INNCB is a public, governative institution internationally recognized as a centre of excellence for the studies of the basic mechanisms of neurological diseases.

Prof. Giuliano Avanzini, who will act as the Project Coordinator, was also elected by INNCB as Principal investigator, coordinating the research activities carried out by the two participating units of the INNCB involved.

Giuliano Avanzini (M, 40%), MD. Former chairman of the department of Clinical Neurosciences; Present Research Coordinator at INNCB. President of the Italian League against Epilepsy (1987-1989); Member Executive Committee of the International League against Epilepsy (ILAE) since 1993; President of ILAE (2001-2005), now past-President; vice-president of European Epilepsy Academy EUREPA; President of the International School of Neurological Sciences and Director of the Epilepsy Summer School, S. Servolo- Venice. IBE-ILAE Ambassador for Epilepsy; Research Award of the American Epilepsy Society; Research interests: Thalamo-cortical system; basic mechanisms of epilepsy; cortical dysphasia; epileptogenic encephalopathies, channelopathies.

Recent relevant publications/patents

1.        Canafoglia L., Ciano C., Panzica F., Scaioli V., Zucca C., Agazzi P., Visani E., Avanzini G., Franceschetti S. (2004 Dec 28) Sensorimotor cortex excitability in Unverricht-Lundborg disease and Lafora body disease. Neurology 63(12):2309-15. 

2.        Curia G., Aracri P., Sancini G., Mantegazza M., Avanzini G., Franceschetti S. (2004) Protein-kinase C-dependent phosphorylation inhibits the effect of the antiepileptic drug topiramate on the persistent fraction of sodium currents.Neuroscience 127(1):63-8. 

3.        Avanzini G., Franceschetti S., Avoni P., Liguori R. (2004) Molecular biology of channelopathies: impact on diagnosis and treatment. Expert Rev Neurother 4:519-39. 

4.        Chan E.M., Young E.J., Ianzano L., Munteanu I., Zhao X., Christopoulos C.C., Avanzini G., Elia M., Ackerley C.A., Jovic N.J., Bohlega S., Andermann E, Rouleau GA,Delgado-Escueta A.V., Minassian B.A., Scherer S.W. (2003) Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet. 35:125-7. 

5.        Ganesh S., Delgado-Escueta A.V., Suzuki T., Francheschetti S., Riggio C., Avanzini G., Rabinowicz A., Bohlega S., Bailey J., Alonso M.E., Rasmussen A., Thomson A.E., Ochoa A., Prado A.J., Medina M.T., Yamakawa K. (2002) Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: exon 1 mutations associate with an early-onset cognitive deficit subphenotype. Hum Mol Genet. 15;11:1263-71. 

For the purposes of EPICURE, the following participating units will be involved:

Division of Neurophysiopatology

Silvana Franceschetti, Phone: 39 0223942250, Fax 39 02.70600775; e-mail franceschetti@istituto-besta.it

Expertise and current research performed: The Division of Neurophysiopatology of the INNCB includes the Clinical Neurophysiology Laboratories, the Epilepsy Center, a Bioengineering Unit and Laboratories devoted to experimental neurophysiology. The Laboratories of Clinical neurophysiology provide the clinical and technical expertise for all aspects of various neurodiagnostic and testing procedures on patients of various ages and medical conditions. The Epilepsy Center performs long-term EEG monitoring suitable to establish a definite diagnosis in patients with complex form of epilepsy or episodic symptoms of uncertain cause. The Laboratory of bioengineering sets up and applies special techniques of digital signal processing and analysis to be applied for diagnostic support, research purposes and innovative clinical applications. The laboratory research is based on a multidisciplinary approach to nervous diseases, namely epilepsies, combining the expertise of clinical, experimental electrophysiological and molecular biology techniques. The research fields include study of in vitro preparation of cortical structures to evaluate intrinsic excitability changes and epileptogenesis at cellular level underlying neocortical epilepsies and experimental models of genetically determined epilepsies (expression of mutants in cell lines and cultured neurons, and study of gene targeted animal models).

