Microscale and macroscale brain disruptions may emerge together in schizophrenia

Reports new study in Biological Psychiatry

Brain abnormalities in schizophrenia have been identified at the microscale (alterations in synaptic connections between neurons) and the macroscale (altered connections between brain regions). Findings of these two levels of abnormalities have emerged separately, but a new study in Biological Psychiatry reports that the microscale and macroscale changes may go hand in hand.

"This study suggests that disturbances in connections between nerve cells in the brain emerge together in schizophrenia," said John Krystal, Editor of Biological Psychiatry.

Research on the neurobiological origins of schizophrenia indicates a reduction in the density of neuronal spines, where neurons form connections with each other to communicate. In parallel, magnetic resonance imaging (MRI) studies have shown reductions in large-scale white matter, the pathways connecting different brain regions. But how changes in these two levels of connectivity relate in schizophrenia remained an open question.

"This is quite remarkable, as in the end they both describe the same system, namely our brain," said first author Martijn van den Heuvel, from the University Medical Center Utrecht in The Netherlands. "So in my book, there has to be a link between these two scales of brain organization."

In their goal to bridge microscale cellular findings with macroscale MRI findings, the authors first studied the micro-macro association in healthy people. They collated data from published studies on spine density and cross-analyzed it with imaging data of long-range white matter connections that they derived from the Human Connectome Project. They found an association between microscale spine density, which indicates neuronal complexity, and the complexity of macroscale connections in the cortex.

To determine how the microscale changes relate to macroscale changes in schizophrenia, the researchers then analyzed spine density changes in schizophrenia, collated from published studies, with data on changes in MRI connectivity. They found a strong overlap in those regions showing the largest effects in spine density reductions and regions showing the largest effects of macroscale connectivity. The results suggest a possible relationship between the often, but independently, reported micro- and macroscale abnormalities.

According to van den Heuvel, bridging neuronal and macroscale connectivity completes an important missing link in schizophrenia research, and provides the first steps in understanding how changes in neuronal properties are related to changes in white matter connectivity in schizophrenia.

"Our study shows that we should no longer interpret neuronal and macroscale findings independently from each other, but that they likely strongly influence each other and are perhaps related to a similar disease origin," said van den Heuvel.

Krystal noted that the finding supports a view of the brain as a highly adaptive organism, where disturbances in some components of brain function result in coordinated effects on brain circuits.

"Understanding the cross-scale link brings us one step closer to understanding the etiology of the disorder," said van den Heuvel, "and this hopefully brings us closer to finding new treatment strategies for this severe psychiatric disorder."