Epilepsy and Neuropharmacology

(Neurophysiological basis of disease)

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Background

• The epilepsies are a common group of chronic neurological conditions that are characterised by recurrent spontaneous unprovoked epileptic seizures.
• Epilepsy is the second most common serious neurological disorder in the community, with approximately 9% of the population having a seizure at some stage in their lifetime and 3% developing epilepsy.
• Although much neglected and misunderstood in the past, epilepsy has emerged over the past decade as one of the most dynamic, exciting and rapidly evolving areas of clinical and basic neuroscience research; but the process is only just beginning with much remaining to be discovered.

Major Research Themes

1. Neurophysiology of seizures/epilepsy and mechanisms anti-epileptic drugs act to control seizures and cause adverse events. Particular interest is factors important in determining individual variability in drug response.
2. Functional neuroimaging in epilepsy and epileptogenesis.
3. Outcome of epilepsy and epilepsy treatment.

Scope of our Research

Epilepsy research at the Department of Medicine (RMH/WH) covers a wide range of basic science and clinical disciplines:

• Neuropharmacology: Utilising basic studies with animal models of epilepsy (GAERS, electrical kinding, kainic acid), as well as human clinical trials of new and established anti-epileptic medications.
• Neuroimaging: Human and animal studies of MRI, PET and SPECT.
• Medical genetics: Pharmacogenetics, epilepsy susceptibility genes.
• Electrophysiology: EEG source localisation and spectral analysis of ictal and interictal epileptiform discharges in different types of epilepsy syndromes.
• Clinical outcome and quality of life studies: Outcome of medical and surgical treatment for epilepsy. Outcome following new onset seizures and epilepsy.

Techniques

• Animal Epilepsy Models: Electrode implantation, EEG recordings, ICV and intraparenchymal catheter implantations.
• Histochemistry: Immunohistochemistry, histology, stereological cell counting, autoradiography.
• Electrophysiology: In vitro brain slice electrophysiological and optophysiological recordings.
• Imaging: MR diffusion, perfusion and spectroscopy, PET, SPECT of humans and small animals.
• Image Analysis: Volumetry, multimodality co-registration, statistical parametric mapping.
• Clinical Neurophysiology: EEG source localisation and spectral analysis of interictal, ictal and intracranial recordings.
• Clinical Outcome Measures: Quality of life and psychosocial instruments.
• Genetics: Clinical genetics, pharmacogenetics, linkage analysis, analysis of gene polymorphisms.

Current Projects (top of page )

Title: Bone health in twins discordant for anti-epileptic drug therapy
Project Leader(s): John D Wark, Terence O'Brien
Research staff: Sue Kantor
Student: Sandra Petty
For more information: Terence O'Brien obrientj@unimelb.edu.au or John Wark jdwark@unimelb.edu.au

Title: PET hypometabolism and MRI perfusion and diffusion changes during acquired epileptogenesis in a rat kindling model of mesial temporal lobe epilepsy
Project Leader(s): Terence O'Brien
Research staff: Simon Foote, Rodney Hicks, Sandra Rees, John Williams
Student: Bianca Jupp
For more information: Terence O'Brien obrientj@unimelb.edu.au

Title: Investigation into The role of neuropeptide Y in a genetic model of absence epilepsy
Project Leader(s): Margaret Morris, Terence O'Brien
Research staff: Rink-Jan Lohman
Student:
For more information: Terence O'Brien obrientj@unimelb.edu.au or Margaret Morris mjmorris@unimelb.edu.au

Title: A prospective study of outcomes following newly diagnosed epilepsy
Project Leader(s): Terence O'Brien, Raju Yerra, Dennis Velakoulis
For more information: Raju Yerra raju.yerra@mh.org.au

Title: A prospective study of neuropsychiatric and neurological outcomes following video-EEG monitoring
Project Leader(s): Sophie Adams, Terence O'Brien, Raju Yerra, Dennis Velakoulis
For more information: Sophie Adams Sophia.adams@mh.org.au

Relationship between quantitative measures of FDG-PET hypometabolism and neuropsycological and post-surgical outcomes in medically refractory TLE.
Project leaders: Terence O’Brien, Anita Vinton, Patricia Desmond, Rod Hicks
For more information: Terence O'Brien obrientj@unimelb.edu.au

