-98. Epub 2004 Aug 25. 
  29. T. Salmenperä, MD, PhD, M. Könönen, MSc, N. Roberts, PhD, R. Vanninen, MD, PhD, A. Pitkänen, MD, PhD and R. Kälviäinen, MD, PhD Hippocampal damage in newly diagnosed focal epilepsy A prospective MRI study.  Neurology 2005;64:62-68 
  30. Liu RSN, Lemieux L, Bell GS, et al. The structural consequences of newly diagnosed epilepsy. Ann Neurol. 2002; 52: 573–580 
  31. Gaillard WD, Kopylev L, Weinstein S, Conry J, Pearl PL, Spanaki MV, Fazilat S,  Vezina LG, Dubovsky E, Theodore WH.  MD  Low incidence of abnormal (18)FDG-PET in children with new-onset partial epilepsy: a prospective study. Neurology 2002 Mar 12;58(5):717-22.

Last Modified October 20, 2015