🧠 Schizophrenia: the unexpected role of the cerebellum

Apathy, social withdrawal, loss of motivation: the so-called "negative" symptoms of schizophrenia are among the most disabling and difficult to treat. A team from the University of Geneva (UNIGE) reveals today the unexpected role of the cerebellum in their emergence, through its ability to modulate the brain's reward system. This mechanism, little explored until now, opens the way to new targeted and non-invasive therapeutic approaches. The study is published in Biological Psychiatry.

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 disabling.

We show that increased regulation of the cerebellum over the reward system is associated with an attenuation of negative symptoms, and vice versa.

Several studies have shown that abnormalities in the reward system—more specifically in the ventral tegmental area (VTA) that produces dopamine—are associated with these symptoms. The VTA appears to be overactive in people with schizophrenia, creating an impression that "everything is equal" and therefore a lack of motivation.

The cerebellum, a hidden regulator

In an innovative study, a team from UNIGE and HUG shows that the cerebellum plays a key role in regulating, or deregulating, this mechanism via the VTA. "Our 'little brain' actually houses 50% of our neurons.

While it has long been confined to its strictly motor role, we are now discovering that it also ensures important emotional and cognitive functions," explains Indrit Bègue, assistant professor in the Laboratory of Neuroimaging and Translational Psychiatry of the Department of Psychiatry at the UNIGE Faculty of Medicine, at the Synapsy Center for Neuroscience Research for Mental Health, and a university hospital physician in the Adult Psychiatry Service of the HUG, who led this work.

By following 146 patients over a period ranging from 3 to 9 months, and by analyzing 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 increased regulation of the cerebellum over the reward system is associated with an attenuation of negative symptoms, and vice versa. This novel mechanism opens perspectives for developing targeted therapeutic approaches," explains Jade Awada, a PhD student in Indrit Bègue's team at the Laboratory of Neuroimaging and Translational Psychiatry of the Department of Psychiatry at the UNIGE Faculty of Medicine as well as at the Synapsy Center for Neuroscience Research for Mental Health, first author of the study. These analyses were carried out by Jade Awada and Farnaz Delavari, co-first author of the study and a researcher in the laboratory of Prof. Stephan Eliez.

An accessible therapeutic target?

Unlike the VTA, located in the deep layers of the brain, the cerebellum is situated 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. "This 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 (2023 Scientific Prize) and the HUG Private Foundation, is already underway on a cohort of patients at Campus Biotech. Results are expected for 2028.