Apathy, social withdrawal, loss of motivation: the so-called “negative” symptoms of schizophrenia are among the most debilitating and difficult to treat. A team from the University of Geneva (UNIGE) today reveals the unexpected role of the cerebellum in their appearance, via its ability to modulate the cerebral reward system. This mechanism, so far little explored, opens the way to new targeted and non-invasive therapeutic approaches.
A neuropsychiatric disorder affecting 1% of the population, schizophrenia is known for its hallucinatory or delusional symptoms. But the disease is also characterized by strong apathy, difficulty feeling pleasure and progressive social withdrawal. These so-called “negative” symptoms, for which there is no treatment, are particularly debilitating.
The team shows, in the study published in “Biological Psychiatry”, that reinforced regulation of the cerebellum on the reward system is accompanied by an attenuation of negative symptoms and vice versa.
Several studies have shown that abnormalities of the reward system – and more specifically of the dopamine-producing ventral tegmental area (VTA) – are associated with these symptoms. The VTA would in fact be overactivated in people with schizophrenia, generating an impression that “everything is equal” and therefore an absence of motivation.
Regulation alleviates symptoms
In an innovative study, a team from UNIGE and HUG shows that the cerebellum plays a key role in the regulation, or deregulation, of this mechanism via the ATV. “Our little brain actually houses 50% of our neurons. If it has long been confined to its strictly motor role, we are now discovering that it also provides important emotional and cognitive functions,” explains Indrit Bègue, assistant professor in the Laboratory of Neuroimaging and Translational Psychiatry of the Department of Psychiatry of the Faculty of Medicine of UNIGE, at the Synapsy Center for Research in Neuroscience for Mental Health, and university hospital doctor in the Adult Psychiatry Department of the HUG, who led his work.
Through the follow-up of 146 patients, over a period ranging from 3 to 9 months, as well as the analysis of an independent validation cohort, the team observed and described for the first time the interconnection between the cerebellum and the VTA in the context of schizophrenia. “We show that enhanced regulation of the cerebellum on the reward system is accompanied by an attenuation of negative symptoms and vice versa. This unique mechanism opens up perspectives for developing targeted therapeutic approaches,” explains Jade Awada, doctoral student in Indrit Bègue’s team and first author of the study. These analyzes were carried out by Jade Awada and Farnaz Delavari, co-first author of the study and researcher in the laboratory of Professor Stephan Eliez.
A clinical trial already underway
Unlike the ATV, located in the deeper layers of the brain, the cerebellum is located on the surface, at the back of the skull. It is therefore much more accessible and can be the subject of non-invasive interventions, such as transcranial magnetic stimulation. “It involves generating magnetic fields near the targeted brain area – here the cerebellum – to stimulate and strengthen it. We are currently evaluating the possibilities of this device to treat the circuit between the cerebellum and the VTA highlighted in our study,” indicates Indrit Bègue.
A randomized controlled trial, funded by the Leenaards Foundation and the HUG Private Foundation, is already underway on a cohort of patients within the Biotech Campus. The results are expected in 2028.
