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Genetic and phylogenetic uncoupling of structure and function in human transmodal cortex
Authors
Sofie Valk,Ting Xu
Casey Paquola,B Park,Richard Bethlehem,Vos R,Jessica Royer,Kharabian S,Şeyma Bayrak,Peter Kochunov,B.T. Yeo,Daniel Margulies,Jonathan Smallwood,SB Eickhoff,Bernhardt Bc,Mark Lauckner,Bo‐yong Park,Reinder Wael,Shahrzad Kharabian-Masouleh,Shahrzad Masouleh,Simon Eickhoff
+19 authors
,Boris BernhardtPublished
Jun 9, 2021
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GENETIC AND PHYLOGENETIC UNCOUPLING OF
STRUCTURE AND FUNCTION IN HUMAN TRANSMODAL CORTEX
Sofie L. Valk1-3, Ting Xu4, Casey Paquola5, Bo-yong Park6,7, Richard A.I. Bethlehem8, Reinder Vos de Wael6,
Jessica Royer6, Shahrzad Kharabian Masouleh2, Şeyma Bayrak1, Peter Kochunov9, B.T. Thomas Yeo10-14, Daniel
Margulies15, Jonathan Smallwood16, Simon B. Eickhoff2,3*, Boris C. Bernhardt6*
1. Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences,
Leipzig, Germany; 2. INM-7, FZ Jülich, Jülich, Germany; 3. Institute of Systems Neuroscience, HHU
Duesseldorf, Duesseldorf, Germany; 4. Center for the Developing Brain, New York City, USA; 5. INM-1, FZ
Jülich, Jülich, Germany; 6.Multimodal Imaging and Connectome Analysis Lab, McConnell Brain Imaging
Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; 7.
Department of Data Science, Inha University, Incheon, South Korea; 6. University of Baltimore, Baltimore,
USA; 8. Department of Psychiatry, Cambridge University, Cambridge UK; 9. Maryland Psychiatric Research
Center, University of Maryland School of Medicine, Baltimore, Maryland, US; 10. Department of Electrical and
Computer Engineering, National University of Singapore, Singapore, Singapore; 11. Centre for Sleep and
Cognition (CSC) & Centre for Translational Magnetic Resonance Research (TMR), National University of
Singapore, Singapore, Singapore; 12. N.1 Institute for Health & Institute for Digital Medicine (WisDM),
National University of Singapore, Singapore, Singapore; 13.Martinos Center for Biomedical Imaging,
Massachusetts General Hospital, Charlestown, Massachusetts, United States of America; 14 Integrative
Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, Singapore;15
Neuroanatomy and Connectivity Lab, Institut de Cerveau et de la Moelle epiniere, Paris, France; 16
Department of Psychology, Queen’s University, Kingston, Ontario, Canada;
CORRESPONDENCE TO
Sofie L Valk, PhD
e. s.valk@fz-juelich.de
* both last co-authors contributed equally
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
STRUCTURE AND FUNCTION IN HUMAN TRANSMODAL CORTEX
Sofie L. Valk1-3, Ting Xu4, Casey Paquola5, Bo-yong Park6,7, Richard A.I. Bethlehem8, Reinder Vos de Wael6,
Jessica Royer6, Shahrzad Kharabian Masouleh2, Şeyma Bayrak1, Peter Kochunov9, B.T. Thomas Yeo10-14, Daniel
Margulies15, Jonathan Smallwood16, Simon B. Eickhoff2,3*, Boris C. Bernhardt6*
1. Otto Hahn Group Cognitive Neurogenetics, Max Planck Institute for Human Cognitive and Brain Sciences,
Leipzig, Germany; 2. INM-7, FZ Jülich, Jülich, Germany; 3. Institute of Systems Neuroscience, HHU
Duesseldorf, Duesseldorf, Germany; 4. Center for the Developing Brain, New York City, USA; 5. INM-1, FZ
Jülich, Jülich, Germany; 6.Multimodal Imaging and Connectome Analysis Lab, McConnell Brain Imaging
Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada; 7.
Department of Data Science, Inha University, Incheon, South Korea; 6. University of Baltimore, Baltimore,
USA; 8. Department of Psychiatry, Cambridge University, Cambridge UK; 9. Maryland Psychiatric Research
Center, University of Maryland School of Medicine, Baltimore, Maryland, US; 10. Department of Electrical and
Computer Engineering, National University of Singapore, Singapore, Singapore; 11. Centre for Sleep and
Cognition (CSC) & Centre for Translational Magnetic Resonance Research (TMR), National University of
Singapore, Singapore, Singapore; 12. N.1 Institute for Health & Institute for Digital Medicine (WisDM),
National University of Singapore, Singapore, Singapore; 13.Martinos Center for Biomedical Imaging,
Massachusetts General Hospital, Charlestown, Massachusetts, United States of America; 14 Integrative
Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, Singapore;15
Neuroanatomy and Connectivity Lab, Institut de Cerveau et de la Moelle epiniere, Paris, France; 16
Department of Psychology, Queen’s University, Kingston, Ontario, Canada;
CORRESPONDENCE TO
Sofie L Valk, PhD
e. s.valk@fz-juelich.de
* both last co-authors contributed equally
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
Valk et al. Genetic and phylogenetic uncoupling of transmodal structure and function
2
ABSTRACT
Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral
flexibility. However, it remains unclear how a static, genetically controlled architecture
supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and
cognitive analyses to understand how the macroscale organization of structure-function
coupling across the cortex can inform its role in cognition. In humans, structure-function
coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern
that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-
function uncoupling in non-human primates had a similar spatial distribution, but we
observed an increased coupling between structure and function in association regions in
macaques relative to humans. Meta-analysis suggested regions with the least genetic control
(low heritable correspondence and different across primates) are linked to social cognition
and autobiographical memory. Our findings establish the genetic and evolutionary uncoupling
of structure and function in different transmodal systems may support the emergence of
complex, culturally embedded forms of cognition.
