A connectome () is a comprehensive map of
neural connections in the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
, and may be thought of as its "
wiring diagram
A wiring diagram is a simplified conventional pictorial representation of an electrical circuit. It shows the components of the circuit as simplified shapes, and the power and signal connections between the devices.
A wiring diagram usually gi ...
". An
organism
In biology, an organism () is any living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy into groups such as multicellular animals, plants, and ...
's
nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
is made up of
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s which communicate through
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s. A connectome is constructed by tracing the neuron in a nervous system and mapping where neurons are connected through synapses.
The significance of the connectome stems from the realization that the structure and function of the human brain are intricately linked, through multiple levels and modes of brain connectivity. There are strong natural constraints on which neurons or neural populations can interact, or how strong or direct their interactions are. Indeed, the foundation of human
cognition
Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...
lies in the pattern of dynamic interactions shaped by the connectome.
Despite such complex and variable structure-function mappings, the connectome is an indispensable basis for the mechanistic interpretation of dynamic brain data, from
single-cell recordings to
functional neuroimaging
Functional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions. It is primarily used a ...
.
Origin and usage of the term
In 2005, Dr.
Olaf Sporns
Olaf Sporns (born 18 September 1963) is Provost Professor in Psychological and Brain Sciences at Indiana University and Scientific Co-Director of the Indiana University Network Science Institute. He is also the founding editor of the academic jour ...
at
Indiana University
Indiana University (IU) is a system of public universities in the U.S. state of Indiana.
Campuses
Indiana University has two core campuses, five regional campuses, and two regional centers under the administration of IUPUI.
*Indiana Universit ...
and Dr. Patric Hagmann at
Lausanne University Hospital
The Lausanne University Hospital (french: Centre hospitalier universitaire vaudois, CHUV), in Lausanne, is one of the five university hospitals in Switzerland.
The Lausanne University Hospital is linked to the Faculty of Biology and Medicine of ...
independently and simultaneously suggested the term "connectome" to refer to a map of the neural connections within the brain. This term was directly inspired by the ongoing effort to sequence the human
genetic code
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
—to build a
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
.
"Connectomics" (Hagmann, 2005) has been defined as the science concerned with assembling and analyzing connectome data sets.
In their 2005 paper, "The Human Connectome, a structural description of the human brain", Sporns et al. wrote:
To understand the functioning of a network, one must know its elements and their interconnections. The purpose of this article is to discuss research strategies aimed at a comprehensive structural description of the network of elements and connections forming the human brain. We propose to call this dataset the human "connectome," and we argue that it is fundamentally important in cognitive neuroscience
Cognitive neuroscience is the scientific field that is concerned with the study of the biological processes and aspects that underlie cognition, with a specific focus on the neural connections in the brain which are involved in mental proces ...
and neuropsychology
Neuropsychology is a branch of psychology concerned with how a person's cognition and behavior are related to the brain and the rest of the nervous system. Professionals in this branch of psychology often focus on how injuries or illnesses of t ...
. The connectome will significantly increase our understanding of how functional brain states emerge from their underlying structural substrate, and will provide new mechanistic insights into how brain function is affected if this structural substrate is disrupted.[ ]
In his 2005 Ph.D. thesis, ''From
diffusion MRI
Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
to brain connectomics'', Hagmann wrote:
It is clear that, like the genome, which is much more than just a juxtaposition of gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
s, the set of all neuronal connections in the brain is much more than the sum of their individual components. The genome is an entity it-self, as it is from the subtle gene interaction that ifeemerges. In a similar manner, one could consider the brain connectome, set of all neuronal connections, as one single entity, thus emphasizing the fact that the huge brain neuronal communication
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. No ...
capacity and computational power critically relies on this subtle and incredibly complex connectivity architecture.
The term "connectome" was more recently popularized by
Sebastian Seung
Hyunjune Sebastian Seung (English: /sung/ or əŋ ) is President at Samsung Electronics & Head of Samsung Research and Anthony B. Evnin Professor in the Princeton Neuroscience Institute and Department of Computer Science. Seung has done influen ...
's ''I am my Connectome'' speech given at the 2010
TED conference
TED Conferences, LLC (Technology, Entertainment, Design) is an American-Canadian non-profit media organization that posts international talks online for free distribution under the slogan "ideas worth spreading". TED was founded by Richard Sau ...
, which discusses the high-level goals of mapping the human connectome, as well as ongoing efforts to build a three-dimensional neural map of brain tissue at the microscale. In 2012, Seung published the book ''
Connectome: How the Brain's Wiring Makes Us Who We Are''.
