SCIENCE ADVANCES | RESEARCH ARTICLE NEUROSCIENCE Copyright © 2020 The Authors, some rights reserved; Shaping brain structure: Genetic and phylogenetic axes exclusive licensee American Association of macroscale organization of cortical thickness for the Advancement Sofie L. Valk1,2,3*, Ting Xu4, Daniel S. Margulies4,5, Shahrzad Kharabian Masouleh1,2, of Science. No claim to 6 7 8 9 original U.S. Government Casey Paquola , Alexandros Goulas , Peter Kochunov , Jonathan Smallwood , Works. Distributed 10,11,12 6 1,2 B. T. Thomas Yeo , Boris C. Bernhardt , Simon B. Eickhoff under a Creative Commons Attribution The topology of the cerebral cortex has been proposed to provide an important source of constraint for the License 4.0 (CC BY). organization of cognition. In a sample of twins (n = 1113), we determined structural covariance of thickness to be organized along both a posterior-to-anterior and an inferior-to-superior axis. Both organizational axes were present when investigating the genetic correlation of cortical thickness, suggesting a strong genetic component in humans, and had a comparable organization in macaques, demonstrating they are phylogenetically conserved in primates. In both species, the inferior-superior dimension of cortical organization aligned with the predictions of dual-origin theory, and in humans, we found that the posterior-to-anterior axis related to a functional topography describing a continuum of functions from basic processes involved in perception and action to more abstract Downloaded from features of human cognition. Together, our study provides important insights into how functional and evolutionary patterns converge at the level of macroscale cortical structural organization. INTRODUCTION flexible human cognition (6). For example, association cortex is A fundamental question in neuroscience is how the structure of the located at maximal distance from regions of primary cortex that are http://advances.sciencemag.org/ cortex constrains its function. Over the course of almost a century, functionally specialized for perceiving and acting in the here and numerous studies have shown that the cerebral cortex is organized now. This increased spatial distance from primary cortex may allow along dimensions that reflect systematic variations in features of association cortex to take on functions that are only loosely con- brain structure and function such as laminar differentiation, gene strained by the immediate environment, allowing internal repre- expression, and structural and functional connectivity (1). These sentations to contribute to cognition and so enhancing the flexibility dimensions have been suggested to reflect the timing of neurogenesis and evolutionary fitness of behavior (6, 7). Accordingly, understand- (2–4). A potential mechanism for the source of neurogenetic differ- ing how the structure of the cortex scaffolds function in a flexible entiation of brain regions is described by the dual origin theory (3, 4). manner requires understanding how macroscale structural features This theory conceptualizes cortical areas as emerging from waves of of the organization of the human cortex emerge. Moreover, previous laminar differentiation that spring from the piriform cortex (paleo- work has implicated macroscale organizational axes of structure and on October 12, 2020 cortex) and the hippocampus (archicortex). The dual structure might function in the impact and progression of pathology. For example, be rooted in heterochronous ontological axes in the developing Parkinson’s and Alzheimer’s disease have been proposed to follow a cortex (3, 4). It has been suggested that a sequential progression trajectory, in which underlying anatomical axes determine the se- of cortical architectonic differentiation arises from each of both quence in which specific regions and networks are progressively origins, which leads to the six-layered proisocortex and isocortex, affected at different disease stages (8). Recently, we have been able resulting in a sensory-fugal organization (5). to show that functional abnormalities in autism spectrum disorder The systematic topological organization of the cerebral cortex has relate to systematic disruptions in large-scale functional organi- been proposed to reflect an architecture that optimizes the balance of zation, providing a parsimonious reference frame in which the externally and internally oriented functioning, which is critical for heterogeneous symptoms of autism spectrum disorder can be understood (9). Although the importance of macroscale axes of cortical organi- 1Institute of Neuroscience and Medicine (INM-7: Brain and Behavior), Research zation in cognition and pathology are now recognized, the degree to Centre Jülich, Jülich, Germany. 2Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. 3Otto Hahn Group Cognitive Neuro- which these topological features of the cerebral cortex are genetically genetics, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, determined remains incompletely understood. Cortical thickness is Germany. 4Center for the Developing Brain, Child Mind Institute, New York, a widely used morphological measure and has been related to the 5 NY, USA. Frontlab, Centre National de la Recherche Scientifique Institut du Cerveau neuronal density, cytoarchitecture, and structural hierarchical or- et de la Moelle Épinière, Paris, France. 6McConnell Brain Imaging Centre, Mon- treal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada. ganization of the cerebral cortex (10, 11). Measured across a popu- 7Institute of Computational Neuroscience, University Medical Center Hamburg- lation, local brain structure shows marked patterns of covariation 8 Eppendorf, Hamburg University, Hamburg, Germany. Maryland Psychiatric Research across the cerebral cortex, termed “structural covariance.” These Center, University of Maryland School of Medicine, Baltimore, MD, USA. 9York Neuro- imaging Center, University of York, York, UK. 10Department of Electrical and Com- macroscale patterns in cortical thickness provide a model of shared puter Engineering, Centre for Sleep and Cognition, Centre for Translational MR maturational and genetic effects on morphology (12–16) and have Research and N.1 Institute for Health, National University of Singapore, Singapore, been linked to both structural and functional connectivity (17, 18). Singapore. 11Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts 12 Structural covariance has been reported to be organized in various General Hospital, Charlestown, MA, USA. NUS Graduate School for Integrative Sci- ences and Engineering, National University of Singapore, Singapore, Singapore. local, genetically determined, communities (12–14). Recent work *Corresponding author. Email: [email protected] shows that interregional genetic correlation is determined by two Valk et al., Sci. Adv. 2020; 6 : eabb3417 25 September 2020 1 of 14 SCIENCE ADVANCES | RESEARCH ARTICLE organizational principles: (i) regions are strongly genetically cor- tion of cortical structure and so provide an important window into related with their counterparts in the opposite cerebral hemisphere, the innate architecture supporting human cognition. and (ii) regions are highly genetically correlated with geometrically nearby regions (13). The local processes that govern the observed distribution of cortical thickness are reasonably well understood. RESULTS For example, associations with structural and functional connec- Axes underlying macroscale coordination of tivity may arise due to shared trophic changes at the synaptic and cortical thickness cellular levels (19) and/or reflect coupled expression of genes We started our analysis by evaluating the topological organization enriched in supragranular layers (20) that are associated with tran- of interregional cortical thickness correlations [henceforth referred scriptomic similarity of local brain regions (21). Both of these effects to as structural covariance (Fig. 1)]. We used the mean thickness converge with postmortem interregional correlations of gene expres- within 400 parcels (25) to create group-level covariance maps based sion (22). Developmentally, macroscale patterns of cortical thickness on individual thickness values of participants from the Human mature with age, possibly because of synchronized neurodevelop- Connectome Project (HCP; S1200). When computing the macro- ment (15) and the expression of common genetic cues during early scale organization of cortical thickness, we controlled for the effects cortical development (15). of age, sex, and global thickness. First, we evaluated the average Together, contemporary theory suggests that (i) macroscale structural covariance as a function of brain network organization patterns in cortical organization make an important contribution to (23). Within-community covariance (mean ± SD, 0.05 ± 0.03) was human cognition and (ii) cortical thickness covariance reflects shared higher than between-community covariance (mean ± SD, −0.01 ± 0.02), Downloaded from maturational and genetic processes and is organized in multiple P < 0.001, and visual, sensory-motor, fronto-parietal, and default communities. However, the reason for their particular spatial rela- mode networks had higher covariance within network relative to tionship remains unclear. Our current study sought to directly random networks [false discovery rate (FDR) q < 0.05], in line with examine the genetic origin of