Draft:Massimo Avoli

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Massimo Avoli (born July 13, 1951) is a Canadian/Italian neuroscientist who has contributed to the field of the fundamental mechanisms underlying epileptic disorders.

Massimo Avoli
Born	(1951-07-13) July 13, 1951 Rome, Italy
Known for	Role of the inhibitory neurotransmitter GABA in the generation of focal interictal and ictal discharges
Scientific career
Fields	Neuroscience, Epilepsy
Institutions	Sapienza University of Rome McGill University

Education and career

Avoli was born and grew up in Rome, Italy, where he attended the Sapienza University of Rome from 1969 to 1979, first to obtain an MD degree (1975) and then a Neurology specialty degree (1979) under the supervision of Mario Manfredi. During these years, he began to be interested in the fundamental mechanisms of epileptiform synchronization in the neurophysiology laboratory of Aldo Brancati.

In 1979, Avoli moved to Canada to work at the Montreal Neurological Institute and Hospital (the Neuro) of McGill University under the supervision of Pierre Gloor, who had been a pupil of Herbert Jasper; there, in 1982, he obtained a PhD working on the thalamocortical mechanisms sustaining generalized absence seizures. After graduating from McGill University, in 1983, Avoli did a postdoctoral stint in Per Andersen’s laboratory at the University of Oslo, Norway, to learn the application of the in vitro brain slice preparation for analyzing the fundamental mechanisms underlying focal epileptic disorders in human and rodent brains. Dr. Andersen’s laboratory, where long term potentiation of synaptic transmission had been discovered a few years earlier, had turned into an “obligatory stop” for several young neuroscientists who would later apply the in vitro brain slice preparation to analyze the mechanisms regulating neural excitability and epileptiform synchronization. To just mention a few: Philip Schwartzkroin, Raymond Dingledine, John Habliz, and Jean-Claude Lacaille.

Since 1983 Avoli served as Assistant Professor (to become Full Professor in 1994) in the Department of Neurology and Neurosurgery of the Faculty of Medicine at McGill University. In 2001 he was called for Chiara Fama by the Sapienza University of Rome where he worked as part-time Professor of Physiology until 2021.

Research and Work

Avoli’s early research (1979-1984) at the Neuro, focused on the contribution of thalamus and neocortex in the generation of generalized spike and wave discharges, an EEG pattern that is the hallmark of absence seizures in humans. His work, performed in collaboration with George Kostopoulos in Gloor’s laboratory, demonstrated that interactions between interconnected cortical and thalamic networks are required for the occurrence of generalized spike and wave discharges; accordingly, either thalamus or cortex per se could not generate such generalized epileptic activity.

Upon his return from Oslo in 1983, Avoli also began to analyze the role of the inhibitory neurotransmitter GABA in the generation of focal interictal and ictal discharges in rodent and human brain slices in vitro. In the 1980s, weakening of inhibition was considered the main mechanism leading to focal interictal and ictal discharges, and thus to epileptic disorders. A turning point in Avoli’s studies was his visit to the laboratory of Daniel Johnston at Baylor College in Houston, Texas. There, in vitro experiments were performed by employing the K⁺ channel blocker 4-aminopyridine (4AP), a convulsant that increases the presynaptic release of both excitatory and inhibitory neurotransmitters. Back to Montreal, Avoli discovered that brain slices maintained in vitro, when treated with 4-aminopyridine (4AP), generate a specific type of slow interictal spike that (i) is mainly contributed by GABA-mediated inhibitory currents; and (ii) precedes (and thus it may initiate) seizure-like electrographic events. Successive work performed in collaboration with Mary Morris (University of Ottawa, Canada), Rüdiger Köhling (University of Mũnster, Germany), Marco de Curtis (Besta Neurological Institute in Milan, Italy) as well as with René Pumain and Jacques Louvel (INSERM, Paris, France) revealed that the main mechanism for these slow interictal spikes to induce seizure-like events rests on synchronous interneuron firing leading to excessive activation of postsynaptic GABA_A receptors that, in turn, causes sizeable increases in extracellular [K⁺] through the activation of the KCC2 co-transporter. It was indeed well known that elevating extracellular [K⁺] induces neuronal hyperexcitability along with seizure activity. Therefore, Avoli’s studies firmly identified a paradoxical role of GABA_A signaling in initiating - and perhaps sustaining - focal seizures characterized at onset by the occurrence of a sentinel spike followed by low-amplitude, high-frequency EEG activity, so-called low-voltage fast (LVF) onset seizures.