Facilities/Equipment: Equipment for electrophysiological recordings of dissociated cells and tissue slices; equipment for molecular biology; Applied Biosystems ABI Prism 3100 sequencer: culture room with sterile hoods and incubators; confocal Microscope and equipment for live cell imaging; animal facility: operating room with equipment for stereotaxic surgery and injections.

Personnel involved in the project

Principal investigator: Silvana Franceschetti, (F) MD, PhD. Chief of Neurophysiology Unit and Epilepsy Centre at the INNCB, Milan; visiting scientist at Max Planck Institute. Munich (1984): PhD in Physiological sciences (1988); member of the editorial board of Epilepsia. Research interests: experimental epileptogenesis; early neocortical development: animal model of neuronal migration disorder; clinical neurophysiology of neurodegenerative disorders in infancy and childhood. Massimo Mantegazza, (M) PhD in Physiology. Junior group leader: Laboratory of Cellular Neurophysiology, INNCB, Milan. Past position: Senior Fellow, Department of Pharmacology, University of Washington, Seattle. Working in the field since 1991. Human Frontier fellow. Research interests: neuronal excitability, ion channels, epilepsy. Elisa Colombo (F) Master Degree in Biology; PhD student; involved in electrophysiological evaluation of sodium-dependent excitability and in cortical neurons and persistent sodium current modulation. Paolo Scalmani (M) Master Degree in Biology; PhD student; working on electrophysiological evaluation of the functional effect of epileptogenic mutation of ion channels. Ferruccio Panzica (M) Bioengineer, Faculty of Electronic Engineering, Politecnico, Milan (Systems-Bioengineering). Bioengineer at the Neurophysiopathology and Unit and Epilepsy center INNCB, Milan (1989-present); tutor for students - Biomedical faculty, Politecnico of Milan; member of working group of centres for epilepsy, Lombardy (2004-present). Research interest: methods and mathematical models for the analysis of EEG, evoked response and EEG-EMG relationships; development of programs for the analysis of firing and electrotonic properties of cortical neurons.

Two PhD students will be appointed: student 1 for mutagenesis, immunocytochemistry and electrophysiological recordings in cell lines; student 2 for electrophysiological recordings in brain slices and dissociated neurons, biocitin labeling, and genotyping.

Recent relevant publications/patents

1.        Mantegazza M., G. Annesi, R. Rusconi, E. Schiavon, R. Restano Cassulini, S. Franceschetti, A. Gambardella, E. Wanke, A. Quattrone (2005) A Loss-of-function Mutation in the α Subunit of Na_v 1.1 Sodium Channel Causes Familial Pure Febrile Seizures. Proceedings of the National Academy of Sciences USA (in press).

2.        Srairi-Abid N., J.I. Guijarro, R.B. Khalifa, M. Mantegazza, A. Cheikh, M.B. Aissa, P.Y. Haumont, M. Delepierre and M. El Ayeb (2005) A new type of scorpion Na⁺-channel toxin like polypeptide active on K⁺ channels. Biochemistry Journal, 388(2):455-464.

3.        Mantegazza M., F.H. Yu, A.J. Powell, J.J. Clare, W.A. Catterall, T. Scheuer (2005). Molecular Determinants for Modulation of Persistent Sodium Current by G Protein bg Subunits. Journal of Neuroscience, 25 (13):3341-3349.

4.        Mantegazza M., Cestèle S. (2005). Beta-scorpion toxin effects suggest electrostatic interactions in domain II of voltage-dependent sodium channels. Journal of Physiology, 568(1):13-30.

5.        Curia G., P. Aracri, G. Sancini, M. Mantegazza, G. Avanzini, S. Franceschetti (2004). PKC-dependent phosphorilation modulates the effect of the antiepileptic drug Topiramate on the persistent fraction of sodium currents. Neuroscience, 127(1): 63-68.

