Images in Mind

The developmental anomalies involved in autism logically have significant consequences on brain function as observed through medical imaging. It wasn’t until the 1980s that the first results emerged, and now, with the refinement of machines, advancements are becoming increasingly significant. Currently, Inserm teams working in this field are at the forefront of research. A journey into the heart of the brain in action...

“Historically, this research began in the 1980s, particularly in the Inserm unit of Gilbert Lelord in Tours, which was already very advanced for its time,” says Monica Zilbovicius from U797 “Inserm-CEA methodological research unit: neuroimaging in psychiatry” in Orsay. “When I arrived in France in 1998, I started collaborating with them, a work that continues notably with Catherine Barthélémy. This connection with researchers who are also clinicians is important because our results heavily depend on a perfect clinical characterization of patients.” Indeed, she is not only the team leader at U619 "Dynamics and Pathology of Cerebral Development," but she is also a child psychiatrist, a professor of neurophysiology, and head of the Development Disorders department at the Tours University Hospital. “This is a unique feature of the Tours team,” she explains: “From the beginning, the entire team of researchers was situated in the hospital wards.”

This clinical-neuroimaging synergy quickly bore fruit. By 2000, Brazilian researcher Monica Zilbovicius obtained her first results, showing that autistic patients exhibited, on one hand, a decrease in resting blood flow in the temporal lobe—specifically the superior temporal gyrus and sulcus (using PET, positron emission tomography)—and on the other hand, a reduction in gray matter concentration in the same areas (using MRI, magnetic resonance imaging). “In addition to functional anomalies, we also found anatomical anomalies. These regions play a crucial role in processing auditory information and integrating several sensory modalities. They also contribute to 'social perception' (such as gaze and facial expression). Dysfunction in these brain regions could thus explain some clinical traits of autism, particularly due to their connections with the limbic system and the frontal and parietal cortices.”

A Multiplication of Collaborations

The researcher has expanded her collaborations to include Marion Leboyer’s team at U513 "Neurobiology and Psychiatry" in Créteil, as well as Nadia Chabane and Marie-Christine Mouren-Simeoni from Robert Debré Hospital (Paris). With Marion Leboyer, Monica Zilbovicius further characterized the functional anomalies in autism. In July 2004, the three teams together published a study in Nature Neuroscience demonstrating that individuals with autism do not activate the regions specific to voice in the superior temporal sulcus in response to human voice, while the activation pattern was normal for non-vocal sounds. This suggests that in autism, there may be an anomaly in the cortical processing of auditory information important for social interactions.

In parallel, with Nadia Chabane and Marie-Christine Mouren-Simeoni, she recently showed that the more severe the autistic syndrome—measured by the ADI-R (Autism Diagnostic Interview-Revised) score—the lower the cerebral blood flow in the left superior temporal gyrus. Thus, hypoperfusion in this area would be linked to the severity of autistic behavior. “We now plan to implement imaging in therapeutic trials.”

Moreover, she has a new project: to combine the findings from neuroimaging research with those from genetic research, collaborating with Arnold Munnich from U781 "Genetics and Epigenetics of Metabolic, Neurosensory, and Developmental Diseases" (Necker Hospital, Paris) and Thomas Bourgeron (Institut Pasteur, Paris). “With this work, we hope to define subgroups of autistic disorders, which could ultimately help refine diagnosis and patient management,” she indicates.

Other Perspectives on the Horizon

Of course, there are other Inserm teams and researchers in this discipline. For instance, Julie Grèzes, an Inserm researcher within the laboratory of Perception and Action Physiology (UMR CNRS-Collège de France, Paris), is interested in another aspect of social interaction disturbances in autism, particularly non-verbal communication.

Nicole Bruneau and Joëlle Martineau, Inserm researchers in Tours (U619), focus on the sensory and sensorimotor peculiarities associated with autism. Nicole Bruneau uses electrical imaging methods based on responses recorded in the electroencephalogram. She shows that brain responses are not modulated according to the intensity of auditory stimulation. This difficulty in "tuning in" to sounds is even more pronounced since autistic children exhibit significant disturbances in communication and language. Joëlle Martineau and her group investigate the relationship between visual perception of movement and socio-emotional interaction. She has demonstrated a deficit in the brain mechanisms involved in postural-motor adjustments in children with autism.

Marie Gomot, also in the same team, is looking into a phenomenon that is still little studied: intolerance to change in autistic patients. “This is the third diagnostic criterion for autism,” she details. “Patients show repetitive behaviors, with an attachment to routine and a genuine fear of change. Even among those with good language skills, we find rigid life habits—always the same type of clothing, for example—and a lack of flexibility in relationships, along with strong reactions if an attempt is made to disrupt a ritual. We thus wondered if there were anomalies in the perception of change and which functions were disturbed.”

Her work combines functional MRI and electrophysiology, meaning the recording of electrical brain activity using electrodes. “This is the most precise non-invasive exploration method in terms of temporal definition, with a precision on the order of milliseconds. However, it was necessary to compensate for the lack of precision in brain localization by employing very complex signal processing algorithms developed by Olivier Bertrand and Marie-Hélène Giard’s team at U280 "Mental Processes and Brain Activation" in Lyon.”

By subjecting patients to specific sequences of auditory stimulation, researchers observed that, when emitting a deviant stimulus—different from the usual pattern—the brain response was very peculiar, with atypical activation in the frontal region. Moreover, the response was quicker and faster than in normal subjects. “Furthermore, these brain anomalies appear to be linked to behavioral indices: the more pronounced the anomaly, the greater the intolerance to change. In collaboration with Simon Baron-Cohen in Cambridge, we later demonstrated through functional MRI that these anomalies originated from a specific region in the left frontal lobe involved in attention processes.”

Towards Centers of Excellence in Autism

The interest in this research extends beyond merely defining the brain mechanisms underlying the disorder. “All of this helps us better understand the pathology, which will certainly contribute to developing appropriate therapeutic strategies. However, we must be careful of excessive 'localizationism' and gradually put together the pieces of the puzzle. Meanwhile, educational partners have been very interested to learn that there is a real biological substrate behind this intolerance to change: the autistic individual has enormous difficulties controlling their reactions. This allows for the consideration of environmental adjustments and the generation of strategies for managing changes,” explains Marie Gomot.

“In France in general, and at Inserm in particular, we have high-level teams, whether in clinical research, genetics, or medical imaging,” emphasizes Monica Zilbovicius. “However, they are few in number, not always integrated into autism diagnostic and management centers, and research often proceeds in an uncoordinated manner. That’s why my colleague Nathalie Boddaert and I advocate for the creation of centers of excellence in the diagnosis, research, and management of autism. This would facilitate the integration of scientific and clinical data and encourage the establishment of networks. These centers could be created within university hospital centers that already have expertise in the field of autism…”