The Neuroarchology concept : Predicting and treating brain disorders

Yéhézkel BEN-ARI
Founder and first director of Inmed
CEO Neurochlore
Founder of the Ben-Ari Institute of Neuroarcheology (IBEN)

Author (« Les 1000 premiers jours », Humensciences)

Abstract: The Neuroarcheology concept (Ben-Ari 2008) posits that an in-utero insult leads to misconnected /misplaced neurons that remain immature and are the direct cause of deleterious sequels. Therefore, to treat disorders born in the womb, we must determine these deviations & use specific antagonists to block immature activity & attenuate the deleterious sequel. Relying on our earlier discovery of the evolutionary preserved developmental GABA polarity shift, we have determined these deviations in animal models and clinical trials to test their relevance.
i) Bumetanide-a universal treatment? : the GABA developmental shift (Ben-Ari et al 1989) is abolished in a large list of developmental, neurodegenerative disorders and traumatic insults. We validated this in autism, Fragile X, Rett syndrome and Maternal Immune Activation. We then used Bumetanide – the most specific antagonist of the chloride importer- in double blind clinical trials to treat Autism, Parkinson Disease and pilot cases of schizophrenia and Fragile X (Lemonnier et al 2017). A 2nd generation bumetanide is actively searched by us and many pharmas today.
ii) Maternity and brain disorders: Using a Machine Learning program to analyze maternity data, we can identify at birth a subpopulation & almost 100% of babies who will or not respectively have an autism diagnosis (Caly et al). If validated, Genesis ML will enable an early identification of babies at risk who can receive psycho-educative treatments that are known to be more efficient in early ages. Moreover, we observed that the in-utero head circumference is bigger in 38% of human fetuses who will become autistic than Neurotypic ones. It is in line with our observations in animal model of ASD where neurons continue to grow during parturition and birth (Cloarec et al) stressing the impact of the inaugurating insult on birth.
iii) A 3D developmental atlas: using the clearing technique and lightsheet fluorescence microscopy, we have constructed a quantitative developmental 3D atlas of all Choline Acetyltransferase and Tyrosine Hydroxylase positive neurons of the rodent brains from E12 to P8. Combined with automated python scripts, this atlas is now used to investigate early changes in animal models of brain disorders.
With my colleagues, I shall summarize the work done since my departure from academia & INMED to start-ups & privately funded research to illustrate how UpToDate basic science combined with conceptual innovation can increase cognitive research and at the same time lead to advances in treatments of medically orphan disorders.

References
1. Ben-Ari, Y. Neuro-archaeology: pre-symptomatic architecture and signature of neurological disorders. Trends in Neurosciences (2008) doi:10.1016/j.tins.2008.09.002.
2. Ben-Ari et al. Giant Synaptic Potentials in immature CA3 hipocampal neurons J Physiol 1989 416: 303-325
3. Lemonnier E, et al. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.” Translational psychiatry 7.3 (2017): e10563.
4. Caly et al. Machine learning analysis of pregnancy data enables early identification of a
subpopulation of newborns with ASD. 2021, Sci Rep Mar 25;11(1):6877.
5. Cloarec et al. Pyramidal growth and increased hippocampal volume during labor and birth in
Autism. Sci AD. 2019, 23;5(1):eaav0394. doi: 10.1126/sciadv.aav0394.

Invité par Rosa Cossart

Inmed meeting room, Monday April 4th, 11 am