The genetic organization of longitudinal subcortical volumetric change is stable throughout the lifespan
Abstract
Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single nucleotide polymorphisms-based analyses of 38127 cross-sectional MRIs showed a similar pattern of genetic volume-volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.
Data availability
The following is included in a separate section in the manuscript:Data availabilityThe study comprises many different data sources. The PI does not have the legal right to share these data directly. UK Biobank data can be obtained from www.ukbiobank.ac.uk. The data repository for the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) dataset can be found at www.cam-can.org/index.php?content=dataset. Access to BASE-II data can be obtained at www.base2.mpg.de/7549/data-documentation. Access to VETSA data can be obtained at https://medschool.ucsd.edu/som/psychiatry/research/VETSA/Researchers/Pages/default.aspx. Betula is described at www.umu.se/en/research/projects/betula---aging-memory-and-dementia/. For data from Barcelona brain studies, see www.neurociencies.ub.edu/david-bartres-faz/. For LCBC Lifespan sample, contact information can be found at https://www.oslobrains.no/presentation/anders-m-fjell/. Part of the developmental sample can be accessed through https://www.fhi.no/en/studies/moba/for-forskere-artikler/research-and-data-access/ (As of 2021, we are in the process of transferring MRI data to this repository). Please note that for all samples, data transfer agreements must be signed and proper ethical and data protection approvals must be in place, according to national legislation. Code used for data analysis accompany the submission as separate files. The correlation matrices constituting the basis for the Mantel tests are also uploaded.
Article and author information
Author details
Funding
European Research Council (283634;725025;313440)
- Anders Martin Fjell
- Kristine Beate Walhovd
the Medical Research Council Cognition & Brain Sciences Unit
- Rogier Andrew Kievit
U.S. National Institute on Aging (AG022381,AG050595)
- William S Kremen
EU Horizon 2020 (732592)
- Kristine Beate Walhovd
Knut and Alice Wallenberg foundation
- Lars Nyberg
Norwegian Research Council
- Anders Martin Fjell
- Kristine Beate Walhovd
Spanish Ministry of Science, Innovation and Universities
- David Bartres-Faz
the California Walnut Commission (NCT01634841)
- David Bartres-Faz
German Federal Ministry of Education and Research (16SV5537/16SV5837/16SV5538/16SV5536K/01UW0808/01UW0706/01GL1716A/01GL1716B)
- Ulman Lindenberger
European Research Council (677804)
- Simone Kühn
Biotechnology and Biological Sciences Research Council
- Rogier Andrew Kievit
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The studies were approved by the Norwegian Regional Committee for Medical and Health Research Ethics South. Written informed consent was obtained from all participants older than 12 years of age and from a parent/guardian of volunteers under 16 years of age. Oral informed consent was obtained from all participants under 12 years of age. Non-Norwegian samples were approved by the relevant ethical review board for each country. Norway (2010/2359; 2010/3407; 2009/200)
Reviewing Editor
- Alex Fornito, Monash University, Australia
Publication history
- Received: January 12, 2021
- Accepted: June 26, 2021
- Accepted Manuscript published: June 28, 2021 (version 1)
- Version of Record published: July 6, 2021 (version 2)
Copyright
© 2021, Fjell et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,119
- Page views
-
- 137
- Downloads
-
- 4
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Physics of Living Systems
- Neuroscience
Running stably on uneven natural terrain takes skillful control and was critical for human evolution. Even as runners circumnavigate hazardous obstacles such as steep drops, they must contend with uneven ground that is gentler but still destabilizing. We do not know how footsteps are guided based on the uneven topography of the ground and how those choices influence stability. Therefore, we studied human runners on trail-like undulating uneven terrain and measured their energetics, kinematics, ground forces, and stepping patterns. We find that runners do not selectively step on more level ground areas. Instead, the body’s mechanical response, mediated by the control of leg compliance, helps maintain stability without requiring precise regulation of footsteps. Furthermore, their overall kinematics and energy consumption on uneven terrain showed little change from flat ground. These findings may explain how runners remain stable on natural terrain while devoting attention to tasks besides guiding footsteps.
-
- Neuroscience
Response variability is an essential and universal feature of sensory processing and behavior. It arises from fluctuations in the internal state of the brain, which modulate how sensory information is represented and transformed to guide behavioral actions. In part, brain state is shaped by recent network activity, fed back through recurrent connections to modulate neuronal excitability. However, the degree to which these interactions influence response variability and the spatial and temporal scales across which they operate, are poorly understood. Here, we combined population recordings and modeling to gain insights into how neuronal activity modulates network state and thereby impacts visually evoked activity and behavior. First, we performed cellular-resolution calcium imaging of the optic tectum to monitor ongoing activity, the pattern of which is both a cause and consequence of changes in network state. We developed a minimal network model incorporating fast, short range, recurrent excitation and long-lasting, activity-dependent suppression that reproduced a hallmark property of tectal activity – intermittent bursting. We next used the model to estimate the excitability state of tectal neurons based on recent activity history and found that this explained a portion of the trial-to-trial variability in visually evoked responses, as well as spatially selective response adaptation. Moreover, these dynamics also predicted behavioral trends such as selective habituation of visually evoked prey-catching. Overall, we demonstrate that a simple recurrent interaction motif can be used to estimate the effect of activity upon the incidental state of a neural network and account for experience-dependent effects on sensory encoding and visually guided behavior.