Depression, schizophrenia, anxiety, addiction, suicide…On the occasion of the on World Mental Health Day on October 10, 2015, the Institut du Cerveau – ICM reports on the research taking place at the institute.
The team “Social and affective neuroscience” led by Philippe Fossati and Nathalie Georges studies the brain perturbations implicated in depression.
By combining functional neuroimaging techniques with behavioral and cognitive tests, the team seeks to understand how depressed patients react emotionally or cognitively by comparing them to control participants. The goal of the research is to identify biomarkers implicated in depression.
The researchers recently showed the contribution of a brain region, the anterior cingulate cortex, to social pain related to being excluded. This region is the same that dysfunctions in patients suffering from depression. This work underlines the importance of social exclusion in depression and will allow for defining new therapeutic targets in this disorder.
Bruno Millet, who joined the team of Nathalie George and Philippe Fossati in 2014, is a specialist in deep brain stimulation and transcranial magnetic stimulation, which he utilizes to treat depression resistant to pharmacological treatment and obsessive compulsive disorder. The goal of their research is to be able to combine these systems in order to propose new and more personalized treatments based on the biological needs of patients.
The team of Luc Mallet is specialized in studying the basal ganglia, an ensemble of deep subcortical regions in the brain. Based on clinical observations and brain imaging techniques, the researchers identified one of these sub-cortical regions, the subthalamic nucleus, as being implicated in the emergence of one the most prominent symptoms of OCD, notably the overwhelming doubt (“Did I turn off the gas? Did I close the door?”), probably underlying verification behavior.
Some severe forms of OCD are resistant to classical treatments involving cognitive and behavioral psychotherapy and/or antidepressants. These are the objects of specific research to develop innovative therapies.
The researchers showed that deep brain stimulation of the subthalamic nucleus, which consists of delivering a continuous current to targeted brain structures, allows attenuation or even complete suppression of symptoms in 75% of patients. This therapy is difficult, but it allows improvement of patient’s lives in the long-term.
The team of Philippe Ravassard and Rolando Meloni is interested in schizophrenia, a severe and handicapping mental health disorder that affects about 1% of the population. The team recently developed a new therapeutic for treating this disorder targeting the Gpr88 receptor. This receptor is a protein present at the surface of the cells and is localized exclusively to the brain. The researchers showed that local inactivation of Gpr88 at the level of the nucleus accumbens, which is situated on the ventral side of the striatum and is affected in schizophrenia, allows regulation of the cognitive behaviors in a schizophrenia model. These behaviors are resistant to treatments frequently used in humans. The work represents an important advance in the validation of a new therapeutic target and a groundbreaking experimental approach for treating schizophrenia.
FRONTOTEMPORAL DEMENTIAS (FTD)
Frontotemporal dementias are rare neurodegenerative disorders that are related to Alzheimer’s disease. These dementias are caused by a degeneration of neurons in the anterior part of the brain, which is called the frontal lobe. This region controls our behavior, and damage of it leads to behavioral modifications that manifest as apathy (loss of motivation or taking initiative), by a loss of control, and a disinhibition of behavior.
The research axes of the Institut du Cerveau – ICM seek, on one hand, to identify genetic mutations responsible for familial forms of FTS, and on the other hand, to identify the markers allowing diagnosing and treating this disorder early.
The teams of Alexis Brice, Severine Boillée, and Edor Kabashi are involved in research for new mutations and identified genes involved in both FTD and in amyotrophic lateral sclerosis (ALS). Mutations of the gene C9orf72, the number one genetic cause for ALS and FTD were identified by Isabelle le Ber and collaborators. The gene TBK1 was identified by Stéphanie Millecamps and collaborators in the team of Séverine Boillée. These 2 studies allowed defining of clinical criteria that will orient patients towards a molecular diagnosis of a mutation in C9orf72.
These same teams determined the frequency of several genetic causes, including SQSTM1, in populations of patients affected by ALS and/or FTD. According to a study led on a cohort of more than 1500 patients, these three teams showed that a long polyglutamine (polyQ) repeat within gene ATXN2 was a risk factor for the development of ALS and ALS-FTD.
Finally, Isabelle Le Ber and Paola Caroppo, in the teams of Alexis Brice and Bruno Dubois, led a study that sought to identify the markers allowing for early diagnosis and treatment for this disorder. The researchers recently showed for the first time that early lesions localized in a precise region of the brain occur 20 years before the appearance of frontotemporal dementias. This major discovery could allow diagnosing the disorder very early, and in the future, to start therapeutic trials and to treat at-risk people even before the first clinical symptoms appear.
Apathy, defined as the loss of motivation and interest, is a common symptom in numerous pathologies, such as depression, schizophrenia, and also Parkinson’s and Alzheimer’s diseases.
Treatments for apathy target dopaminergic and noradrenergic neurons, which play an important role in motivation. In order to determine the respective specificity of these two types of neurons, the team of Mathias Pessiglione, Sébastien Bouret, and Jean Daunizeau performed a behavioral study. Motivation determines many aspects of our behavior, including the choice of our actions and generating the necessary energy for these actions. The researchers showed that the dopaminergic neurons intervene when a decision is made while noradrenergic neurons contribute to generating the necessary energy to take action. This discovery is fundamental because these two aspects of behavior could be preferentially targeted in apathetic patients.
Finally, thanks to the PRISME platform, the team of Bruno Dubois and Richard Lévy are developing an innovative project, EcoCapture, for an ecological study of apathy. Thanks to body sensors, the behavior of apathetic patients will be analyzed in a semi-natural situation. This project is being undertaken in collaboration with the company ERDF. The goal is to use the data obtained to bring people who have experienced a neurological deficit, with problems related to making decisions or behavior, back to work.
The team of Mathias Pessiglione, Sébastien Bouret, and Jean Daunizeau study how the brain makes decisions. Their work allowed identification of a region of the brain responsible for attributing value and the different factors that influence our choices. Decrypting the mechanisms behind motivation allows for betting understanding of the pathologies in which motivation is altered.
With this goal in mind, Jean Daunizeau, one of the three team leaders, had the idea to develop the application BRAiN’US in collaboration with a start-up incubated at the Institut du Cerveau – ICM.
BRAiN’US brings together 8 games that test different cognitive capacities. Thanks to executive cognitive functions (such as attention or memory), the brain is able to control information flow and to continuously adapt our behavior in function of our objectives (such as driving a car, playing music, planning a strategy, remembering an event, etc.). The BRAiN’US games were created to analyze these different functions: short-term memory with “3 steps behind,” the ability to interrupt an action in preparation with “Flyswatter,” the ability to anticipate the behavior of others with “The appointment time,” and the ability to identify the action that will produce the largest prize with, “A picky chick.”
The data, anonymous and confidential, from this unique scientific experiment with 28,000 participants to date will be analyzed with mathematical models in order to quantitatively synthesize the different mental mechanisms that determine decision making.
Decrypting the normal functioning of the brain will allow for better understanding of the nature of cognitive and behavioral troubles of patients suffering from neurological or psychiatric pathologies.
Beyond fundamental research, BRAiN’US could be able to benefit the clinical domain by allowing better early diagnosis for certain neurological or psychiatric pathologies and even lead to the development of new therapies.
Of course, motivation is not localized in one brain region but emerges from cooperation between many zones arranged in a network. The researchers therefore invented a mathematical model to describe the way the brain systems coordinate with each other in order to control behavior. Applied to recordings from brain activity of healthy subject making a series of decisions, the method will allow both understanding of how relevant information is treated and transformed across the neuronal networks to lead to behavior, and will also allow for predicting the type of functional deficits induced by brain lesions.