The comparative connectome

Lead Research Organisation: University of Oxford
Department Name: Clinical Neurosciences

Abstract

What makes humans unique? Relative to our body size, we have the largest brain of any primate. This massive brain allows us to dominate the planet, while our closest animal cousins, the great apes, are relegated to small patches of Africa and Indonesia. However, exactly what changed in our brain when it got bigger and how this relates to our uniquely human behaviors, such as spoken language, advanced tool-making, and bipedal walking, remains a mystery. In this project, we try to solve this mystery, by comparing the architecture of our brain to that of a range of other primates.

If we want to understand what makes our brain different, it is not enough to compare it to that of just one other ape or monkey. We differ in many respects from other primates and thus any differences we find might find can be related to many behaviors. If we want to understand how different behaviors are related to particular changes in our brain, we have to compare our brain to that of a range of other primates, each with different behaviors. Therefore, in this project we aim to map the connections and brain regions of a range of different primates.

We will use new developments in neuroimaging to scan the brain of primates post-mortem. We will obtain the brains from animals that have lived in zoos and that have died through causes completely unrelated to our research. This will allow us to study more species than ever before without any ethical constraints. By using neuroimaging we can obtain different types of information from each brain, such as how big specific brain regions are, where they are located, and how they are connected. This project will be based at the University of Oxford's FMRIB centre. The Fellow and a post-doctoral research assistant will conduct the majority of the work, in collaboration with the MRI Physics Group at FMRIB.

We will investigate differences in brains related to three types of behavior that we believe are particularly well developed in humans: language, tool use, and general decision-making.

Human language has been suggested to be possible due to a series of new connections between the temporal and frontal cortex of the human brain. However, it has recently been suggested that some of these connections are already present in great apes, such as gorillas, which mean they might not be exclusively related to language. By comparing these connections between monkeys, apes, and humans we can test this idea, and see which connections are special to which group of animals.

Human tool-making has been essential in our conquest of the world. It is thought that we integrate much more complex conceptual information into our tool use than other animals do. This can have happened in two ways, by the formation of a new pathway in the brain specifically for using tools or by elaborating on existing pathways for reaching and grasping in the parietal and premotor cortex of monkeys. We will compare the pathways connecting parietal and premotor cortex in humans and monkeys and see whether there is a new pathway in humans that might mediate tool behavior.

The most distinctive part of our human brain is the prefrontal cortex, which is very large in the human brain and has been related to our decision-making abilities However, whether this size is the reason that our brain is capable of complex behavior or whether it is due to the extended connections with the rest of the brain that bring our frontal cortex more information than in the monkey is unknown. We can only study this by comparing both the size and the connections of the frontal cortex across species. This way, we can see whether in our brain the relationship between size and connections of the frontal cortex is as predicated based on other primates or whether there is something special about our case.

Together, this work will help us understand not only what makes us different from other animals, but also what makes these animals different from one another.

Technical Summary

The current project aims to exploit phylogenetic diversity in primate brain organization to understand the human brain. There has recently been a rapid acceleration of our understanding of the connections between areas of the human brain, through efforts such as the Human Connectome Project, but their role can only be fully understood if we study them in a comparative context. We will collect high-resolution neuroimaging data from post-mortem samples from great and lesser apes and Old and New World monkeys, providing a large data resource to create a "comparative connectome", mapping the areas and connections in the brains of these species and providing quantitative comparisons between them. We will use this unique resource to study three particularly human specializations.

First, we will investigate the phylogenetic origin of the connections between areas in temporal and frontal cortex mediating language in the human brain. By collecting both diffusion-weighted MRI data that allows the visualization of connections between brain areas and myelin maps that allow the localizing of individual brain regions we can test whether connections that seem expanded in the human brain actually invade new cortical territory or that their target areas have shifted due to cortical expansion.

Second, we will investigate the neural basis of human tool use. We will map the parallel parietal-premotor pathways that mediate various types of motor behavior in primates and test whether human tool use relies on newly formed pathway in the human brain or on an elaboration of an existing primate pathway.

Finally, we will investigate what is likely the most famous human specialization: our large frontal cortex. By exploiting phylogenetic diversity, we will determine whether the connectivity of the human frontal cortex is a natural result of its size or whether it forms a unique specialization.

Planned Impact

ACADEMIC BENEFICIARIES

The scope of the project is such that it will be of interest to researchers in a wide variety of fields. Indeed, the project provides a new type of data that can be used by researchers. These benefits are described separately in the 'Academic beneficiaries section'.

SOCIETY BENEFICIARIES

Research on animals, whether fundamental or medically related, evokes strong opinions in society. These days research on animals is widely viewed within the ethical framework of the '3Rs'. These three Rs reflect Replacement, Reduction, and Refinement of animal research. The current project addresses all three categories. The project focuses on the use of diffusion MRI to study the connections between areas of the brain. Given that the study of connectivity still mostly employs invasive and often terminal research in animals, this method has tremendous potential in the Replacement and Reduction of animal research. With regard to the Refinement, because this project focuses on diffusion MRI in post-mortem brain samples, it allows us to study a much wider range of primates than has even been possible without resulting in animal suffering.