Methods
Brain networks can be defined at different levels of scale, corresponding to levels of
spatial resolution
In physics and geosciences, the term spatial resolution refers to distance between independent measurements, or the physical dimension that represents a pixel of the image. While in some instruments, like cameras and telescopes, spatial resolutio ...
in brain imaging (Kötter, 2007, Sporns, 2010). These scales can be roughly categorized as macroscale, mesoscale and microscale. Ultimately, it may be possible to join connectomic maps obtained at different scales into a single hierarchical map of the neural organization of a given species that ranges from single neurons to populations of neurons to larger systems like cortical areas. Given the methodological uncertainties involved in inferring connectivity from the primary experimental data, and given that there are likely to be large differences in the connectomes of different individuals, any unified map will likely rely on ''
probabilistic
Probability is the branch of mathematics concerning numerical descriptions of how likely an Event (probability theory), event is to occur, or how likely it is that a proposition is true. The probability of an event is a number between 0 and ...
'' representations of connectivity data (Sporns et al., 2005).
Macroscale
A connectome at the macroscale (
millimeter
330px, Different lengths as in respect to the electromagnetic spectrum, measured by the metre and its derived scales. The microwave is between 1 meter to 1 millimeter.
The millimetre (American and British English spelling differences#-re, -er, ...
resolution) attempts to capture large brain systems that can be parcellated into anatomically distinct modules (areas, parcels or nodes), each having a distinct pattern of connectivity. Connectomic databases at the mesoscale and macroscale may be significantly more compact than those at cellular resolution, but they require effective strategies for accurate anatomical or functional parcellation of the neural volume into network nodes (for complexities see, e.g., Wallace et al., 2004).
Established methods of brain research, such as axonal tracing, provided early avenues for building connectome data sets. However, more recent advances in living subjects has been made by the use of non-invasive imaging technologies such as
diffusion-weighted magnetic resonance imaging (DW-MRI) and
functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area o ...
(fMRI). The first, when combined with tractography allows reconstruction of the major fiber bundles in the brain. The second allows the researcher to capture the brain's network activity (either at rest or while performing directed tasks), enabling the identification of structurally and anatomically distinct areas of the brain that are functionally connected.
Notably, the goal of the
Human Connectome Project
The Human Connectome Project (HCP) is a five-year project sponsored by sixteen components of the National Institutes of Health, split between two consortia of research institutions. The project was launched in July 2009 as the first of three Grand ...
, led by the WU-Minn consortium, is to build a ''structural and functional map'' of the healthy human brain at the macro scale, using a combination of multiple imaging technologies and resolutions.
Recent advances in connectivity mapping
Throughout the 2000s, several investigators have attempted to map the large-scale structural architecture of the human cerebral cortex. One attempt exploited cross-correlations in cortical thickness or volume across individuals (He et al., 2007). Such gray-matter thickness correlations have been postulated as indicators for the presence of structural connections. A drawback of the approach is that it provides highly indirect information about cortical connection patterns and requires data from large numbers of individuals to derive a single connection data set across a subject group. Other investigators have attempted to build whole-brain connection matrices from DW-MRI imaging data.
The
Blue Brain Project
The Blue Brain Project is a Swiss brain research initiative that aims to create a digital reconstruction of the mouse brain. The project was founded in May 2005 by the Brain and Mind Institute of ''École Polytechnique Fédérale de Lausanne'' (EP ...
is attempting to reconstruct the entire mouse connectome using a
diamond knife
A diamond knife is a very sharp knife in which the edge is made from diamond, invented by Humberto Fernández-Morán in 1955. Diamond knives are used for medical and scientific applications where an extremely sharp and long-lasting edge is essent ...
sharpened to an atomic edge, and electron microscopy for imaging tissue slices.
Challenge for macroscale connectomics
The initial explorations in macroscale human connectomics were done using either equally sized regions or anatomical regions with unclear relationship to the underlying functional organization of the brain (e.g.
gyral and
sulcal-based regions). While much can be learned from these approaches, it is highly desirable to parcellate the brain into functionally distinct parcels: brain regions with distinct architectonics, connectivity, function, and/or topography (Felleman and Van Essen, 1991).
Accurate parcellation allows each node in the macroscale connectome to be more informative by associating it with a distinct connectivity pattern and functional profile. Parcellation of localized areas of cortex have been accomplished using diffusion
tractography
In neuroscience
Neuroscience is the scientific study of the nervous system (the brain, spinal cord, and peripheral nervous system), its functions and disorders. It is a multidisciplinary science that combines physiology, anatomy, molecular b ...
(Beckmann et al. 2009) and functional connectivity (Nelson et al. 2010) to non-invasively measure connectivity patterns and define cortical areas based on distinct connectivity patterns. Such analyses may best be done on a whole brain scale and by integrating non-invasive modalities. Accurate whole brain parcellation may lead to more accurate macroscale connectomes for the normal brain, which can then be compared to disease states.
