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New Study Finds Possible Root of Schizophrenia Symptoms

Cerebellar-prefrontal network connectivity is linked to schizophrenia symptoms.

 Wikipedia/Public Domain
Early-20th-century anatomical illustration of the human brain showing the cerebellum (Latin for "little brain") and prefrontal cortex from below. "Cerebellar" means 'relating to or located in the cerebellum.'
Source: Wikipedia/Public Domain

A first-of-its-kind study from Harvard Medical School’s Beth Israel Deaconess Medical Center (BIDMC) reports that a breakdown of functional connectivity between the cerebellum and prefrontal cortex may be the underlying anatomical cause for certain schizophrenia symptoms. This paper, “Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia,” was published January 30 in The American Journal of Psychiatry.

For this pioneering research, the authors used a two-step approach to identify and empirically test a cerebellum-to-prefrontal cortex network model of schizophrenia symptoms.

"There's an enormous body of research asking how people with schizophrenia are different from people without it, but there is scant literature using imaging in people with schizophrenia to pin down the biological differences between those who are very symptomatic and those who are less so," lead author Roscoe Brady Jr., MD, Ph.D., assistant professor of psychiatry at BIDMC, said in a statement. "If we can pin down what's different, maybe we can intervene."

The first step of this two-pronged study used data-driven resting-state functional connectivity analysis based on neuroimaging. This analysis illuminated that the robustness of network connectivity between the cerebellum and prefrontal cortex corresponds to symptom severity in schizophrenia.

The second phase of their research found that five days of twice-daily transcranial magnetic stimulation (TMS) to the cerebellar midline restored cerebellum-to-prefrontal cortex functional connectivity and alleviated disabling schizophrenia symptoms.

Some of the negative schizophrenia symptoms that benefited from TMS included difficulty with non-verbal communication, the anhedonic inability to experience pleasure, and a crippling lack of motivation. The cerebellum-to-prefrontal cortex network was not associated with delusions or hallucinations.

"For some people with schizophrenia, the non-invasive brain stimulation had a powerful impact; for others, it wasn't as powerful," Brady said. "In all cases, re-connecting the network explained how much improvement the patient experienced. For the first time, we know what brain circuit to go after."

The authors explain the significance of these results, “A breakdown of connectivity in a specific dorsolateral prefrontal cortex-to-cerebellum network directly corresponded to negative symptom severity. Restoration of network connectivity with TMS corresponded to amelioration of negative symptoms, showing a statistically significant strong relationship of negative symptom change in response to functional connectivity change.”

"We wanted to find out if we could restore that brain circuit through non-invasive brain stimulation, and if we could, would people get better?" corresponding author Mark Halko, Ph.D., assistant professor of neurology at BIDMC's Berenson-Allen Center for Non-Invasive Brain Stimulation, said in a statement. "The answer is they absolutely do get better. It's a very provocative finding.”

These findings by Brady et al. (2019) demonstrate that a functional connectivity breakdown between the cerebellum and the right dorsolateral prefrontal cortex is associated with negative symptom severity observed in schizophrenia. Additionally, this research shows that improving functional connectivity between the so-called “little brain” and specific regions of the prefrontal cortex using transcranial magnetic stimulation (TMS) can ameliorate the severity of schizophrenia symptoms.

These discoveries are a potential game-changer and advance our understanding of the cerebellum and how it works. Notably, legendary cerebellar researcher and cerebellum thought leader Jeremy Schmahmann of Harvard Medical School's Massachusetts General Hospital (MGH) is a co-author of this study. Schmahmann is founder and director of the Laboratory for Neuroanatomy and Cerebellar Neurobiology at MGH.

The latest findings on restoring cerebellum-to-prefrontal cortex network connectivity and improved schizophrenia symptoms via non-invasive brain stimulation were published for the first time online today. Hopefully, in the months and years ahead, these discoveries will help some of the millions of people around the globe who are currently disabled by chronic, treatment-resistant schizophrenia symptoms.


Roscoe O. Brady Jr., Irene Gonsalvez, Ivy Lee, Dost Öngür, Larry J. Seidman, Jeremy D. Schmahmann, Shaun M. Eack, Matcheri S. Keshavan, Alvaro Pascual-Leone, Mark A. Halko. "Cerebellar-Prefrontal Network Connectivity and Negative Symptoms in Schizophrenia." The American Journal of Psychiatry (First published online: January 30, 2019) DOI: 10.1176/appi.ajp.2018.18040429