Making Connections: Molecular and connectomic contributions to disease and disorder in the human brain

Author: ​Alexander Albury

Lay summary of article by Hansen JY et al. 2022 examining relationship between multimodally infomred brain connectivity across disorders

It's easy to picture the brain as a tangle of wires, criss-crossing and carrying information in all directions. But there's order in the chaos of our brains, with each of these connections serving a purpose by facilitating communication between the many cooperating brain areas necessary for complex behaviors. And in such a densely connected network, few things happen in isolation. Just as this broad connectivity serves to support the transportation of resources and information through the network, it also makes the brain more susceptible to disorders that can disrupt this delicate system.

A multidisciplinary group of researchers set out to investigate how much neurological disorders are caused by factors limited to a specific brain region, versus how much they depend on variability and abnormalities in larger brain networks.

In a paper published in Nature in 2022, Justine Y. Hansen and colleagues examined the relationship between connectivity—how parts of the brain connect to each other—and molecular vulnerability—the characteristics of individual cells in specific brain regions, in the presentation and progression of 13 common diseases and disorders, including ADHD, schizophrenia, depression, and epilepsy.

---

Using a combination of magnetic resonance imaging (MRI), magnetoencephalography (MEG), and positron emission tomography (PET) scans as well as gene expression data from close to 50,000 participants, the authors found that local, molecular features such as synapse density and neuron myelination, are more related to disorders and disease than connectivity across larger brain areas. However, the contributions of molecular attributes and connectivity vary across diseases. For example, epilepsy and schizophrenia are more heavily influenced by connectivity across brain regions, while ADHD and depression are more influenced by molecular characteristics within brain regions.

And although they found that many disorders are largely driven by molecular features, these features also interact with structural networks to shape how brain abnormalities progress. Local abnormalities in densely connected hub regions, or “epicenters”, such as the sensorimotor cortex, are implicated in multiple neurological diseases. If a part of the brain is important for many neurological functions, disruptions in that part are likely to affect other parts of the brain.

Their results also revealed the similarities in brain characteristics between the 13 disorders studied. In line with their findings on the role of molecular vulnerability, disorder similarity was specifically driven by similarity in molecular features rather than connectivity.
Altogether, the results provide a clearer picture of the progression of the 13 disorders studied, as well as broaden our understanding of the complex interactions across brain regions in neurological disease. These kinds of large-scale studies go a long way in helping us understand the mess of wires we carry around in our heads.

Original Research:  Hansen, J. Y., Shafiei, G., Vogel, J. W., Smart, K., Bearden, C. E., Hoogman, M., Franke, B., van Rooij, D., Buitelaar, J., McDonald, C. R., Sisodiya, S. M., Schmaal, L., Veltman, D. J., van den Heuvel, O. A., Stein, D. J., van Erp, T. G. M., Ching, C. R. K., Andreassen, O. A., Hajek, T., … Misic, B. (2022). Local molecular and global connectomic contributions to cross-disorder cortical abnormalities. Nature Communications, 13(1), Article 1. https://doi.org/10.1038/s41467-022-32420-y 

Justine Y. Hansen is the recipient of the 2023 Karl Zilles Award in Integrative Neuroscience. Read our interview with Justine here!