Pathways through cerebral
white matter
White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distribution ...
can be charted by
histological
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
dissection
Dissection (from Latin ' "to cut to pieces"; also called anatomization) is the dismembering of the body of a deceased animal or plant to study its anatomical structure. Autopsy is used in pathology and forensic medicine to determine the cause o ...
and
staining
Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...
, by degeneration methods, and by
axonal tracing. Axonal tracing methods form the primary basis for the systematic charting of long-distance pathways into extensive,
species
In biology, a species is the basic unit of classification and a taxonomic rank of an organism, as well as a unit of biodiversity. A species is often defined as the largest group of organisms in which any two individuals of the appropriate s ...
-specific anatomical connection matrices between
gray matter
Grey matter is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil (dendrites and unmyelinated axons), glial cells (astrocytes and oligodendrocytes), synapses, and capillaries. Grey matter is distinguis ...
regions. Landmark studies have included the areas and connections of the
visual cortex
The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...
of the
macaque
The macaques () constitute a genus (''Macaca'') of gregarious Old World monkeys of the subfamily Cercopithecinae. The 23 species of macaques inhabit ranges throughout Asia, North Africa, and (in one instance) Gibraltar. Macaques are principally ...
(Felleman and Van Essen, 1991)
and the
thalamocortical system in the feline brain (Scannell et al., 1999). The development of
neuroinformatics
Neuroinformatics is the field that combines informatics and neuroscience. Neuroinformatics is related with neuroscience data and information processing by artificial neural networks. There are three main directions where neuroinformatics has to be ...
databases for anatomical connectivity allow for continual updating and refinement of such anatomical connection maps. The online macaque cortex connectivity tool CoCoMac (Kötter, 2004) and the
temporal lobe
The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain.
The temporal lobe ...
connectome of the
rat
Rats are various medium-sized, long-tailed rodents. Species of rats are found throughout the order Rodentia, but stereotypical rats are found in the genus ''Rattus''. Other rat genera include ''Neotoma'' ( pack rats), ''Bandicota'' (bandicoot ...
are prominent examples of such a database.
Mesoscale
A "mesoscale" connectome corresponds to a spatial resolution of hundreds of micrometers. Rather than attempt to map each individual neuron, a connectome at the mesoscale would attempt to capture anatomically and/or functionally distinct neuronal populations, formed by local circuits (e.g.
cortical column
A cortical column is a group of neurons forming a cylindrical structure through the cerebral cortex of the brain perpendicular to the cortical surface. The structure was first identified by Mountcastle in 1957. He later identified cortical minicolu ...
s) that link hundreds or thousands of individual neurons. This scale still presents a very ambitious technical challenge at this time and can only be probed on a small scale with invasive techniques or very high field
magnetic resonance imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...
(MRI) on a local scale.
Microscale
Mapping the connectome at the "microscale" (
micrometer Micrometer can mean:
* Micrometer (device), used for accurate measurements by means of a calibrated screw
* American spelling of micrometre
The micrometre ( international spelling as used by the International Bureau of Weights and Measures; ...
resolution) means building a complete map of the neural systems, neuron-by-neuron. The challenge of doing this becomes obvious: the number of neurons comprising the brain easily ranges into the billions in more complex organisms. The human
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
alone contains on the order of 10
10 neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s linked by 10
14 synaptic connections. By comparison, the number of
base-pairs in a human genome is 3×10
9. A few of the main challenges of building a human connectome at the microscale today include: data collection would take years given current technology, machine vision tools to annotate the data remain in their infancy, and are inadequate, and neither theory nor algorithms are readily available for the analysis of the resulting ''brain-graphs''. To address the data collection issues, several groups are building high-throughput serial
electron microscope
An electron microscope is a microscope that uses a beam of accelerated electrons as a source of illumination. As the wavelength of an electron can be up to 100,000 times shorter than that of visible light photons, electron microscopes have a hi ...
s (Kasthuri et al., 2009; Bock ''et al''. 2011). To address the machine-vision and image-processing issues, the Open Connectome Project
is ''alg-sourcing'' (algorithm outsourcing) this hurdle. Finally, statistical
graph theory
In mathematics, graph theory is the study of ''graphs'', which are mathematical structures used to model pairwise relations between objects. A graph in this context is made up of '' vertices'' (also called ''nodes'' or ''points'') which are conne ...
is an emerging discipline which is developing sophisticated
pattern recognition
Pattern recognition is the automated recognition of patterns and regularities in data. It has applications in statistical data analysis, signal processing, image analysis, information retrieval, bioinformatics, data compression, computer graphi ...
and inference tools to parse these brain-graphs (Goldenberg et al., 2009).