Around 2010, Avoli’s work was extended to in vivo models of mesial temporal lobe epilepsy such as those induced by an initial status epilepticus caused by systemic injection of pilocarpine or kainic acid. In these experiments, which were performed in collaboration with Drs. Maxime Levesque, attention was often directed to the relation between pathological high-frequency oscillations (HFOs, 80-500 Hz) and the occurrence of interictal spikes and focal seizures. HFOs are categorized as (i) ripples (80-200 Hz) - which may represent population IPSPs generated by principal neurons entrained by synchronously active GABAergic interneuron - and (ii) fast ripples (250-500 Hz) that may mirror the abnormally synchronous firing of principal cells.  Avoli’s experiments demonstrated that progression from interictal to ictal activity in LVF onset seizures is characterized by higher ripple rates compared to fast ripples; in contrast, interictal to ictal discharge transition in seizures with hypersynchronous (HYP) onset [9] - which coincides with a series of focal spikes at a frequency of approx 2Hz - is associated with higher fast ripple compared to ripple rates. Moreover, during ictal activity, ripples predominate in LVF while fast ripples prevail in HYP onset seizures. The specific involvement of interneurons and principal cells in LVF and HYP onset seizures, respectively, was also confirmed in successive in vivo and in vitro experiments employing the optogenetic stimulation of interneurons or principal cells; these studies demonstrated that LVF onset seizures are induced by optogenetic activation of interneurons while those induced by the optogenetic activation of principal cells have a HYP onset pattern.

Avoli’s most recent studies have focused on catamenial epilepsy that is characterized by increased seizure frequency or severity during specific phases of the menstrual cycle. Results obtained in Avoli’s laboratory from in vivo and in vitro experiments in rodents have shown that parvalbumin-positive interneurons in cortical structures become hyperexcitable during the periovulatory phase (i.e., in coincidence with proestrus/estrus when estrogen blood levels are high), thus playing a role in worsening seizures in this specific type of catamenial epilepsy.

Awards and honors

Massimo Avoli is currently among the top scientists in Neurosciences Italy and serves as an Editorial Board Member of Current Neuropharmacology, Neurobiology of Disease and Frontiers in Cellular Neuroscience. In 1987, he received the Korrespondierenden Mitglied of the German League against Epilepsy and a recognition as a member of the Neurologia Italiana nel Mondo from the Istituto Neurologico C. Besta and the Italian National Research Council. In 1991, he was named Ontario-Quebec Neuroscience Lecturer and in 1995, he was awarded the Stiftung Michael Prize for Epilepsy Research. In 2017, he received the Wilder Penfield Award from the Canadian League Against Epilepsy, in 2021 the Basic Research in Epilepsy Award from the American Epilepsy Society, and in 2022 the Premio Venezia from the Chambre de Commerce Italienne au Canada for collaborative studies between the Neuro of McGill University and the Istituto Neurologico Carlo Besta. In 2023 Avoli became Professore Onorario at the Faculty of Medicine, Sapienza University of Rome, Italy.

Personal life

Avoli is married to Alfonsa Martelli and has two daughters, Chiara and Emanuela. Avoli was an avid, intermediate skier and tennis player until knee problems stopped these hobbies. He likes to paint and he is a fan of the Irish singer/composer Van Morrison.