More evidence for abnormal connectivity in schizophrenia

Schizophrenia is a debilitating neuropsychiatric disorder with a prevalence of ~ 1%. Like many other neuropsychiatric disorders, schizophrenia seems to be fairly heritable and it is now associated with many risk genes. Despite the progress gained in uncovering the neural mechanisms underlying this disorder, the exact causes of schizophrenia remain largely unknown. For instance, many studies in animals and humans have shown mixed findings as they relate to the specific deficits of schizophrenia. There have been reports of decreased connectivity, decreased activity, increased connectivity, increased activity, more neurons, less neurons, numerous affected brain regions, and discrepancies of when and where and how these changes take place. In other words, schizophrenia is a messy disorder. Despite these contrasting reports, it is clear that a  specific brain region, the prefrontal cortex (PFC), is involved in this psychiatric disorder. In the most recent issue of The Journal of Neuroscience, researchers identify changes in the PFC of schizophrenic patients using a technique that monitors blood flow in the brain as an assay for studying brain activity.

In this study, Anticevic et al. harnessed the power of fMRI and blood-oxygenation-level-dependent (BOLD) analysis, techniques used to study activity and connectivity indirectly by using changes in blood flow, as a means of studying how active brain cells are in a given region at a given time. Specifically, these researchers studied 129 patients diagnosed with schizophrenia and 106 healthy controls, comparing the results from these two groups to determine whether or not the brains from the schizophrenic subjects have increased PFC or whole-brain functional connectivity compared to the control subjects. Previous work in the field has found decreases in both connectivity and activation in the PFC, however these studies were done in patients who had been living with schizophrenia for an extended period of time. For this reason, the functional differences between schizophrenics and controls at a much earlier time of disease development remain unknown. To investigate these early deficits, the 129 schizophrenic patients were non-medicated individuals with early-course schizophrenia, a method that allowed researchers to avoid the confounds presented when studying patients on long-term medication or who have had the disease for many years  .

As the authors hypothesized that the PFC would show hyperconnectivity in the patients with early-course schizophrenia (ECS), they mostly focused on this region. BOLD analysis revealed that the PFC of the ECS patients showed increased connectivity compared to the controls. More specifically, the hyper connectivity was localized to the medial region of the PFC.  The authors also tested whether or not other PFC regions might show the opposite pattern, as decreased connectivity has been reported in schizophrenia, but has not been investigated in ECS. In this case, no significant differences were found, suggesting that for ECS, hypoconnectivity is not evident in the PFC. Additionally, the authors applied their analysis to the entire brain, looking for changes in connectivity in either direction. This analysis showed that there were many instances of hyper- and hypoconnectivity in the ECS brains. Together these results indicate that functional connectivity is significantly altered in ECS brains.

The Positive and Negative  Syndrome Scale (PANSS) is a tool used by clinicians to determine the severity of symptoms in individuals with schizophrenia. To determine whether or not the differences in ECS connectivity are related to symptoms associated with schizophrenia, Anticevic et al. correlated overall PANSS scores with the findings from the BOLD analysis. The authors found that the patients with higher PFC connectivity were more likely to have more severe symptoms as measured by the PANSS scores. There was no correlation between reduced connectivity and symptom severity. The authors also tested whether or not the hyperconnectivity could be used as a predictive value. To this end, using established techniques, authors were able to classify patients with >60% accuracy, indicating that determining PFC functional connectivity in ECS may have diagnostic value when combined with results from other techniques/tests.

As indicated by the variable findings related to the disease mechanisms of schizophrenia, understanding this neuropsychiatric disorder is no small task. Significant progress will most likely be made with new and outstanding methods and technology, but until then, it is important to carry out rigorous, controlled experiments at both the microscopic and macroscopic levels to continue to develop a model for the cause and development of schizophrenia and other neuropsychiatric disorders. This paper provides another set of data to support PFC involvement in schizophrenia, specifically suggesting that hyperconnectivity in medial PFC areas exists in early-course patients, a finding that is correlated to symptom severity and may even be used to help in patient classification. To further understand the meaning of these findings it will be necessary to study the PFC at a similar disease time point at both the cellular and molecular level. Such investigations may provide insights into the specific causes of hyperconnectivity in the PFC that may vary in other brain regions and may even lead to the identification of a future therapeutic target.

 

Anticevic, A., Hu, X., Xiao, Y., Hu, J., Li, F., Bi, F., et al. (2015). Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change. Journal of Neuroscience, 35(1), 267–286. doi:10.1523/JNEUROSCI.2310-14.2015

 

 

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