Current non-invasive imaging techniques cannot capture the brain's activity on a neuron-by-neuron level. Mapping the connectome at the cellular level in
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s currently requires post-mortem (after death) microscopic analysis of limited portions of brain tissue. Non-optical techniques that rely on high-throughput
DNA sequencing
DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. Th ...
have been proposed recently by
Anthony Zador (CSHL).
[ ]
Traditional histological circuit-mapping approaches rely on imaging and include
light-microscopic techniques for
cell staining
Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...
, injection of labeling agents for
tract tracing, or chemical brain preservation,
staining
Staining is a technique used to enhance contrast in samples, generally at the microscopic level. Stains and dyes are frequently used in histology (microscopic study of biological tissues), in cytology (microscopic study of cells), and in the ...
and reconstruction of serially sectioned tissue blocks via electron microscopy (EM). Each of these classical approaches has specific drawbacks when it comes to deployment for connectomics. The staining of single cells, e.g. with the
Golgi stain, to trace cellular processes and connectivity suffers from the limited resolution of light-microscopy as well as difficulties in capturing long-range projections. Tract tracing, often described as the "
gold standard
A gold standard is a monetary system in which the standard economic unit of account is based on a fixed quantity of gold. The gold standard was the basis for the international monetary system from the 1870s to the early 1920s, and from the la ...
" of
neuroanatomy
Neuroanatomy is the study of the structure and organization of the nervous system. In contrast to animals with radial symmetry, whose nervous system consists of a distributed network of cells, animals with bilateral symmetry have segregated, defin ...
for detecting long-range pathways across the brain, generally only allows the tracing of fairly large cell populations and single axonal pathways. EM reconstruction was successfully used for the compilation of the
''C. elegans'' connectome (White et al., 1986).
However, applications to larger tissue blocks of entire nervous systems have traditionally had difficulty with projections that span longer distances.
Recent advances in mapping neural connectivity at the cellular level offer significant new hope for overcoming the limitations of classical techniques and for compiling cellular connectome data sets (Livet et al., 2007; Lichtman et al., 2008). Using
Brainbow
Brainbow is a process by which individual neurons in the brain can be distinguished from neighboring neurons using fluorescent proteins. By randomly expressing different ratios of red, green, and blue derivatives of green fluorescent protein in in ...
, a combinatorial color labeling method based on the
stochastic
Stochastic (, ) refers to the property of being well described by a random probability distribution. Although stochasticity and randomness are distinct in that the former refers to a modeling approach and the latter refers to phenomena themselv ...
expression of several
fluorescent protein Fluorescent proteins include:
* Green fluorescent protein (GFP)
* Yellow fluorescent protein
Yellow fluorescent protein (YFP) is a genetic mutant of green fluorescent protein (GFP) originally derived from the jellyfish '' Aequorea victoria''. Its ...
s,
Jeff W. Lichtman
Jeff W. Lichtman (born 1951) is an American neuroscientist. He is the Jeremy R. Knowles Professor of Molecular and Cellular Biology and Santiago Ramón y Cajal Professor of Arts and Sciences at Harvard University. He is best known for his pionee ...
and colleagues were able to mark individual neurons with one of over 100 distinct colors. The labeling of individual neurons with a distinguishable hue then allows the tracing and reconstruction of their cellular structure including long processes within a block of tissue.
In March 2011, the journal ''
Nature
Nature, in the broadest sense, is the physics, physical world or universe. "Nature" can refer to the phenomenon, phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. ...
'' published a pair of articles on micro-connectomes: Bock et al.
and Briggman et al.
In both articles, the authors first characterized the functional properties of a small subset of cells, and then manually traced a subset of the processes emanating from those cells to obtain a partial subgraph. In alignment with the principles of
open science, the authors of Bock et al. (2011) have released their data for public access. The full resolution 12 terabyte dataset from Bock et al. is available at ''NeuroData''.
In 2012, a
citizen science
Citizen science (CS) (similar to community science, crowd science, crowd-sourced science, civic science, participatory monitoring, or volunteer monitoring) is scientific research conducted with participation from the public (who are sometimes re ...
project called ''
EyeWire'' began attempting to
crowdsource
Crowdsourcing involves a large group of dispersed participants contributing or producing goods or services—including ideas, votes, micro-tasks, and finances—for payment or as volunteers. Contemporary crowdsourcing often involves digit ...
the mapping of the connectome through an interactive game. Independently, important topologies of functional interactions among several hundred cells are also gradually going to be declared (Shimono and Beggs, 2014). Scaling up ultrastructural circuit mapping to the whole
mouse brain
The mouse brain refers to the brain of Mus musculus. Various brain atlases exist.
For reasons of reproducibility, genetically characterized, stable strains like C57BL/6 were chosen to produce high-resolution images and databases. Well known onli ...
is currently underway (Mikula, 2012). An alternative approach to mapping connectivity was recently proposed by Zador and colleagues (Zador et al., 2012).
