Studying the Brain from Every Angle
Observing the brain means looking in a mirror that will reveal its function. This is the principle of Inserm Unit 1253 in Tours – better known under the name of iBrain.
Since 1988, the researchers at iBrain have approached psychiatry through biological phenomena. A daring and possibly quite radical approach at a time when the intellectual climate was such that psychoanalysis was still being used to try to elucidate the origin of mental disorders. However, iBrain – founded by Gilbert Lelord, a child psychiatrist, and Léandre Pourcelot, a physician specialized in ultrasound imaging – decided to focus on brain imaging in order to further fundamental research, diagnosis and therapy. The unit has subsequently grown around two major research activities: one of the most common developmental disorders in children – autism, and the most common psychiatric disease in adults – depression.
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Just this once, the brain is given to us to see physically. Because tractography only produces an image of the displacement of water molecules through white-fiber bundles and is not a perfect illustration of the actual anatomy, it is sometimes difficult to evaluate the level of proof associated with an MRI image. In order to reduce this uncertainty and validate the techniques used for research and clinical practice, Christophe Destrieux and his team are using an uncommon method in which the image is compared with the organ – namely the in vivo data with the ex vivo data.
© Inserm/François Guénet
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The researchers enrolled one hundred healthy volunteers wishing to donate their bodies to science. These volunteers undergo an MRI when alive and then, following their death, their brain is stored for digitization in 3D. This involves splitting it into some thirty steps, following which the surface and texture of the sections are meticulously acquired by CT scanning. The anatomy of the whole brain is then reconstituted using software, helping not just with the evaluation, quality control and calibration of the imaging machines, but also with the preparation of an anatomic atlas of the white matter. -
Patients with autism present sensory particularities making them extremely sensitive to events occurring in their immediate environment. And what if these characteristics – which can be observed on the electrophysiological level – could help with defining an autism biomarker? Psychologist and neuroscientist Marie Gomot is studying the neuron circuits involved in these specific perceptions. Here a subject is being shown a sequence of neutral and emotional facial expressions in order to obtain their response to the change, and more precisely to the emotional variations of others: people with autism experience difficulties in social interactions because they have difficulty interpreting emotions. The findings are then transferred to the clinical setting where they will help with the development of new methods useful for early diagnosis. -
The development of the synapses and neuronal activity are fundamental processes. They underpin our cognitive, motor and communication functions, and enable us to acquire and memorize new information. In autism, intellectual disability and neurodegenerative diseases such as amyotrophic lateral sclerosis, the structure of the nerve cells can be altered by genetic mutations. To understand this phenomenon, researcher Frédéric Laumonnier is using cell preparations taken from the embryonic hippocampus or cortex of mice in order to reproduce the stages of neuronal development in vitro, particularly the formation of the synapses. An epifluorescence microscope is used to observe, four days later, the development of dendrites and magnificent neurons with the characteristic form. -
Acoustician Ayache Bouakaz leads a team that has developed contrast agents in the form of gas microbubbles. These make it possible to improve the quality of ultrasounds – and in particular to better characterize the nature, benign or malignant, of the lesions observed during medical examination. By observing them under the microscope, the researchers saw that these microbubbles dilated and compressed under the effect of ultrasound following an oscillation movement. This led them to devise an innovative protocol which involved injecting the microbubbles into the general circulation of patients with cancer and then bombarding the tumors with ultrasound in a targeted manner to create mechanical stress at vascular wall level. The latter, made more permeable by the "massage" performed by the microbubbles, will enable drugs to penetrate the cancerous cells better – increasing their efficacy 3 to 5-fold. This approach also makes it possible to get drugs across the blood-brain barrier to the brain, as can be seen here in rats thanks to a staining technique. -
Treatment with antidepressants is not always effective in people with a major depressive episode. In order to find a way out of this therapeutic impasse, Catherine Belzung and Alexandre Surget are exploring the mechanisms of hippocampal neurogenesis in adults using an animal model of depression. Mice are subjected to mild but prolonged stress (environmental disruptions, modification of feeding routines, etc.) – a procedure capable of inducing behavioral changes similar to depression and which can be counteracted by antidepressant treatment. The researchers then modulate this adult neurogenesis and the activity of the new neurons produced in order to understand their role in a context of strong socioenvironmental stress. -
Johnny Vercouillie, Sylvie Chalon and Maria-Joao Santiago Ribeiro, members of the team of Patrick Emond (from left to right), pose proudly in front of a PET imaging machine used, among other things, for the development of radiopharmaceutical drugs that emit gamma rays. The latest tracer to date, LBT-999, makes it possible to explore the dopamine transporter in the central nervous system. In the long-term it could help establish an early diagnosis of Parkinson’s disease: dopamine is the key element of communication between the dopaminergic neurons in our brain, whose destruction is responsible for this degenerative disease – the most common after Alzheimer’s.
