Neuroarcheology: Pioneering concept reshapes understanding of brain disorders and treatment approaches

MARSEILLE, France, 13 May 2025 -- In a compelling Genomic Press interview published today, neuroscience pioneer Dr. Yehezkel Ben-Ari reveals how his revolutionary "Neuroarcheology" concept is changing how scientists understand and approach brain disorders, offering new hope for conditions previously considered untreatable.

Developmental Mechanisms at the Core of Brain Disorders

working four decades at France's premier research institutions CNRS and INSERM, Dr. Ben-Ari's groundbreaking work has fundamentally transformed our understanding of how the brain develops and malfunctions. In his 1^st activity, he described the fundamental sequence of events occurring in Temporal Lobe epilepsies and why and how "seizures beget seizures" (H Jackson). Then, nominated head of a laboratory located within a maternity, he shifted to study brain development.  His most seminal discovery (made with Dr Cherubini) – that the neurotransmitter GABA shifts from excitatory to inhibitory during normal brain development – has become a cornerstone principle in neuroscience, validated across all species from worms to humans being therefore preserved throughout evolution.

"This shift, where GABA excites immature neurons before shifting to inhibition, is a fundamental process in brain development," explains Dr. Ben-Ari. "It illustrates vividly why the developing brain is not simply a small adult brain but one with unique features."

What makes Dr. Ben-Ari's approach particularly revolutionary is his observation that in certain brain disorders, notably epilepsy,autism and many other disorders, this developmental pattern reruns – GABA abnormally excites neurons again in a "return to an immature state." This insight led to his formulation of the Neuroarcheology concept, which suggests that many disorders originating in utero involve the formation of misplaced or misconnected neural networks retaining immature characteristics paving the way to treatments based on silencing these "immature" networks 

"Neuroarcheology also challenges the notion of a direct link between the 'inaugurating insult' such as an in utero genetic mutation and the disorder," Dr. Ben-Ari notes. "It's the consequences of this event rather than the event itself that should be the target of treatments."

From Fundamental Science to Clinical Applications

The interview reveals how Dr. Ben-Ari has courageously transitioned from basic research to practical therapeutic applications. Upon reaching France's mandatory retirement age, rather than stepping away from science, he founded therapeutic ventures targeting the prediction and treatment ofautism spectrum disorders, and brain tumors based on his Neuroarcheology concept.

Dr. Ben-Ari and his team discovered that bumetanide, an inhibitor of the chloride transporter NKCC1, can help restore normal inhibitory GABA function. In two double-blind, randomized phase 2 clinical trials, they demonstrated that bumetanide attenuates core symptoms of autism spectrum disorder (ASD) in children, findings since validated by seven other research teams involving over 1,030 children over the world .

But science rarely follows a straight path. Despite these promising results, their phase 3 trial failed – a common occurrence in developmental disorder research. What sets Dr. Ben-Ari apart is his perseverance in the face of setbacks. Rather than abandoning his approach, he collaborated with artificial intelligence experts to reanalyze all the phase 3 data.

"We found that, indeed, a significant percentage of children do respond to bumetanide, and specific clinical parameters can identify them," he says. "This paves the way for identifying subpopulations of children with ASD that will benefit from bumetanide treatment."

This personalized approach raises intriguing questions: Could the heterogeneity of neurodevelopmental disorders explain why broad treatments often fail in late-stage trials? Might targeted therapies based on specific developmental mechanisms prove more effective than one-size-fits-all approaches?

Early Prediction and Intervention

Perhaps most remarkable is Dr. Ben-Ari's work on early prediction of autism. Reasoning that if autism originates in the womb, signs might be detectable already at birth, his team compared maternity data in children born in the same maternity with and without ASD using machine learning   

"We showed that, indeed, at birth, almost all neurotypical children and almost half of those who will be diagnosed later with ASD later can be identified," Dr. Ben-Ari explains. "This directly demonstrates that ASD is born in utero and will facilitate early use of psycho-educative tools to attenuate ASD." This program called "Pelargos" also enables to identify some of the in utero parameters that are instrumental in ASD pathogenesis providing a possible explanation to the heterogeneity of ASD (Caly et al 2021).  

This breakthrough could dramatically change intervention timelines. ASD are diagnosed usually at ages >5, well after the peak plasticity period around 2-3rd years. Might targeting developmental mechanisms prove more effective than addressing symptoms after they've fully manifested? At any rate, it is manifest that studying brain development is instrumental to predict,  understand and treat ASD.

Expanding to Brain Tumors

Expending Dr. Ben-Ari's Neuroarcheology concept to other disorders, he is presently testing ,  NKCC1 inhibitors in brain tumors. indeed, recent studies suggest that GABA exerts depolarising actions in brain tumours, contributing to generate  hyperactivity that aggravates the prognosis. Dr. Ben-Ari reasoned that a single treatment might not be efficient to both kill cells and blocks the deleterious hyperactivity. With neuro-oncologist Dr. François Berger,  the team is presently testing the effects of a combination of drugs to both block hyperactivity (with Bumetanide) and produce cell death with the  cytoskeleton acting agent Mebendazole.  

Julio this is not yet submitted we must leave it quiet for the moment ,  

An Unconventional Scientific Journey

Throughout the interview, Dr. Ben-Ari emphasizes the value of breaking from convention and following unexpected observations – even when they initially seem unimportant or contradictory.

"When facing a major unexpected observation, we tend to hesitate and consider this as being either unimportant or artefactual," reflects Dr. Ben-Ari. "Our discovery of the GABA actions shift was so unexpected  that we left it aside for over one year and failed to comprehend its major importance for two decades fully."

Dr. Ben-Ari's scientific journey underscores a crucial insight for researchers: significant discoveries often emerge from side roads, not highways. As he puts it, "Discoveries are always made on side roads, never on highways, implying that it is crucial to migrate from one domain to another rather than do all your life the same thing and become the world expert on neuron X or molecule Y."

Dr. Yehezkel Ben-Ari's Genomic Press interview is part of a larger series called Innovators & Ideas that highlights the people behind today's most influential scientific breakthroughs. Each interview in the series offers a blend of cutting-edge research and personal reflections, providing readers with a comprehensive view of the scientists shaping the future. By combining a focus on professional achievements with personal insights, this interview style invites a richer narrative that both engages and educates readers. This format provides an ideal starting point for profiles that delve into the scientist's impact on the field, while also touching on broader human themes. More information on the research leaders and rising stars featured in our Innovators & Ideas -- Genomic Press Interview series can be found in our publications website: https://genomicpress.kglmeridian.com/.

The Genomic Press Interview in Genomic Psychiatry titled "Yehezkel Ben-Ari: The Neuroarcheology concept: From brain development to predicting, understanding, and treating brain disorders," is freely available available via Open Access on 13 May 2025 in Genomic Psychiatry at the following hyperlink: https://doi.org/10.61373/gp025k.0050.

About Genomic Psychiatry: Genomic Psychiatry: Advancing Science from Genes to Society (ISSN: 2997-2388, online and 2997-254X, print) represents a paradigm shift in genetics journals by interweaving advances in genomics and genetics with progress in all other areas of contemporary psychiatry. Genomic Psychiatry publishes peer-reviewed medical research articles of the highest quality from any area within the continuum that goes from genes and molecules to neuroscience, clinical psychiatry, and public health.

Visit the Genomic Press Virtual Library: https://issues.genomicpress.com/bookcase/gtvov/