Molecular and connectomic vulnerability shape cross-disorder cortical abnormalities

Abstract

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N=21,000 patients and N=26,000 controls, collected using a harmonized processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find that regional molecular vulnerability and macroscale brain network architecture interact to drive the spatial patterning of cortical abnormalities in multiple disorders. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, medial temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local biological attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

Three components of human brain gene expression reflect normative developmental programmes with specific links to neurodevelopmental disorders

“…If so, the lack of an association between G1 and SCZ may be due to limited signal-to-noise, and remains a question for future research. Overall, our results complement recent findings pointing to shared molecular and structural underpinnings across psychiatric disorders [81][82][83][84][85] .…”

Mapping Pharmacologically-induced Functional Reorganisation onto the Brain’s Neurotransmitter Landscape

“…Correlating this matrix of regional co-susceptibility to disease-associated perturbations against the previously derived matrix of regional co-susceptibility to pharmacological perturbations, we found a statistically significant relationship (Spearman’s rho = 0.29, p < 0.001 after regressing out the effect of Euclidean distance) (Figure 6C). This result goes beyond a recent demonstration that molecular similarity and disorder similarity are correlated 109 , by showing that a correlation also exists between different kinds of perturbations: anatomical and pharmacological.…”

“…To address this question, we computed matrices of pharmacological co-susceptibility and neurotransmitter co-expression between pairs of regions, by correlating respectively the regional patterns of drug-induced FC changes (across all subjects), and the regional patterns of neurotransmitter expression across all 18 receptor and transporter PET maps. To account for spatial autocorrelation in molecular and FC attributes, we regressed out from both matrices the exponential trend with Euclidean distance [109][110][111][112] .…”

Mitochondrial dysfunction underlies cortical atrophy in prodromal synucleinopathies

“…These data were processed previously 78 and used in several studies assessing the impact of connectivity on atrophy. 17,[79][80][81] After exclusion of 4 connectivity maps with aberrant scores (3 structural, 1 functional), the individual structural matrices were transformed into a group-consensus structural connectivity matrix that preserved the brain's edge length distribution; 82 self-connections were converted to zero.…”