Zador's technique, called BOINC (barcoding of individual neuronal connections) uses high-throughput DNA sequencing to map neural circuits. Briefly, the approach consists of labelling each neuron with a unique DNA barcode, transferring barcodes between synaptically coupled neurons (for example using
''Suid herpesvirus 1'', SuHV1), and fusion of barcodes to represent a synaptic pair. This approach has the potential to be cheap, fast, and extremely high-throughput.
In 2016, the
Intelligence Advanced Research Projects Activity
The Intelligence Advanced Research Projects Activity (IARPA) is an organization within the Office of the Director of National Intelligence responsible for leading research to overcome difficult challenges relevant to the United States Intellige ...
of the United States government launched
MICrONS
The micrometre ( international spelling as used by the International Bureau of Weights and Measures; SI symbol: μm) or micrometer (American spelling), also commonly known as a micron, is a unit of length in the International System of Unit ...
, a five-year, multi-institute project to map one cubic millimeter of rodent visual cortex, as part of the
BRAIN Initiative
The White House BRAIN Initiative (Brain Research through Advancing Innovative Neurotechnologies) is a collaborative, public-private research initiative announced by the Obama administration on April 2, 2013, with the goal of supporting the devel ...
. Though only a small volume of biological tissue, this project will yield one of the largest micro-scale connectomics datasets currently in existence.
Mapping functional connectivity
Using fMRI in the
resting state and during tasks, functions of the connectome circuits are being studied. Just as detailed road maps of the Earth's surface do not tell us much about the kind of vehicles that travel those roads or what cargo they are hauling, to understand how neural structures result in specific functional behavior such as
consciousness
Consciousness, at its simplest, is sentience and awareness of internal and external existence. However, the lack of definitions has led to millennia of analyses, explanations and debates by philosophers, theologians, linguisticians, and scien ...
, it is necessary to build theories that relate functions to anatomical connectivity. However, the bond between structural and functional connectivity is not straightforward. Computational models of whole-brain network dynamics are valuable tools to investigate the role of the anatomical network in shaping functional connectivity. In particular, computational models can be used to predict the dynamic effect of
lesions
A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals.
Types
There is no designated classifi ...
in the connectome.
As a network or graph
The connectome can be studied as a network by means of
network science
Network science is an academic field which studies complex networks such as telecommunication networks, computer networks, biological networks, cognitive and semantic networks, and social networks, considering distinct elements or actors repre ...
and graph theory. In case of a micro-scale connectome, the nodes of this network (or
graph
Graph may refer to:
Mathematics
*Graph (discrete mathematics), a structure made of vertices and edges
**Graph theory, the study of such graphs and their properties
*Graph (topology), a topological space resembling a graph in the sense of discre ...
) are the neurons, and the edges correspond to the
synapse
In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell.
Synapses are essential to the transmission of nervous impulses from ...
s between those neurons. For the macro-scale connectome, the nodes correspond to the ROIs (
regions of interest), while the edges of the graph are derived from the axons interconnecting those areas. Thus connectomes are sometimes referred to as ''brain graphs'', as they are indeed graphs in a mathematical sense which describe the connections in the brain (or, in a broader sense, the whole nervous system).
One group of researchers (Iturria-Medina et al., 2008) has constructed connectome data sets using
diffusion tensor imaging
Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
(DTI) followed by the derivation of average connection probabilities between 70–90 cortical and
basal brain gray matter areas. All networks were found to have small-world attributes and "broad-scale" degree distributions. An analysis of
betweenness centrality
In graph theory, betweenness centrality (or "betweeness centrality") is a measure of centrality in a graph based on shortest paths. For every pair of vertices in a connected graph, there exists at least one shortest path between the vertices such ...
in these networks demonstrated high centrality for the
precuneus
In neuroanatomy, the precuneus is the portion of the superior parietal lobule on the medial surface of each brain hemisphere. It is located in front of the cuneus (the upper portion of the occipital lobe). The precuneus is bounded in front by th ...
, the
insula, the
superior parietal and the superior
frontal cortex
The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betwe ...
. Another group (Gong et al. 2008) has applied DTI to map a network of anatomical connections between 78 cortical regions. This study also identified several hub regions in the human brain, including the precuneus and the
superior frontal gyrus
In neuroanatomy, the superior frontal gyrus (SFG, also marginal gyrus) is a gyrus – a ridge on the brain's cerebral cortex – which makes up about one third of the frontal lobe. It is bounded laterally by the superior frontal sulcus.
The su ...
.