Public engagement is of vital importance for science. Especially in these times of austerity it is important that scientists ensure that the general public understands the goal of their work. The work in this project focuses on understanding the differences between different primates. By extension, this work contributes to the understanding of our place in nature. This topic is ideally suited to public engagement. Books on the relationship between humans and other animals and on the working of the human brain are consistently found on the best-seller lists, such as Frans de Waal's books on human-like behaviour in non-human primates and Dick Swaab's book "We are our brain".

Changes in climate and the destruction of the habits of many animal and plant species routinely make the headlines. Changing public opinion has, fortunately, created a lot of attention for the conservation of the habitats of the species studied in this project. By developing a better understanding of the adaptations of primates to their environment, this project is able to inform this work and to provide a link between fundamental neuroscience and behavioural science and applied conservation science.

HEALTH

Disorders of brain function, both in psychiatry and neurology, represent an important and increasing proportion of health problems in the Western world. Although the proposal is aimed at comparative and evolutionary neuroscience, the methods that are developed in the context of the project have the potential to be applied to our understanding of impairments in the human brain. The applicant has in the past assisted researchers in clinical fields in adopting his approach to their work (e.g., Brazil et al., 2009, Biol Psychiatry; Brazil et al., 2013, Front Psychol; Johnen et al., 2015, eLife). The methods developed for this project to compare the brains of different species can be used to study differences between individuals of the same species, such as human brains in health and disease. The applicant has had repeated discussions with Prof Masud Husain of the University of Oxford to attempt such an application of the analysis toolbox he is developing (see Pathways to Impact) and currently is engaged in a pilot project to test whether his methods can be used to detect the impact of small strokes on the communication between brain areas. If successful, this pilot is expected to lead to a grant applicant in which the applicant is a collaborator for the autumn 2016 grant cycle.


ECONOMIC BENEFICIARIES

Education and research are thriving export sectors for the UK. By basing the fellowship in a university environment in which the fellow is actively involved in teaching, he will contribute to this economic benefit.

Publications

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Zimmermann M (2018) Is the extrastriate body area part of the dorsal visuomotor stream? in Brain structure & function

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Thiebaut De Schotten M (2019) Large-scale comparative neuroimaging: Where are we and what do we need? in Cortex; a journal devoted to the study of the nervous system and behavior

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PRIMatE Data Exchange (PRIME-DE) Global Collaboration Workshop And Consortium. Electronic Address: Michael.milham@childmind.org (2020) Accelerating the Evolution of Nonhuman Primate Neuroimaging. in Neuron

 
Description We have developed a way to compare the organisation of different species' brains. This allowed us to investigate whether there are parts of the human brain that are unique to our species, in other words that are not present in other primates. We found that the temporal cortex of the human brain, which houses a number of areas associated with language, is uniquely organised in our brain. A number of connections to different brain regions come together here in our brain, allowing us to integrate different types of information much more easily than other animals can.
Exploitation Route We will release our data and analysis tools on the web, so that other researchers can use them freely.
Sectors Other

 
Title Xtract - a command-line tool for automated tractography 
Description XTRACT (cross-species tractography) can be used to automatically extract a set of carefully dissected tracts in humans and macaques (other species to come). It can also be used to define one's own tractography protocols where all the user needs to do is to define a set of masks in standard space (e.g. MNI152) XTRACT reads the standard space protocols and performs probabilistic tractography (probtrackx2) in the subject's native space. Resultant tracts may be stored in either the subject's native space or in standard space. The user must provide the crossing fibres fitted data (bedpostx) and diffusion to standard space registration warp fields (and their inverse). 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? Yes  
Impact This tool can be used to generate comparable white matter atlases in different species and across different datasets and labs, allowing us to standardize terminology and results for white matter organization of different species' brain for the first time. So far, it has been used on humans and macaque monkeys, it is currently applied to both human patients and to other primate species. 
URL https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/XTRACT
 
Title PRIME-DE 
Description Open repository for non-human primate resting state functional magnetic resonance imaging data, consisting of contributions from 11 universities, including data from the Wellcome Centre for Integrative Neuroimaging of the University of Oxford. These are data I helped collect and formed the basis of previous publications (Noonan et al., 2014, PLoS Biol); I am now the main contact between the repository management and Oxford. A paper describing the database is under review and on the bioRvix preprint server. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact The database has just been launched, but sharing these type of neuroimaging data from non-human primates is expected to reduce the need for future scans and thus of future animal use. 
URL http://fcon_1000.projects.nitrc.org/indi/indiPRIME.html
 
Title Whole brain comparative anatomy using connectivity blueprints 
Description We have developed a method to quantitatively compare whole-brain organization between species using diffusion-weighted magnetic resonance imaging. We define each part of the cortex in terms of its 'connectivity fingerprint', i.e., it set of connections to the major white matter tracts of the brain. These white matter tracts can be identified across species, allowing us to create a common 'tract space' for the different brains. We can use this technique to identify homologous areas across species, transform cortical maps between species, and determine areas of unique specialization. A proof-of-principle paper comparing the human and macaque monkey brain is currently under review and on bioRxiv (Mars et al., 2018, bioRxiv). The code will be released online as soon as the paper is accepted for publication. 
Type Of Material Data analysis technique 
Year Produced 2018 
Provided To Others? No  
Impact So far, we have used the method to compare human and macaque monkey brains. We have already received requests for collaboration to use this as a tool to study brain changes related to domestication in carnivores (Paul Manger) and to study specialized systems in the primate brain (John Duncan). 
 
