Evolution of Higher Function May Have Set the Stage for Schizophrenia in Humans

4 brains ranging in sizes.
An evolution of the human brain over time
The investigators noted that “modifications in brain circuitry in service of developing more complex brain functionality in humans may have potentially also shaped aspects of human-specific brain dysfunction.

The cortical dysconnectivity characteristic of schizophrenia may result from evolutionary modifications that support higher brain function, according to study results published in Brain. The study, led by Martijn van den Heuvel of the Connectome Laboratory at Vrije Universiteit Amsterdam in The Netherlands, examined in vivo neuroimaging data from adult humans and chimpanzees.

Investigators compared the species’ connectome layouts based on magnetic resonance imaging data in 58 humans (mean age, 42.5±9.8 years) and 22 chimpanzees (mean age, 29.4±12.8 years). In addition, the study analyzed 3 schizophrenia datasets with 118 patients and 113 healthy controls total. To ensure specificity given overlapping neural phenotypes in psychiatric disorders, datasets for 7 other brain disorders were also included.

Related Articles

Scans were processed in FreeSurfer and parcellated according to the Desikan-Killiany atlas. Connectivity was then reconstructed with deterministic fiber tracking, and the investigators used fractional anisotropy as a measure of connectivity strength and tract integrity. To assess brain dysconnectivity, they performed edgewise comparisons of connectome maps and determined t-statistics. Connections were considered specific to humans if they were seen in more than 60% of human subjects and 0% of chimpanzees, whereas shared connections had to be observed in 60% of both groups.

To determine whether connections seen in humans were unique to the evolution of homo sapiens, investigators also conducted post hoc analyses comparing human and chimpanzee connections with those of the brain in rhesus macaques (n=8).

The chimpanzee and human brain networks showed a strong binary connectome overlap of 94% (P <.001) and an overall correlation in connectivity strength (r = 0.93; P <.001). Investigators observed 27 human-specific connections (3.5% of the total connectome) compared with 7 chimpanzee-specific connections (1.1%), and the 2 groups shared 428 connections.

Evaluations of schizophrenia-related brain dysconnectivity demonstrated human patient-control differences of lower fractional anisotropy in the isthmus, parietal and temporal cortices, insula, and precuneus, among others.

Subsequently, when exploring schizophrenia-related dysconnectivity and human evolutionary modifications, human-specific connections displayed a significantly higher level of congruence with the pattern of schizophrenia dysconnectivity compared with the set of human-chimpanzee shared connections in all 3 schizophrenia datasets (P = .019, P =.012, and P =.005). The level of human-chimpanzee connectivity difference was also moderately correlated with schizophrenia dysconnectivity in all 3 datasets (r = 0.17; P =.021; r = 0.22; P =.001; and r = 0.17; P =.034). Second to human-specific connections, shared connections more common in humans demonstrated high levels of schizophrenia-related dysconnectivity (P = .0020, P =.004, and P =.010).

The investigators found no significant involvement of human-specific connections in other brain disorders. In the post hoc analysis comparing human and chimpanzee connections with those seen in rhesus macaques, the set of connections unique to humans showed significantly greater involvement compared with the set of species-shared connections in the 3 datasets (P <.001, P =.031, and P =.0020).

The investigators noted that “modifications in brain circuitry in service of developing more complex brain functionality in humans may have potentially also shaped aspects of human-specific brain dysfunction.” Study limitations included the relatively sparse availability of connectome data from different primate species and the variety of employed methodologies and experimental conditions used to derive connectomes.

“Our findings suggest that evolutionary modifications to connections of the human cerebrum are associated with the pattern of cortical dysconnectivity in schizophrenia,” the investigators wrote, “Compared to our closest living relative the chimpanzee, connections present only in humans showed on average a higher involvement in schizophrenia pathology than the majority class of connections that are shared between the two species.”


van den Heuvel MP, Scholtens LH, de Lange SC, et al. Evolutionary modifications in human brain connectivity associated with schizophrenia [published online November 14, 2019]. Brain. doi:10.1093/brain/awz330