Cerebellar-prefrontal brain connectivity may shape negative symptoms in psychosis
A new study has found that stronger communication between the cerebellum and the dorsolateral prefrontal cortex—a part of the brain associated with higher-order thinking—is linked to reduced severity of negative symptoms in people with psychotic disorders. These negative symptoms were also associated with poorer verbal memory. The findings suggest that targeting cerebellar-prefrontal connectivity could help inform new treatment approaches for symptoms that remain largely resistant to existing medications. The research was published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. Psychosis is a mental health condition marked by a disconnection from reality. This can involve hallucinations, delusions, or disorganized thinking—often referred to as positive symptoms because they represent an addition to typical experience. However, many people with psychosis also experience negative symptoms, which reflect a loss or reduction in normal functions. These might include apathy, reduced emotional responsiveness, decreased speech, and social disengagement. While positive symptoms often respond to antipsychotic medications, negative symptoms tend to be more persistent and less treatable. They are strongly linked to poor quality of life, difficulty in daily functioning, and long-term disability. Despite their importance, the brain mechanisms behind negative symptoms are not well understood. Previous small-scale studies had suggested that reduced communication between the cerebellum—a region traditionally associated with movement—and the dorsolateral prefrontal cortex (DLPFC), which plays a role in executive functions like planning and decision-making, might be related to the severity of negative symptoms in schizophrenia. One early study even found that increasing this cerebellar-prefrontal connectivity using non-invasive brain stimulation reduced symptom severity in a small group. However, these earlier findings were based on limited sample sizes. The researchers behind the current study sought to test whether this relationship holds up in a much larger and more diverse sample of people with psychosis spectrum disorders. They also wanted to explore whether cognitive performance—particularly memory—might play a role in this brain-behavior link. “Negative symptoms are a significant predictor of disability for people with psychotic disorders, yet the underlying brain circuitry remains unknown,” said study author Heather Burrell Ward, director of Neuromodulation Research and the Vanderbilt Psychiatry Residency Research Track, and assistant professor at Vanderbilt University Medical Center. “Importantly, current medications are minimally effective in treating negative symptoms. Previous work from co-author Roscoe Brady, Jr., MD, PhD observed that cerebellar-prefrontal brain connectivity was related to negative symptoms and that using noninvasive brain stimulation increased connectivity in that circuit and improved negative symptoms. These findings were exciting, but they involved small samples (n=44 and n=11), so we wanted to test if this same pattern of brain connectivity was also linked to negative symptoms in a much larger sample of people with psychotic disorders.” The new study involved 260 adults diagnosed with a range of psychotic disorders, including both affective and nonaffective forms. Affective psychoses refer to conditions such as bipolar disorder with psychotic features, while nonaffective psychoses include schizophrenia and related disorders. Participants underwent brain scans using functional magnetic resonance imaging (fMRI) while in a resting state. This allowed researchers to assess how different brain regions communicate when a person is not actively engaged in a task. The research team used a specific cerebellar region identified in earlier work as a starting point—or “seed”—and measured how strongly this region connected with the DLPFC. At the same time, they assessed the severity of participants’ negative symptoms using a standardized clinical rating scale. They also administered cognitive tests measuring memory, attention, verbal fluency, and processing speed. The researchers controlled for factors like age, sex, the type of scanner used, and overall scan quality. They also examined whether results differed across subtypes of psychosis or were influenced by variables such as antipsychotic medication or duration of illness. The main finding was that stronger connectivity between the cerebellum and the left dorsolateral prefrontal cortex was associated with lower negative symptom severity. This relationship appeared to be specific to negative symptoms, as connectivity did not relate to positive symptoms or levels of depression. Importantly, the association held true across different types of psychotic disorders and stages of illness, and it remained significant even after controlling for potential confounds like head motion during the scan. “We were excited to see that the relationship between cerebellar-prefrontal connectivity and negative symptoms did not differ by diagnosis, meaning that same brain circuit is involved in negative symptoms across the psychosis spectrum in both nonaffective psychoses (e.g., schizophrenia) and affective psychoses (e.g., bipolar disorder with psychotic features),” Ward told PsyPost. The researchers also found a modest link between cerebellar-prefrontal connectivity and performance on a test of delayed verbal memory. People who showed stronger brain connectivity between these two regions tended to do better at recalling words after a delay. No other cognitive domains showed a similar relationship. When the researchers explored whether verbal memory might explain part of the connection between brain connectivity and negative symptoms, they found that delayed verbal learning partially accounted for the link. In other words, people with better verbal memory tended to show stronger connectivity and fewer negative symptoms. This suggests that cognitive function may be one pathway through which cerebellar-prefrontal connectivity relates to symptom severity. The study also confirmed earlier findings that negative symptoms are broadly associated with cognitive impairments. In this sample, individuals with more severe negative symptoms performed worse on nearly all areas of cognitive testing, including attention, memory, and language-related tasks. The results add weight to the idea that communication between the cerebellum and prefrontal cortex plays an important role in the expression of negative symptoms across the psychosis spectrum. The findings align with prior studies and extend them by using a much larger and more diverse group of participants. The study also offers preliminary evidence that memory performance—specifically delayed verbal recall—may be a partial bridge linking brain connectivity and symptoms. “We have shown that cerebellar-prefrontal connectivity is related to negative symptoms in psychotic disorders,” Ward explained. “This provides further evidence for a brain circuit that could be targeted with a variety of treatments (e.g., medication or brain stimulation) to treat the debilitating negative symptoms associated with psychotic disorders.” While the study had several strengths, including its large sample size and comprehensive analysis, it also had limitations. The data were collected at a single site, and the brain scans were not optimized specifically for studying the cerebellum. This may have limited the precision of some measurements. In addition, the study was cross-sectional, meaning that it captured a snapshot in time. As a result, it cannot determine whether reduced connectivity causes negative symptoms or whether the symptoms themselves affect brain communication. “Future studies should test if changes in this brain circuit over time lead to changes in negative symptom severity,” Ward said. The findings support the need for clinical trials that test whether enhancing cerebellar-prefrontal connectivity can lead to symptom improvement in people with psychosis. Prior pilot work using brain stimulation techniques has shown promise, and this study provides a stronger foundation for expanding such approaches. “As a psychiatrist, my long-term goal is to develop novel brain stimulation treatments for people with psychotic disorders that are highly effective and have minimal side effects,” Ward added. “This analysis was led by Sean Yarrell, MEd, who is now a graduate student in the lab of co-author (and colleague) Alexandra Moussa-Tooks, PhD at Indiana University, and Sophia Blyth, BA, who is now a graduate student in Will Pelham’s lab at UCSD.” The study, “Cerebellar-Prefrontal Connectivity Predicts Negative Symptom Severity Across the Psychosis Spectrum,” was authored by Sean A. Yarrell, Sophia H. Blyth, Alexandra B. Moussa-Tooks, Baxter P. Rogers, Anna Huang, Neil D. Woodward, Stephan Heckers, Roscoe O. Brady, and Heather Burrell Ward.
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