Description Collaboration with Josh Balsters and Valerio Zerbi on mouse/macaque/human brain mapping 
Organisation ETH Zurich
Country Switzerland 
Sector Academic/University 
PI Contribution We compare the organization of the mouse, macaque, and human cortico-striatal system. I provided methods for comparative neuroscience and, through ongoing collaborations within Oxford, macaque data.
Collaborator Contribution We compare the organization of the mouse, macaque, and human cortico-striatal system. The performed analyses and provided mouse data.
Impact The resulting paper (Balsters JH, Zerbi V, Sallet J, Wenderoth N, & Mars RB, Primate homologs of mouse cortico-striatal circuits, bioRxiv 834481, doi:10.1101/834481) is currently on bioRxiv and under review in a peer-reviewed journal.
Start Year 2018
 
Description Collaboration with Josh Balsters and Valerio Zerbi on mouse/macaque/human brain mapping 
Organisation Royal Holloway, University of London
Department Department of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution We compare the organization of the mouse, macaque, and human cortico-striatal system. I provided methods for comparative neuroscience and, through ongoing collaborations within Oxford, macaque data.
Collaborator Contribution We compare the organization of the mouse, macaque, and human cortico-striatal system. The performed analyses and provided mouse data.
Impact The resulting paper (Balsters JH, Zerbi V, Sallet J, Wenderoth N, & Mars RB, Primate homologs of mouse cortico-striatal circuits, bioRxiv 834481, doi:10.1101/834481) is currently on bioRxiv and under review in a peer-reviewed journal.
Start Year 2018
 
Description Participating in the Primate Data Exchange consortium (PRIME-DE) 
Organisation Child Mind Institute
Country United States 
Sector Hospitals 
PI Contribution This is a large consortium dedicated to making non-human primate neuroimaging data more accessible to researchers world-wide. We have provided from previous projects and from our current award. We also participated in their annual meeting as session leader and contributed to consortium publications.
Collaborator Contribution This is large consortium with data from various countries, hosted by Mike Milham.
Impact The database (http://fcon_1000.projects.nitrc.org/indi/indiPRIME.html) and two publications: - Milham MP, Ai L, Koo B, Xu T, Amiez C, Balezeau F, Baxter MG, Blezer ELA, Brochier T, Chen A, Croxson PL, Damatac CG, Dehaene S, Everling S, Fiar DA, Fleysher L, Freiwald W, Froudist-Walsh S, Griffiths TD, Guedj C, Hadj-Bouziane F, Hamed SB, Harel N, Hiba B, Jarraya B, Jung B, Kastner S, Klink PC, Kwok SC, Laland KN, Leopold DA, Lindenfors P, Mars RB, Menon RS, Messinger A, Meunier M, Mok K, Morrison JH, Nacef J, Nagy J, Ortiz Rios M, Petkov CI, Pinsk M, Poirier C, Procyk E, Rajimehr R, Reader S, Roelfsema PR, Rudko DA, Rushworth MFS, Russ BE, Sallet J, Schmid MC, Schwiedrzik CM, Seidlitz J, Sein J, Shmuel A, Sullivan EL, Ungerleider L, Thiele A, Todorov OS, Tsao D, Wang Z, Wilson CRE, Yacoub E, Ye F, Zarco W, Zhou Y, Margulies DS, & Schroeder C, An open resource for nonhuman primate imaging, Neuron 100:61-74 (2018), doi:10.1016/j.neuron/2018.08.039 - The PRIMatE Data Exchange (PRIME-DE) Global Collaboration Workshop and Consortium, Accelarating the evolution of nonprimate neuroimaging, Neuron 105:600-603 (2020), doi:10.1016/j.neuron.2019.12.023
Start Year 2018
 
Description Evolution of the Brain Masterclass 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact I taught in the masterclass for the general public at the Natural History Museum in Oxford.
Year(s) Of Engagement Activity 2017
 
Description PubhD Oxford talk by team member 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A DPhil student from my lab gave a talk and informal Q&A in the pub for the general public.
Year(s) Of Engagement Activity 2017
 
Description WINdow on the Brain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact As part of the "WINdow on the brain" event series, I hosted a table at a science cafe at the Natural History Museum in Oxford, talking to members of the general public about comparative neuroscience.
Year(s) Of Engagement Activity 2017