Epilepsy Clinic and Experimental Neurophysiology Unit

Roberto Spreafico, ph. +39 02/23942242, fax +39 02/7060775, email: spreafico@istituto-besta.it

Expertise and current research performed: the Epilepsy Clinic and Experimental Neurophysiology Unit of INNCB is internationally recognized as a centre of excellence for the studies of the basic mechanisms of neurological diseases. The unit is devoted to study epilepsies from bench to bad side and particularly addressed to investigate the pathogenesis and physiopathology of epileptogenic malformations of cortical development in human and animal models. Five dedicated beds for epileptic patients (two equipped for prolonged Video-EEG monitoring), fully equipped laboratories for neuroanatomy and experimental neurophysiology are part of the unit. The unit is operating at clinical and research level in synergy with the Epilepsy Surgery Centre at the Niguarda Hospital in Milan. The unit is currently involved in the following research projects: 1) diagnostic pre-surgical assessment and surgical guidelines for drug resistant epileptic patients candidates for epilepsy surgery (leader of a multicenter Italian group supported by the National Ministry of Health); 2) Mesial temporal lobe epilepsy with and without hippocampal sclerosis: electroclinical features, prognosis and pathogenetic mechanisms (supported by Italian Ministry of research); 3) Role of gap junctions in infantile epilepsy and disorders of cortical development (leader of a multicenter project sponsored by Mariani Foundation). The unit is also involved in identification, classification and morphofunctional correlations of malformations of cortical development in epileptic patients

Facilities/Equipment: five beds for epileptic patients; two of which equipped for continuous Video-EEG monitoring (Micromed equipment). Two fully equipped anatomy labs for routine anatomy, neuropathology, immunocytochemistry, in situ hybridization. Two fully equipped labs for experimental neurophysiology. In addition at the INNCB the following facilities are available: animal housing, two confocal microscopes, laser dissecting microscope, two electron microscope, molecular biology labs.

Personnel involved in the project

Principal investigator: Roberto Spreafico (M), MD, PhD. Chief of the Epilepsy Clinic and Experimental Neurophysiology Unit; appointed as Scientific Vice-Director of the INNCB, Milan. Camillo Golgi Award for Neuroanatomy from the National Academy of Lincei received in1985. Invited professor of Anatomy and Physiology at the University of North Carolina, professor of Anatomy and Physiology at the University of Milan. Scientific interests: basic to clinical neuroscience with particular focus on the thalamo-cortical system and on developmental neuropathology and epilepsy.