Hagmann et al. (2007)
[ ] constructed a connection matrix from fiber densities measured between homogeneously distributed and equal-sized ROIs numbering between 500 and 4000. A quantitative analysis of connection matrices obtained for approximately 1,000 ROIs and approximately 50,000 fiber pathways from two subjects demonstrated an exponential (one-scale) degree distribution as well as robust small-world attributes for the network. The data sets were derived from diffusion spectrum imaging (DSI) (Wedeen, 2005), a variant of diffusion-weighted imaging
that is sensitive to intra-voxel heterogeneities in diffusion directions caused by crossing fiber tracts and thus allows more accurate mapping of axonal trajectories than other diffusion imaging approaches (Wedeen, 2008).
The combination of whole-head DSI datasets acquired and processed according to the approach developed by Hagmann et al. (2007)
with the graph analysis tools conceived initially for animal tracing studies (Sporns, 2006; Sporns, 2007) allow a detailed study of the network structure of human cortical connectivity (Hagmann et al., 2008). The human brain network was characterized using a broad array of network analysis methods including core decomposition, modularity analysis, hub classification and
centrality
In graph theory and network analysis, indicators of centrality assign numbers or rankings to nodes within a graph corresponding to their network position. Applications include identifying the most influential person(s) in a social network, key ...
. Hagmann ''et al''. presented evidence for the existence of a structural core of highly and mutually interconnected brain regions, located primarily in posterior medial and parietal cortex. The core comprises portions of the
posterior cingulate cortex
The posterior cingulate cortex (PCC) is the caudal part of the cingulate cortex, located posterior to the anterior cingulate cortex. This is the upper part of the "limbic lobe". The cingulate cortex is made up of an area around the midline of the ...
, the precuneus, the
cuneus
The cuneus (; plural cunei) is a smaller lobe in the occipital lobe of the brain. The cuneus is bounded anteriorly by the parieto-occipital sulcus and inferiorly by the calcarine sulcus.
Function
The cuneus (Brodmann area 17) receives visua ...
, the
paracentral lobule
In neuroanatomy, the paracentral lobule is on the medial surface of the cerebral hemisphere and is the continuation of the precentral and postcentral gyri. The paracentral lobule controls motor and sensory innervations of the contralateral low ...
, the
isthmus of the cingulate, the banks of the
superior temporal sulcus
The superior temporal sulcus (STS) is the sulcus separating the superior temporal gyrus from the middle temporal gyrus in the temporal lobe of the brain. A sulcus (plural sulci) is a deep groove that curves into the largest part of the brain, t ...
, and the
inferior and
superior parietal cortex, all located in both
cerebral hemisphere
The vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...
s.
A subfield of connectomics deals with the comparison of the brain graphs of multiple subjects. It is possible to build a consensus graph such the
Budapest Reference Connectome
The Budapest Reference Connectome server computes the frequently appearing anatomical brain connections of 418 healthy subjects.
It has been prepared from diffusion MRI datasets of the Human Connectome Project into a reference connectome (or b ...
by allowing only edges that are present in at least
connectomes, for a selectable
parameter. The Budapest Reference Connectome has led the researchers to the discovery of the Consensus Connectome Dynamics of the human brain graphs. The edges appeared in all of the brain graphs form a connected subgraph around the
brainstem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is cont ...
. By allowing gradually less frequent edges, this core subgraph grows continuously, as a
shrub
A shrub (often also called a bush) is a small-to-medium-sized perennial woody plant. Unlike herbaceous plants, shrubs have persistent woody stems above the ground. Shrubs can be either deciduous or evergreen. They are distinguished from trees ...
. The growth dynamics may reflect the individual
brain development
The development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...
and provide an opportunity to direct some edges of the human consensus brain graph.
Alternatively, local difference which are statistically significantly different among groups have attracted more attention as they highlight specific connections and therefore shed more light on specific brain traits or pathology. Hence, algorithms to find local difference between graph populations have also been introduced (e.g. to compare case versus control groups).
Those can be found by using either an adjusted
t-test
A ''t''-test is any statistical hypothesis testing, statistical hypothesis test in which the test statistic follows a Student's t-distribution, Student's ''t''-distribution under the null hypothesis. It is most commonly applied when the test stati ...
,
or a sparsity model,
with the aim of finding statistically significant connections which are different among those groups.
The possible causes of the difference between individual connectomes were also investigated. Indeed, it has been found that the macro-scale connectomes of women contain significantly more edges than those of men, and a larger portion of the edges in the connectomes of women run between the two hemispheres.
In addition, connectomes generally exhibit a
small-world character, with overall cortical connectivity decreasing with age.
The aim of the as of 2015 ongoin
HCP Lifespan Pilot Projectis to identify connectome differences between 6 age groups (4–6, 8–9, 14–15, 25–35, 45–55, 65–75).
More recently,
connectogram Connectograms are graphical representations of connectomics, the field of study dedicated to mapping and interpreting all of the white matter fiber connections in the human brain. These circular graphs based on diffusion MRI data utilize graph theor ...
s have been used to visualize full-brain data by placing cortical areas around a circle, organized by lobe.