When the first clinical signs appear, around 70-80% of the neurons are already affected. However, with this imaging, it could be possible to detect neuronal degeneration at a very early stage, and to distinguish the disease from other less common pathologies with similar symptoms.
Classify diseases to improve their treatment
Currently at the helm of iBrain is neuroscientist Catherine Belzung. She is keen to orient its scientific strategy towards personalized medicine, in the hope of reducing the therapeutic difficulties commonly encountered in psychiatry. "In the case of depression, only 40% of patients respond to antidepressants. These treatments target causes that are probably not the universal causes of the condition, explains the researcher. We think that depression exists in various forms, which need to be pinpointed precisely." In other words, the various psychiatric diseases do not form homogeneous entities: the aim is to split them into various subtypes. "Currently, we use antidepressants that act on neurotransmission. But we can envisage that there are other forms of depression – linked to various phenomena, such as neuroinflammation”, she clarifies enthusiastically.
A comment surprisingly informed by the history of medicine. "In the 19th century, fever was not treated as a symptom but as a condition in its own right whose causes were undifferentiated, she adds. It was only later that we understood that it was just a sign concealing various illnesses. It was this comparison that led to the definition of my research program. Depression caused by a monoaminergic neurotransmission deficiency requires treatment with antidepressants. Depression caused by neuroinflammation requires treatment with other substances. Likewise, another type of depression related to brain connectivity possibly exists which could be tackled with neurostimulation-based treatments."
Yet these various forms of depression express themselves in identical ways – a bit like fever. In order to determine who is suffering from what, the researchers have developed imaging tools to produce images of neurotransmission, neuroinflammation, and so on. Once the subtype has been identified, it will be possible to tailor the treatment to the disease. To define a veritable typology of depression enabling the majority of patients to be treated effectively, the researchers are on a quest to find inexpensive and easy-to-use markers for routine use. The existing tools are not always appropriate – plasma markers, for example, would be preferable. It is one of the subsequent challenges that iBrain has set itself.
Fourteen approaches
The key particularity of iBrain is its location in a small town where it is impossible to access the thousands of subjects needed to perform clinical studies. This means that very specific hypotheses need to be formulated on how patient populations can be stratified. To do that, the unit brings together psychiatrists who come up with hypotheses, and experts in health technologies who develop the tools needed to refine the diagnosis. This is the opposite of the big data approach which would involve analyzing the genome of thousands of subjects in order to identify similarities, for example.
This refined approach demands continuous interaction among researchers from various specialist fields – fourteen, to be precise. Linguistics, philosophy, physics, chemistry, traditional medical disciplines such as neurology, biology and the neurosciences: there is a bit of everything! "Having all these people working together in an integrated way is very effective. Obviously, this also requires human qualities in terms of diplomacy, compromise and communication given that we have researchers hailing from very different academic cultures collaborating within a very small structure", states Belzung. The team’s linguists, for example, work on the expression of people with autism – some of whom have communication disorders or possess atypical language on the grammatical level. The philosophers, for their part, are interested in a relatively new movement known as "philosophy in the sciences" – they study the scientific concepts within the laboratory itself, analyze their use and semantic aspects, then formulate proposals to refine these concepts. A rich tapestry supplemented by a multi-scale scientific approach that facilitates the transfer to the clinical setting of discoveries made in animals.
A time of major discoveries
Health technologies (ultrasound, radiopharmaceuticals) which were not intended to have direct applications in the field of psychiatry have, in Tours, enabled considerable progress to be made in several domains. For example, the history of the unit is marked by the discovery of the first autism genes, the discovery of the contribution of neurogenesis in the effects of antidepressants, and the validation of the hypothesis according to which autism is due to brain disorders and not an emotional deficit. The teams have also developed new tracers, such as dopaminergic system marker LBT-999. The previous Unit Director, radiopharmaceuticals specialist Denis Guilloteau, had established a public-private structure associated with a cyclotron making it possible to manufacture radiolabeled molecules and develop new ones.
Within the unit, the mission of the Imaging, Biomarkers and Therapy team is now to invent and develop new technological approaches for the exploration of pathologies in which iBrain is specialized: autism and depression, as well as intellectual disability, amyotrophic lateral sclerosis, Parkinson’s and Alzheimer’s. Thanks to the flows of reciprocal hypotheses circulating between the specialists in health technologies and those in neurosciences and psychiatry, the brain is being targeted from all sides. "We will see the brain as it really is, eventually!", smiles Belzung.
