The Role of Evolution on Brain Connectivity in Schizophrenia
Post by Elisa Guma
What's the science?
Schizophrenia is a debilitating psychiatric disorder characterized by hallucinations, delusions, and cognitive dysfunction, often associated with impaired brain connectivity. The genetic origin, human-specific traits, and similar prevalence observed across societies (1% of the population is affected globally) have led to the idea that human brain evolution may have played a role in the development of the disorder. This week in Brain, van den Heuvel and colleagues aim to investigate schizophrenia-related changes in brain connectivity in the context of evolutionary changes in the human brain by comparing humans and chimpanzees.
How did they do it?
To measure brain connectivity, the authors studied diffusion-weighted imaging data (sensitive to the integrity of the brain’s white matter tracts and myelin levels) from individuals with schizophrenia and gender-matched healthy control subjects, as well as from chimpanzees. Connectome maps were created by 1) subdividing the cerebral cortex into 114 subdivisions based on a commonly used brain atlas, and then 2) calculating cortico-cortical connectivity between every subdivision or brain region and every other brain region. The measure of cortico-cortical connectivity was based on whether each pair of brain regions were interconnected by common diffusion-weighted streamlines (measuring common white matter tracts). The authors compared the connectome maps of individuals with schizophrenia to those of controls to examine differences in brain connectivity. In order to confirm whether the results they observed were schizophrenia specific, they performed the same analysis for a variety of other neuropsychiatric and neurological disorders including major depressive disorder, bipolar disorder, obsessive-compulsive disorder, autism spectrum disorder, a behavioural variant of frontotemporal dementia, and mild cognitive impairment. The authors also performed their analysis in a separate cohort of schizophrenia and control subjects to ensure their results were not biased by the data acquisition of their original sample.
To determine the human-specific connections in the brain, the authors compared the connectome maps between humans and chimpanzees. Connections that were present in at least 60% of the human subjects and 0% of the chimpanzees were classified as human-specific connections (and vice-versa for chimpanzee-specific connections). Human-chimpanzee-shared connections were classified as those present in at least 60% of humans and 60% of chimpanzees. To investigate the evolutionary nature of dysconnectivity (i.e. reduced connectivity) in schizophrenia, the authors compared human-specific connection patterns to brain dysconnectivity patterns due to schizophrenia. The authors extended their cross-species comparison to include rhesus macaques, a more distantly related primate species, to further investigate the evolutionary specialization of the human-specific connections they identified. Finally, the authors validated their findings by repeating the analysis using a different brain atlas that is designed to map homologous regions across humans and chimpanzees and subdivides cortical areas into 38 rather than 114 regions.
What did they find?
First, the authors show that many brain regions involved in higher-order processing had greater dysconnectivity in patients with schizophrenia. These findings were consistent with previous studies. Next, the authors found a 94% overlap between the human and chimpanzee cortico-cortical networks, with 3.5% human-specific connections, and 1.1% chimpanzee-specific connections. Many of the brain regions identified to be human-specific are involved in language networks and important for semantic comprehension. The authors also identified human-specific connections in regions implicated in cognitive control, social cognition, emotional processing, and bonding behaviour. Interestingly, these behaviours are often impaired in individuals with schizophrenia. In fact, the authors found high similarity between patterns of schizophrenia dysconnectivity and human-specific connections in comparison to connections shared by both humans and chimpanzees. This held true when the authors extended their cross-species comparison to include macaques, and when the data were analyzed with the alternative brain atlas. Furthermore, the human-specific connections were not associated with brain dysconnectivity patterns for any other disorders. There were trend level associations with bipolar disorder, which shares a genetic background with schizophrenia, as well as some symptoms like psychosis.
What's the impact?
These findings provide compelling evidence for the hypothesis that human brain evolution may have played a role in the development of schizophrenia. The authors show that human-specific features of cortical connectivity are associated with patterns of cortical dysconnectivity in individuals with schizophrenia, suggesting that evolutionary pressure to develop higher-order functions may have rendered the brain vulnerable to dysfunction. In future work, it could be interesting to see how these patterns extend to other measures of brain function.
Van den Heuvel et al. Evolutionary modifications in human brain connectivity associated with schizophrenia. Brain (2019). Access the original scientific publication here.