Life events – whether positive or negative – induce mood variations, while being in a good mood would induce a “rosy outlook”, leading us to view events (or prospects) as more positive than they objectively are. Such reciprocal interaction is also supported by clinical observations. We and others recently used computational modeling to study this phenomenon: we showed that mood can be described as a leaky accumulation of prediction errors about feedbacks. The influence of feedback on mood is reciprocal, the same feedback being more positively perceived when mood is higher. Different individuals can integrate the same sequence of events in different ways, resulting in different mood levels. We coupled this approach with functional MRI and demonstrated that mood was reflected in the baseline activity of two regions: ventromedial prefrontal cortex (vmPFC) and bilateral anterior insula (aIns), with positive and negative encoding respectively. However, in this preliminary works, the time scale of induced mood fluctuations was around a couple of minutes, which is very short compared to everyday mood fluctuations. Their amplitude was also extremely small compared to pathological (or even normal) ones. The goal of this project is to bridge the gap between lab experiments and everyday normal but also pathological mood fluctuations by operating a triple change of scale: in terms of number of participants, time-scale, and amplitude. More specifically, we aim to test (1) to what extent the very same computational principle could underlie mood fluctuations at these very different time scales (2) to what extent our neuro-computational approach of mood fluctuations and its impact on decision-making can discriminate patients with different types of mood disorder from healthy participants, and predict their clinical outcome and (3) to what extent vmPFC and aIns baseline activities reflect not only short-term minimal experimentally induced mood fluctuations but also every day normal mood fluctuations, as well as day-to-day variations in decision-making. In a first work package, we will analyze three large datasets: subjective mood ratings collected in the general population, a validated depression questionnaire completed by more than 400 000 participants over the past 17 years, and clinically relevant variables (such as the daily number of consultations for depression, or the daily number of suicide attempts) extracted from a clinical data warehouse. We aim to demonstrate that the same computational model accounts both for short-time mood fluctuations in the context of a lab experiment and long-term normal and pathological mood fluctuations at a population scale In a second work package, we will compare two groups of patients with mood disorders, bipolar disorder or recurrent depressive disorder, to healthy controls using a neuro-computational approach. Critically, we will combine a short-term evaluation coupled with fMRI and a long-term follow-up thanks to a dedicated smartphone application. We aim to demonstrate that mood disorders are characterized by a specific computational fingerprint describing how of positive and negative events are integrated into a mood signal, which in return affects decision-making. Moreover, we will use this computational fingerprint to predict clinical outcomes. Finally, we will rely on a very specific condition, patients with drug-resistant epilepsy for which stereotactical EEG is required, to obtain a continuous recording of our two regions of interest over a few days. This will allow us to investigate the brain correlates of mood and their impact on decision-making at a relevant time-scale.

Recent studies have shown that a single administration of psilocybin, the active compound of magic mushrooms, has a fast-acting and long-lasting efficacy in treatment-resistant depression. Psilocybin is also well-known to induce acute psychedelic effects, characterized by important changes in self and external world perception, and resulting from the activation of 5-HT2A receptors in the brain. The intensity and the duration of these acute subjective effects, which last 4 to 6 hours, hinder psilocybin integration in routine care. Indeed, they entail risks (anxiety, endangerment), lead to exclusion criteria and so far impose the continuous presence of a caregiver to prevent and manage side effects. Importantly, preclinical results suggest that psychedelic effects may not be necessary for psilocybin antidepressant effects. Instead, antidepressant effects may arise from a direct action of psilocybin on growth factor receptors in the brain, enhancing neuroplasticity regardless of 5-HT2A receptors activation and psychedelic effects. With this proposal, we aim at dissociating psilocybin therapeutic and psychedelic effects, by giving trazodone, an antidepressant with 5-HT2A receptor antagonist activity which counteracts psilocybin’s psychedelic effects, prior to psilocybin intake. In a proof-of-concept double-blind randomized controlled trial, patients with treatment-resistant depression (n = 100) will receive either psilocybin alone (n = 25) or preceded by one of two possible doses of trazodone (5 mg and 30 mg, n = 25 in each group) in order to partially or totally suppress its psychedelic effects ; or trazodone 30 mg and placebo (n = 25). On top of classical measures of improvement and side effects in each group, we will collect cognitive and neuroimaging measures (EEG and MRI) before, during and after treatment. We will characterize the neurocognitive substrates of the psychedelic experience in relation to 5-HT2A receptors availability and study factors underlying, predicting and mediating clinical response. More specifically, we will explore the mechanisms underpinning the psychedelic experience phenomenology. Using an innovative analytic approach allowing to decompose psychedelic experience into dimensions, we will map those dimensions onto perceptual and cerebral alterations at the individual level. Similarly, we will isolate therapeutic response dimensions and measure associated perceptual, emotional, motivational and neuroplasticity changes. This study has the potential to discover a novel single-shot, fast-acting and long-lasting antidepressant treatment combination, psilocybin-trazodone. This combination could be more efficient and less constraining than conventional antidepressants which have to be taken on a daily basis for weeks, on the one hand ; and safer and more accessible than psilocybin alone, on the other hand. Moreover, it will provide a mechanistic understanding of psychedelic effects on perception at the individual level, and reveal the cognitive and neural substrates of psilocybin fast-acting antidepressant property. Finally, this project, which could be the first academic study using psilocybin to treat depression in France, will boost the career of Lucie Berkovitch, the study’s principal investigator, and promote an evidence-based medicine approach which is crucial to prevent abuses in the psychedelic field. More broadly, this study is an opportunity to raise public awareness of current issues in mental health care.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with dementia, cognitive decline and memory loss. AD is characterized by the pathological formation of intraneuronal aggregates of tau protein and extracellular aggregates of amyloid ß (Aß). The view of the brain as an immune-privileged organ has moved towards a pivotal role of the crosstalk between brain-resident and peripheral immune cells in both physiological and pathological conditions. Hence, better understanding the peripheral-central immune crosstalk is crucial to develop new therapies in neurological conditions. In this line, B cells are found in the brain of AD patients and AD-like mice, although their impact on disease progression remains unclear and their manipulation led to controversial results. As resident immune cells of the central nervous system (CNS), microglia are primarily responsible for phagocytotic clearance of Aß. However, there is an increasing recognition that exacerbated neuroinflammation and dysfunction of microglia play a critical role in AD. Our lab has recently developed an experimental protocol in which B cells are cultured in vitro to become anti-inflammatory. Our preliminary data indicate that these B cells exert potent anti-inflammatory effects in the central nervous system, downregulate microglial AD relevant genes and improve cognitive deficits in AD-like mice. In light of these data, our objectives are i) to deeply characterize the phenotypes and functions of B cells infiltrating the brain of AD-like mice at different disease stages, ii) to test whether such anti-inflammatory B cells can positively impact disease development and/or progression in models of AD-like pathology and iii) to characterize phenotypically and functionally B cells at the periphery along disease progression in AD patients, in order to highlight potential correlations with clinical presentation and disease severity. The iBregAD project aims to pioneer a novel immunotherapy for AD by harnessing in vitro anti-inflammatory B cells. This innovative approach seeks to modulate neuroinflammation and neurodegeneration, offering a novel approach to disease modification. By influencing CNS environment, anti-inflammatory B cells hold potential in attenuating the neuroinflammatory processes characteristic of AD. Chronic neuroinflammation is widely implicated in AD progression, contributing to neuronal damage and cognitive decline. Through their ability to mitigate neuroinflammation, anti-inflammatory B cells may offer neuroprotective benefits, preserving neuronal integrity and retarding disease advancement. Notably, our project stands out for its originality and ambition in elucidating the intricate interplay between B cells in peripheral and central immune systems. Additionally, it aims to unravel the cellular and molecular mechanisms through which anti-inflammatory B cells orchestrate CNS inflammatory remodeling during AD progression. This deeper understanding not only enhances our comprehension of the disease but also holds promise for identifying novel biomarkers crucial for advancing therapeutic interventions, ultimately enhancing the quality of life for patients.

