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Time and space in brain development and disease

Exactly when and where individual neurons develop is as important to understanding brain diseases as is knowing the underlying genetics.


New research from Newcastle University, United Kingdom, and published in the academic journal Trends in Cognitive Science, shows for the first time how morphological changes in the brain help shape its neural networks - the human connectome.

A review of brain research carried out over the past 15 years shows that in addition to genetic and environmental influences, the exact appearance of each neuron during development and its position in the brain, are key to ensuring the right connections between neurons are made.

These connections ultimately determine how the brain is wired as an adult. Cognition and behavior in developmental diseases (such as schizophrenia, autism, and ADHD) each respond to how the network of neurons is organized in the brain.

As explained by study author Marcus Kaiser PhD, Professor, Neuroinformatics, Newcastle University, Newcastle upon Tyne, United Kingdom:

"A great deal of work has been done on genetic factors of developmental brain disorders. But, the importance of the spatial layout and of the exact time when regions and connections originate during brain development, has largely been forgotten. In fact, our work shows that time and space during brain maturation are critical. If we can better understand these physical changes then it could lead to new treatments and better diagnosis for a variety of conditions."
In humans, brain development begins from the very early stages of life and continues right through into adult life. In fact, new studies show brain changes take place up to the age of 40 years in humans.

Marcus Kaiser PhD, Professor, Neuroinformatics, Newcastle University, Newcastle upon Tyne, United Kingdom

While some work has been done to understand connections on a micro-scale within specific areas of the brain, such as with epilepsy, we are only just beginning to understand how connections are formed on a macro scale, between brain regions and through the spinal cord.
Brain neurons tend to grow in straight lines, searching out other neurons to form a connection. Only if the neuron hits an obstacle - an impassable molecule or chemical trigger - will it change direction.

"Imagine trying to pass through a crowded room in a straight line to get to someone at the other side. It is more likely you will bump into someone early on than simply passing through without hitting anyone until you hit your final, faraway target.

"In the same way, short-distance connections occur more often than long-distance connections during brain development."

The distance a neuron needs to travel before it hits its target is also critical to development, adds Kaiser.

"Neurons generally follow chemical signals but the cells can only detect chemicals over a distance of 1cm. In adult humans, connections between different brain regions are often longer than 10cm and through the spinal cord they can be longer than 1m. So to get these connections right the neurons must develop the connections very early on in development while the organism is small.

"Timing in brain development is absolutely key. Indeed, experimental studies that link delays during brain maturation to developmental brain diseases are now starting to appear."

Kaiser adds: "Analysing the network of connections, or the connectome, and using computer simulations of brain development now gives us the tools to better understand the formation of the human brain."

Future Work
Computational challenges for modelling human connectome development are getting the parameters for detailed simulations of biological systems and the complexity of running large-scale models. Parameters for axon growth, synapse formation, and neural activity could be determined through in vitro experiments of resected human tissue [94] or of human cell cultures. While the Human Brain Project does not model brain network development [95], there are simulators for detailed growth and synapse formation along dendritic trees (NetMorph [96]), and for migration and connection formation in populations of neurons (Cx3D [97, 98]). In our lab, we are developing simulators of brain tissue activityii [99] and, together with CERN Openlab and academic collaborators, of brain tissue developmentiii [100]. This review presented several potential mechanisms for the formation of long-distance connections, asymmetric connections, network hubs, and network modules. Yet, there might be more undiscovered mechanisms that can influence developmental features of human structural connectivity. Understanding these mechanisms will inform us about the emergence of architectures that enable higher cognitive functions and the factors that limit these functions for neurodevelopmental diseases. We hope that this contribution will provide a framework for future studies on these mechanisms.

Author: Marcus Kaiser Search for articles by this author Affiliations ICOS Research Group, School of Computing Science, Newcastle University, Newcastle upon Tyne, UK Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK



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This schematic reflects mechanisms relating to time and space. Temporal sequences of events,
such as the birth of a neuron, the time after which axon growth starts, and competition
for space on a target neuron at the time of synapse, each can influence network features.
Development in three-dimensional space, growth on a straight line, the local
concentration of growth factors at the axonal growth cone, and axon growth along
previously established fibers (fasciculation), also influence network topology.
Image Credit: ICOS Research Group, School of Computing Science, Newcastle University



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