Carolina Frassoni (F), degree in Biology, interest on developmental biology, neuroanatomy, epilepsy. Rita Garbelli (F), Phd in Biology, interest on neurobiology, epilepsy, electron microscopy. Maria Cristina Regondi  (F), technician. Flavio Villani (M), MD and specialist in Neurology, interest on epilepsy, pre-surgical investigation, sleep disorder.  Marco de Curtis (M). MD, Head of Laboratory of System Physiology. Associate-Head Epilepsy Clinic and Experimental Neurophysiology Unit. 1988-1991: Assistant Researcher Dept. Physiology, New York University; 1997/98: Visiting scientist ETL, Tsukuba, Japan. 1999: Michael International Price. Italian MinSan grants 1992-2005; HFSPO grant (1996-1999); EC grant VSAMUEL (1999-2002); sub-contractor EC grant LEUCHRON. Director of Advanced International Courses Bridging clinical with experimental epileptology 1 and 2, Venice, Italy (2002 and 2005). Research interest: clinical and experimental neurophysiology and epileptology. Laura Uva (F). Doctoral Degree in Biology; PhD student; Associate Researcher; working in the field of animal models and neurophysiology since 2001. Research interests: neurophysiology; involved in experimental activities on acute models of ictogenesis and in chronic animal models of epilepsy (pilocarpine and PTZ-LPS). Giorgio Battaglia (M) MD. Head of the Molecular Neuroanatomy Laboratory and Associate Professor in Clinical Epileptology in the Epilepsy Center. Research Associate at the University of North Carolina at Chapel Hill; Secretary of the ILAE (International League against Epilepsy) Neurophysiology subcommittee. Scientific interest: clinical and experimental epileptology, clinical, genetic, and neuropathologic features of human cerebral dysgeneses, neurogenesis and epileptogenesis in cerebral heterotopia of experimental animals, motor neuron degeneration, pathogenetic role of the Survival Motor Neuron protein in Spinal Muscular Atrophy. Tiziana Granata, (F) MD: Associated in Child Neurology at the INNCB. MD degree (1985); Speciality Board in Child Neurology (1989), she is working in the field of clinical epileptology. Professional expertises and research interest: epilepsy in childhood, with particular interest in early onset seizures and in epileptic disorders resulting from progressive encephalopathy, from malformation of cortical development and from brain inflammation. Franco Taroni (M) MD. Postdoctoral studies in the Department of Human Genetics, Yale University. Head of the Laboratory of Molecular and Cellular Pathology at the INNCB, Milan. Appointed professor of Neurogenetics, Postdoctoral School of Medical Genetics, University of Milan. Research interests: genetic and molecular bases of several hereditary neurological disorders including mitochondrial Beta-oxidation defects, peripheral neuropathies, spastic paraplegias, spinocerebellar ataxias, and cortical dysplasias. Giorgio Lo Russo, (M) MD Head of the “C.Munari” Center for epilepsy Surgery, Niguarda, Milan. Working in the same institution since 1993. Researcher at the Neurosurgical department, University of Torino, Italy (1980-1993), Assistant Professor at the Neurosurgical Unit, Hôpital S.te Anne, Paris (1989-1993) Research Interest: Epilepsy surgery and cerebral dysplasia. Laura Tassi, (F) MD Diplome d’Etudes Approfondies, Neuroscience, University of Lyon, France (1992). Stages at INSERM Unit-Service de Neurochirurgie, Hôpital Ste. Anne-Paris (1989-1990) and at Stage at Neurological Clinic of thr Grenoble University, Neurosurgery Clinic, INSERM, Grenoble (1990); Neurological Clinic-Grenoble-France (1990-1994) assistant at Neurosurgical Department Niguarda Hospital, Milan (1990-present). Research Interest: Epilepsy surgery and cerebral dysplasia.

One PhD student to be identified.

Recent relevant publications/patents

1.        Alonso-Nanclares L., Garbelli R., Sola RG., Pastor J., Tassi L., Spreafico R., DeFelipe J. (2005) Microanatomy of the dysplastic neocortex from epileptic patients. Brain 128: 158-173.

2.        Tassi L., Colombo N., Cossu M., Mai R., Francione S., Lo Russo G., Galli C., Bramerio M., Battaglia G., Garbelli R., Meroni A., Spreafico R. (2005) Electroclinical, MRI and neuropathological study of 10 patients with nodular heterotopia, with surgical outcomes. Brain 128: 321-337

3.        Majores M., Blumcke I., Urbach H., Meroni A., Hans V., Holthausen H., Elger CE., Schramm J., Galli C., Spreafico R., Wiestler OD., Becker AJ. (2005) Distinct allelic variants of TSC1 and TSC2 in epilepsy- associated cortical malformations without balloon cells. J Neuropathol Exp Neurol 64(7): 629-637.

4.        Palmini A., Najm I., Avanzini G., Babb T., Guerrini R., Foldvary-Schaefer N., Jackson G., Luders HO., Prayson R., Spreafico R., Vinters H.V. (2004) Terminology and classification of the cortical dysplasias. Neurology 62 suppl 3: 2-8.

5.        Mai R., Tassi L., Cossu N., Francione S., Lo Russo G., Garbelli R., Ferrario A., Galli C., Taroni F., Citterio A., Spreafico R. (2003) A neuropathological, stereo-EEG and MRI study of subcortical band heterotopia. Neurology 60: 1834-1838.