Title: The neuropharmacological mechanisms underlying the aggravation of absence seizures by carbamazepine utilising a genetic rat model
Project Leader(s): Terence O'Brien, Margaret Morris
Research staff:
Student: Thomas Zheng
For more information: Terence O'Brien obrientj@unimelb.edu.au or Margaret Morris mjmorris@unimelb.edu.au

Title: Genetics of osteoporosis associated with anti-epileptic drugs
Project Leader(s): Sof Andrikopoulos, John Wark, Margaret Morris, Damian Myers, Terence O'Brien
Student: Susan Senn
For more information: Terence O'Brien obrientj@unimelb.edu.au or John Wark jdwark@unimelb.edu.au

Title: The effect of gender and gonadal hormones on the susceptibility to epileptogenesis in the rat amygdala kindling model
Project Leader(s): Terence O'Brien, Margaret Morris
Research staff: Rink-Jan Lohman
For more information: Terence O'Brien obrientj@unimelb.edu.au or Margaret Morris mjmorris@unimelb.edu.au

Title: The effect of corticosteroids in the pathogenesis of mesial temporal temporal lobe epilepsy utilising a rat kindling model
Project Leader(s): Terence O'Brien, Michael Salzburg, Margaret Morris
Research staff: Rink-Jan Lohman
Student:
For more information: Terence O'Brien obrientj@unimelb.edu.au or Michael Salzburg msalzber@bigpond.net.au or Margaret Morris mjmorris@unimelb.edu.au

Title: EEG source localisation of interictal and ictal epileptiform discharges in patients with medical refractory partial epilepsy
Project Leader(s): Terence O'Brien, Christine Kilpatrick
Student:
For more information: Terence O'Brien obrientj@unimelb.edu.au

Title: A prospective study of changes in quality of life of following Inpatient video-EEG monitoring
Project Leader(s): Terence O'Brien obrientj@unimelb.edu.au , Christine Kilpatrick

Post-traumatic brain injury and epilepsy onset: Imaging the brain to investigate neural circuits appropriate therapy interventions
Dr. Damian Myers, e-mail: Ph: 8344 6449, e-mail: damianem@unimelb.edu.au
Assoc. Professor Terence J. O’Brien, Ph: 8344-3260, e-mail: obrientj@unimelb.edu.au
Prof. Rodney Hicks, Ph: 9656 1834, e-mail:  rod.hicks@petermac.org

Serial in vivo FMZ-PET imaging to predict seizure onset and medically refractory seizures in a small animal model of TLE
Dr. Damian Myers, e-mail: Ph: 8344 6449, e-mail: damianem@unimelb.edu.au
Assoc. Professor Terence J. O’Brien, Ph: 8344-3260, obrientj@unimelb.edu.au
Prof. Rodney Hicks, Ph: 9656 1834, e-mail: rod.hicks@petermac.org

Investigation of the effects that anti-epilepsy therapies have on bone health
Dr. Damian Myers, damianem@unimelb.edu.au, Assoc. Professor Terence J. O’Brien, obrientj@unimelb.edu.au , Prof. John Wark, jdwark@unimelb.edu.au

Dendritic morphology of hippocampal neurons: Neurogenic changes during epileptogenesis in a small animal model of TLE
Location: Department of Medicine, University of Melbourne, The Royal Melbourne Hospital and the Mental Health Research Institute, Parkville
Supervisors: Dr Damian Myers, A/Prof David Finkelstein and Professor Terence O’Brien obrientj@unimelb.edu.au
Contact details:  Tel: 8344 6449 Email: damianem@unimelb.edu.au