Inner circles then depict cortical metrics on a color scale. White matter fiber connections in DTI data are then drawn between these cortical regions and weighted by
fractional anisotropy Fractional anisotropy (FA) is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A ...
and strength of the connection. Such graphs have even been used to analyze the damage done to the famous traumatic brain injury patient
Phineas Gage
Phineas P. Gage (18231860) was an American railroad construction foreman known for his improbable survival of an accident in which a large iron rod was driven completely through his head, destroying much of his brain's left frontal lobe, and ...
.
[ ]
Statistical graph theory is an emerging discipline which is developing sophisticated pattern recognition and inference tools to parse these brain graphs (Goldenberg et al., 2009).
Recent research studied the brain as a signed network and indicated that hubness in positive and negative subnetworks increases the stability of the brain network. It highlighted the role of negative functional connections that are paid less attention to.
Plasticity of the connectome
At the beginning of the connectome project, it was thought that the connections between neurons were unchangeable once established and that only individual synapses could be altered.
However, recent evidence suggests that connectivity is also subject to change, termed
neuroplasticity
Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of Neural circuit, neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that diffe ...
. There are two ways that the brain can rewire: formation and removal of synapses in an established connection or formation or removal of entire connections between neurons. Both mechanisms of rewiring are useful for learning completely novel tasks that may require entirely new connections between regions of the brain.
However, the ability of the brain to gain or lose entire connections poses an issue for mapping a universal species connectome. Although rewiring happens on different scales, from microscale to macroscale, each scale does not occur in isolation. For example, in the ''C. elegans'' connectome, the total number of synapses increases 5-fold from birth to adulthood, changing both local and global network properties.
Other developmental connectomes, such as the muscle connectome, retain some global network properties even though the number of synapses decreases by 10-fold in early postnatal life.
Macroscale rewiring
Evidence for macroscale rewiring mostly comes from research on grey and white matter density, which could indicate new connections or changes in axon density. Direct evidence for this level of rewiring comes from primate studies, using viral tracing to map the formation of connections. Primates that were taught to use novel tools developed new connections between the interparietal cortex and higher visual areas of the brain. Further viral tracing studies have provided evidence that macroscale rewiring occurs in adult animals during
associative
In mathematics, the associative property is a property of some binary operations, which means that rearranging the parentheses in an expression will not change the result. In propositional logic, associativity is a valid rule of replacement f ...
learning. However, it is not likely that long-distance neural connections undergo extensive rewiring in adults. Small changes in an already established
nerve tract
A nerve tract is a bundle of nerve fibers (axons) connecting nuclei of the central nervous system. In the peripheral nervous system this is known as a nerve, and has associated connective tissue. The main nerve tracts in the central nervous syste ...
are likely what is observed in macroscale rewiring.
Mesoscale rewiring
Rewiring at the mesoscale involves studying the presence or absence of entire connections between neurons.
Evidence for this level of rewiring comes from observations that local circuits form new connections as a result of
experience-dependent plasticity in the visual cortex. Additionally, the number of local connections between pyramidal neurons in the primary
somatosensory cortex
In physiology, the somatosensory system is the network of neural structures in the brain and body that produce the perception of touch (haptic perception), as well as temperature (thermoception), body position (proprioception), and pain. It is ...
increases following altered whisker sensory experience in rodents.
Microscale rewiring
Microscale rewiring is the formation or removal of synaptic connections between two neurons and can be studied with longitudinal two-photon imaging. Dendritic spines on
pyramidal neurons
Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal cor ...
can be shown forming within days following sensory experience and learning.
Changes can even be seen within five hours on
apical tufts of layer five pyramidal neurons in the primary motor cortex after a seed reaching task in primates.
Datasets
Humans
The
Human Connectome Project
The Human Connectome Project (HCP) is a five-year project sponsored by sixteen components of the National Institutes of Health, split between two consortia of research institutions. The project was launched in July 2009 as the first of three Grand ...
, sponsored by the
National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
(NIH), was created with the goal of mapping the 86 billion neurons (and their connections) in a
human brain
The human brain is the central organ of the human nervous system, and with the spinal cord makes up the central nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. It controls most of the activities of the ...
.
Model organisms
Roundworm
The first (and so far only) fully reconstructed connectome belongs to the
roundworm
The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-parasitic nematodes also known as eelworms. They are a diverse animal phylum inhabiting a broa ...
''
Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
.'' The major effort began with the first electron micrographs published by White, Brenner et al., 1986.