Sepsis is a general, uncontrolled and systemic inflammation due to an infection. In serious cases of sepsis (called septic choc) mortality can range between 40% and 50% and concerns 200.000 people in the USA every year. Nowadays patient management is getting better and mortality diminishes, however patients are facing more and more long-term sequelae. As a result, among survivors, half of the patients will suffer of acquired neuromyopathy, meaning an important muscle weakness which can be disabling for up to 5 years after hospitalization. Many studies showed that this muscle weakness involved 1) the impairment of muscular membrane excitability, 2) mitochondrial dysfunction leading to bioenergetic failure and oxidative stress and 3) proteolysis, mainly related to an activation of the ubiquitin-proteasome pathway. These mechanisms can be triggered by various factors, notably systemic inflammatory mediators, endocrine dysfunction, immobilization, drugs and electrolyte disturbances. We showed that in addition to these impairments the muscle stem cells (called satellite cells) were dysfunctional. Indeed in healthy situation muscle regeneration is very efficient. Upon muscle injury they are activated, they divide, multiply and fuse in order to regenerate muscle fibres. We have shown in mice that after a sepsis the satellite cells were impaired and that muscle regeneration was not occurring properly. This dysfunction was due to a decrease mitochondrial mass and a drop in ATP content triggering apoptosis upon activation of the satellite cells. We used Mesenchymal Stem Cell (MSCs) treatment after sepsis for their immunoregulatory and anti-apoptotic properties to reduce the noxious effect of sepsis on satellite cells. We showed that regeneration was significantly improved post-injury with decreased necrosis and fibrosis. The mitochondrial mass and ATP in the satellite cells were recovered and the systemic inflammation was reduced. The cellular mechanisms of MSCs rescue and the characterization of human SCs after sepsis are essential steps before being able to transfer this therapy to the clinics. Interestingly we have also observed that MSCs were able to transfer healthy mitochondrial material to impaired satellite cells to rescue them. At the functional level the force of septic mice increased when injected with MSCs. For this study we have two goals: First we want to understand by which mechanism(s) the mitochondrial material transfer occurs and secondly by collecting human muscle samples from septic patients we would like to isolate the satellite cells and characterise their state (genomic, metabolic and basic cellular behaviour) in order to assess their regenerative capacity. This will allow us to confirm the observation made in the mice models. This translational study will allow us to develop new therapies to avoid or cure the negative impact of sepsis on muscle stem cells and to a broader view on the acquired neuromyopathies in the intensive care units that concerns virtually all patients that stay bedridden and intubated for more than seven days at the hospital.

The detection of consciousness in coma patients is a major clinical issue in critical care (ICU). Sound stimulation holds tremendous promise to reach to these patients but, despite much research, it remains plagued with critical limitations. Project Sounds4Coma brings together academic and medical experts in acoustics, system science, neurophysiology and critical care, to propose a radically novel, 'data-driven' approach to using sound in the ICU. Building on recent advances in system science methods for neuroscience, the project will (1) create new computational methods able to engineer sound stimuli that are optimized and personalized for coma diagnosis, (2)identify novel neural scalp and intracranial EEG markers of covert consciousness in response to these sounds and (3)conduct pre-clinical studies testing the ability for the new sounds and markers to improve consciousness diagnosis in coma patients, in two newly built ICU rooms specially designed for the project.