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
2
ABSTRACT
Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral
flexibility. However, it remains unclear how a static, genetically controlled architecture
supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and
cognitive analyses to understand how the macroscale organization of structure-function
coupling across the cortex can inform its role in cognition. In humans, structure-function
coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern
that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-
function uncoupling in non-human primates had a similar spatial distribution, but we
observed an increased coupling between structure and function in association regions in
macaques relative to humans. Meta-analysis suggested regions with the least genetic control
(low heritable correspondence and different across primates) are linked to social cognition
and autobiographical memory. Our findings establish the genetic and evolutionary uncoupling
of structure and function in different transmodal systems may support the emergence of
complex, culturally embedded forms of cognition.
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
Valk et al. Genetic and phylogenetic uncoupling of transmodal structure and function
3
INTRODUCTION
Cognition helps an animal to satisfy core biological goals in a changing environmental
context. In humans, cognition allows our species to successfully navigate through a broad
array of situations and socio-cultural contexts. Although the need for flexible cognition is
well-established, it remains unclear how a relatively static brain organization can give rise to
functional patterns with sufficient flexibility to navigate complex culturally-rich landscapes,
such as those found in human societies.
Contemporary perspectives suggest that higher-order, abstract, cognition is grounded in a
cortical organization that encompasses parallel axes of microstructural differentiation and
function 1[for nomenclature: Supplementary Table 1]. On the one hand, sensory/motor
systems as well as unimodal association cortices are involved in operations related to
perceiving and acting in the outside world. These systems are differentiated from transmodal
systems that are less tied to a specific modality, and are increasingly engaged in abstract and
self-generated cognition together with communication with the “internal milieu” 1-4. These
functional differences are reflected in well-established differences in the microstructure of
sensory/motor and transmodal cortex. Histological studies have shown that unimodal sensory
and motor regions show more distinctive lamination patterns relative to agranular/dysgranular
transmodal cortex with less apparent lamination 5. Complementing these findings, in vivo
studies have shown that transmodal regions have overall lower myelin content 6-9, yet more
complex dendritic arborization patterns which could facilitate integrative processing and
increased potential for plastic adaptations 10. According to its classic definition 1, transmodal
cortex encompasses both paralimbic cortices as well as heteromodal association networks 11,
notably the default mode and fronto-parietal functional networks that are specifically
expanded in humans11. These latter two networks are known to participate in a broad class of
abstract cognitive processes, including autobiographical memory 12,13, language 14-16, as well
as executive control 2,17,18.
Post-mortem studies in non-human animals together with emerging data in humans 19-21
suggest that regions with a similar cytoarchitecture are also more likely to be structurally and
functional interconnected, an observation framed as the “structural model” of brain
connectivity 22,23. Yet, how mappings in cortical structure and function vary across different
cortical areas remains to be established. Recent in vivo work suggests that structure-function
coupling as measured by the association of white matter tractography and functional
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
3
INTRODUCTION
Cognition helps an animal to satisfy core biological goals in a changing environmental
context. In humans, cognition allows our species to successfully navigate through a broad
array of situations and socio-cultural contexts. Although the need for flexible cognition is
well-established, it remains unclear how a relatively static brain organization can give rise to
functional patterns with sufficient flexibility to navigate complex culturally-rich landscapes,
such as those found in human societies.
Contemporary perspectives suggest that higher-order, abstract, cognition is grounded in a
cortical organization that encompasses parallel axes of microstructural differentiation and
function 1[for nomenclature: Supplementary Table 1]. On the one hand, sensory/motor
systems as well as unimodal association cortices are involved in operations related to
perceiving and acting in the outside world. These systems are differentiated from transmodal
systems that are less tied to a specific modality, and are increasingly engaged in abstract and
self-generated cognition together with communication with the “internal milieu” 1-4. These
functional differences are reflected in well-established differences in the microstructure of
sensory/motor and transmodal cortex. Histological studies have shown that unimodal sensory
and motor regions show more distinctive lamination patterns relative to agranular/dysgranular
transmodal cortex with less apparent lamination 5. Complementing these findings, in vivo
studies have shown that transmodal regions have overall lower myelin content 6-9, yet more
complex dendritic arborization patterns which could facilitate integrative processing and
increased potential for plastic adaptations 10. According to its classic definition 1, transmodal
cortex encompasses both paralimbic cortices as well as heteromodal association networks 11,
notably the default mode and fronto-parietal functional networks that are specifically
expanded in humans11. These latter two networks are known to participate in a broad class of
abstract cognitive processes, including autobiographical memory 12,13, language 14-16, as well
as executive control 2,17,18.
Post-mortem studies in non-human animals together with emerging data in humans 19-21
suggest that regions with a similar cytoarchitecture are also more likely to be structurally and
functional interconnected, an observation framed as the “structural model” of brain
connectivity 22,23. Yet, how mappings in cortical structure and function vary across different
cortical areas remains to be established. Recent in vivo work suggests that structure-function
coupling as measured by the association of white matter tractography and functional
.CC-BY-NC-ND 4.0 International licenseavailable under a
was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made
The copyright holder for this preprint (whichthis version posted June 9, 2021.;https://doi.org/10.1101/2021.06.08.447522doi:bioRxiv preprint
100%