Based on this seminal work, the first ever connectome (then called "neural circuitry database" by the authors) for ''C. elegans'' was published in book form with accompanying floppy disks by Achacoso and Yamamoto in 1992. The very first paper on the computer representation of its connectome was presented and published three years earlier in 1989 by Achacoso at the Symposium on Computer Application in Medical Care (SCAMC). The ''C. elegans'' connectome was later revised
[ ] and expanded to show changes during the animal's development.
Fruit fly
Different sections of nervous tissue from fruit flies are currently being mapped, including a partial section of the brain ("the hemibrain") and the entire
ventral nerve cord
The ventral nerve cord is a major structure of the invertebrate central nervous system. It is the functional equivalent of the vertebrate spinal cord. The ventral nerve cord coordinates neural signaling from the brain to the body and vice versa, in ...
.
Mouse
Partial connectomes of a mouse
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
and mouse
primary visual cortex
The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus and ...
have also been successfully constructed.
The first full connectome of a mammalian circuit was constructed in 2021. This construction included the development of all connections between the CNS and a single muscle from birth to adulthood.
Eyewire game
''
Eyewire'' is an online game developed by American scientist
Sebastian Seung
Hyunjune Sebastian Seung (English: /sung/ or əŋ ) is President at Samsung Electronics & Head of Samsung Research and Anthony B. Evnin Professor in the Princeton Neuroscience Institute and Department of Computer Science. Seung has done influen ...
of
Princeton University
Princeton University is a private university, private research university in Princeton, New Jersey. Founded in 1746 in Elizabeth, New Jersey, Elizabeth as the College of New Jersey, Princeton is the List of Colonial Colleges, fourth-oldest ins ...
. It uses
social computing
Social computing is an area of computer science that is concerned with the intersection of social behavior and computational systems. It is based on creating or recreating social conventions and social contexts through the use of software and tech ...
to help map the connectome of the brain. It has attracted over 130,000 players from over 100 countries.
See also
*
Connectomics
Connectomics is the production and study of connectomes: comprehensive maps of connections within an organism's nervous system. More generally, it can be thought of as the study of neuronal wiring diagrams with a focus on how structural connectivi ...
*
Brain connectivity estimators
Brain connectivity estimators represent patterns of links in the brain. Connectivity can be considered at different levels of the brain's organisation: from neurons, to neural assemblies and brain structures. Brain connectivity involves different ...
*
Drosophila connectome The ''Drosophila'' connectome, once completed, will be a complete list of the roughly 135,000 neurons in the brain of the fruit fly ''Drosophila melanogaster'', along with all of the connections (synapses) between these neurons. As of 2020, the ''D ...
*
Human Connectome Project
The Human Connectome Project (HCP) is a five-year project sponsored by sixteen components of the National Institutes of Health, split between two consortia of research institutions. The project was launched in July 2009 as the first of three Grand ...
*
Interactome In molecular biology, an interactome is the whole set of molecular interactions in a particular cell. The term specifically refers to physical interactions among molecules (such as those among proteins, also known as protein–protein interactions, ...
*
List of animals by number of neurons
The following are two lists of animals ordered by the size of their nervous system. The first list shows number of neurons in their entire nervous system, indicating their overall neural complexity. The second list shows the number of neurons i ...
*
Neural coding
Neural coding (or Neural representation) is a neuroscience field concerned with characterising the hypothetical relationship between the stimulus and the individual or ensemble neuronal responses and the relationship among the electrical activity o ...
*
Brain atlas
A brain atlas is composed of serial sections along different anatomical planes of the healthy or diseased developing or adult animal or human brain where each relevant brain structure is assigned a number of coordinates to define its outline or vol ...
*
Outline of brain mapping
The following outline is provided as an overview of and topical guide to brain mapping:
Brain mapping – set of neuroscience techniques predicated on the mapping of (biological) quantities or properties onto spatial representations of the ...
*
Outline of the human brain
The following outline is provided as an overview of and topical guide to the human brain:
Human brain – central organ of the nervous system located in the head of a human being, protected by the skull. It has the same general structure as the ...
References
External links
Database of hundreds of braingraphs with different resolutions and weight functions at braingraph.org The NIH Blueprint for Neuroscience Research*
TED
TED may refer to:
Economics and finance
* TED spread between U.S. Treasuries and Eurodollar
Education
* ''Türk Eğitim Derneği'', the Turkish Education Association
** TED Ankara College Foundation Schools, Turkey
** Transvaal Education Depa ...
talk by
Sebastian Seung
Hyunjune Sebastian Seung (English: /sung/ or əŋ ) is President at Samsung Electronics & Head of Samsung Research and Anthony B. Evnin Professor in the Princeton Neuroscience Institute and Department of Computer Science. Seung has done influen ...
I am my connectomeEyeWire, a citizen science game to map the retinal connectomeMITK Diffusion: Free software for the processing of diffusion-weighted MR data including connectomics
{{Genomics
Cognitive neuroscience
Computational neuroscience