Most Significant Publications

1. Petty SJ, Paton LM, O'Brien TJ, Makovey J, Erbas B, Sambrook P, Berkovic SF, Wark JD. Effect of antiepileptic medication on bone mineral measures. Neurology 2005;65:1358-1363. [I.F. 5.678]
2. Jupp B, Williams JP, Tesiram YA, Vosmansky M, O’Brien TJ. Hippocampal T2 signal changye during amgdala kindling epileptogenesis. Epilepsia 2006;47:41-46. [I.F. 3.227]
3. Szoeke CIE, Newton M, Wood JM, Goldstein D, Berkovic SF, OBrien TJ, Sheffield LJ. Pharmacogenetics in Epilepsy – A Review. Lancet Neurology 2006;5:189-196. [I.F. 12.167]
4. Liu L,  Zheng T, Morris MJ, Wallengren C, Clarke A, Reid C, Petrou S, O’Brien TJ. The mechanism of carbamazepine aggravation of absence seizures. J Pharmacol Exp Ther 2006 319: 790-798. [I.F. 4.098]
5. Vinton A, Carne R, Hicks RJ, Desmond PM, Kilpatrick C, Kaye AH, O’Brien TJ. The extent of resection of FDG-PET hypometabolism relates to outcome of temporal lobectomy. Brain. 2007 130:548-60 [I.F. 7.353]
6. Morris MJ, Gannan E, Stroud LM, Beck-Sickinger A, O’Brien TJ. Neuropeptide Y suppresses absence seizures in a genetic rat model primarily through effects on Y receptors. Eur J Neurosci 21007 25: 1136-1143 [I.F. 3.949]
7. O’Brien, TJ, Kilpatrick, C, Vogran, S, Morris, K & Cook, MJ (1996). Temporal lobe epilepsy caused by mesial temporal sclerosis and foreign tissue lesions: A clinical and electrographic study of 46 pathologically proven cases. Brain, 119:2133–41.
8. O’Brien, TJ, Newton, MR, Cook, MJ, Berlangieri, SU, Kilpatrick, C, Morris, K & Berkovic, SF (1997). Hippocampal atrophy is not a Major Determinant of regional hypometabolism in temporal lobe epilepsy. Epilepsia, 38:74–80.
9. Stroud, LM, O’Brien, TJ, Jupp, B, Wallengren, C & Morris, MJ (2005). Neuropeptide Y suppresses absence seizures in a genetic rat model. Brain Research, 1033:151–6.
10. O’Brien, TJ,Moses, H, Cambier, D & Cascino, GD (2002). Age of meningitis or encephalitis is independently predictive of outcome from an anterior temporal lobectomy. Neurology, 58:104–09.
11. O’Brien, TJ, Meara, FM, Matthews, H & Vajda, FJ (2001). Prospective study of the incidence of local cutaneous reactions in patients receiving IV phenytoin. Neurology, 57:1511–14.
12. O’Brien, TJ, Hicks, RJ, Ware, R, Binns, DS, Murphy, M & Cook, MJ (2001). The utility of a 3-D, large-field-of-view, penn-pet scanner in the presurgical evaluation of partial epilepsy. J Nuclear Medicine, 42:1158–65.
13. Vajda, F, O’Brien, TJ, Cook, M, Hitchcock, A, Graham, J, Lander, C & Eadie, M (2004). Critical dose-effect relationship for sodium valproate and teratogenicity in pregnancy. Journal of Clinical Neurosciences, 11(8):854–8.
14. O’Brien, TJ, So, EL, Meyer, FB, Parisi, JE & Jack, CR Jr (1999). Progressive hippocampal atrophy in longstanding intractable temporal lobe epilepsy. The Annals of Neurology, 45:526–9.
15. O’Brien, TJ, So, EL, Mullan, BP, Hauser, MF, Brinkmann, B, Jack, CR, Cascino, GD, Meyer, FB & Sharbrough, FW (1999). Detection of localized hypoperpefusion by subtraction SPECT co-registered to MRI improves the sensitivity and specificity of postictal SPECT in intractable partial epilepsy. Neurology, 52:137–46.
16. O’Brien, TJ, So, EL, Mullan, BP, Hauser, MF, Brinkmann, B, Bohnen, NI, Cascino, GD, Hanson, DP, Jack, CR & Sharbrough, FW (1998). Subtraction ictal SPECT co-registered to MRI improves clinical usefulness of SPECT in localizing the surgical seizure focus. Neurology, 50:445–4.
17. Taher, TR, Salzberg, M, Morris, MJ, Rees, S & O’Brien, TJ (2005). Chronic low-dose corticosterone supplementation enhances acquired epileptogenesis in the rat amygdala kindling model of TLE. Neuropsychopharmacology, online publication:
    <http://www.acnp.org/citations/NPP013105040491/default.pdf)>.

Collaborators

EPIGEN: An international consortium dedicated to tackling epilepsy through genetics