Connectome 5th

10/10/22
Brain network construction

and analysis
Xuhong Liao
2022-10-10
School of Systems Science

Beijing Normal University
liaoxuhong@bnu.edu.cn
单击此处编辑母版标题样式
q Brain networks
q Basic definitions
Ø Nodes (vertices) & links (edges)
Suárez et al. (2020) Trends Cog Neurosci

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Multi-scale organization of the brain
Multi-scale spatial organization: Molecule, cell, system, behavior, cognition
突触囊树突棘神经过程神经元局部回路全脑
Optical microscope Naked eyes
电子显微镜
光激活定位显微镜/随机光学重构显微镜
受激发射损耗/可逆饱和光学荧光跃迁显微镜
激光扫描共聚焦显微镜
双光子
激光片层扫描显微镜
磁共振
Mascaro et al (2015) J Biomed Opt 3
q Brain networks
Too small to resolve with the naked eye

q Node Need microscopic techniques
Ø Microscopic
Ø Mesoscopic
Ø Macroscopic Can be resolved
with without
microscopic
methods
q Link (edge)
Ø Anatomical connection: anatomical connections between neural elements
Ø Functional connection: statistical dependence in activity
Ø Effective connection: at the neuronal level, uncover direct and causal
influences between neural elements (e.g., neuronal circuit model)
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Brain network construction (Microscopic)
q Node definition
Ø Neuron
Researchers chart each neuron by tracing its thousands of projections

through stacks of hundreds of overlapping brain-slice images.
ü Main body of an individual neuron: optical/light microscopy (0.25-0.5 micrometer

resolution)
ü Synapses: mainly nanometer-resolution electron microscopy
Higher resolution means smaller fields of view and so more pictures.

And more pictures mean more data.
Landhuis (2017) Nature 5
Brain network construction (Microscopic)
q Node and connectivity

Ø Neuron Acquire images on
the tissue blockface
1x2 mm2
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65-year-old female
Ø Neuron
• 7404 sections at 20-um thickness • Total data: 1 Tbyte

• Images of maximal 13,000 by 11,000 pixels • Acquisition time: ~ 1000 hours
(10-by-10-um pixel size)
Amunts et al. (2013) Science 7
骆清铭院士团队在正常与阿尔兹海默症模型中分别解析了基底前脑神经元的长程投射模式
荧光显微光学切片断层成像技术
(fluorescence micro-optical
sectioning tomography)
Spatial resolution:
0.23 um x 0.23 um x 1 um
Tian et al. (2022) PNAS 8
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Ø Neuron, functional connectivity
• Structure constrains function in many areas of biology
• Anatomical networks act as constraints on the possible repertoire of
functional network states
• It is the activity unfolds on the network structure that drives behavior
The concept of a cell assembly -- by Hebb (1949)

Multiple, distinct features of a stimulus can be represented as a coherent entity
through the joint activity of distributed, interconnected neurons
Communication-through-coherence hypothesis:
Coordinated oscillatory activity is thought to mediate neuronal communication

Ø Neuron, functional connectivity
Measuring neuronal activity with invasive electrophysiology:
• Insert electrodes into distinct parts of the brain
• Multi-electrode arrays
• Calcium imaging: measures intracellular calcium levels (across large distances)
Orientation preference
Spatial proximity
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Brain network construction (Mesoscopic)
Ø Neural populations or cell assemblies
Inject the fluorescent dye or other tracer molecule into specific brain areas, dissect the
brain tissue, observe the tracer uptake
Examples of tract-tracing
q http://homepage.psy.utexas.edu/homepage/class/Psy308/Salinas/Methods/Slide05.GIF
q http://www.popsci.com/future-human/article/2008-07/mapping-human-mind 11
Inject the fluorescent dye or other tracer molecule into specific brain areas, dissect the
brain tissue, observe the tracer uptake
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Mapping the connectome of the fruit fly (~ 16,000 neurons)
Genetic labeling and

confocal imaging
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Functional connectivity networks estimated from local field potentials
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Measuring functional connectivity with extracellular fields
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Brain network construction (Macroscopic)
Structural MRI
MRI
Cortical morphology
Spatial resolution: ~1 mm
Diffusion MRI
White matter fiber tracts

EEG MEG
Functional MRI
Neural activity：BOLD signal

Temporal resolution: ~1 s
Multimodal neuroimaging techniques (e.g., MRI, EEG and MEG) enable the
noninvasive mapping of the human connectome.
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Nodes can be defined in various ways according to the neuroimaging data

considered，such as EEG electrodes, MEG sensors or reconstructed brain
sources of EEG/MEG signals using biophysical models.
Liao et al. (2017) Neurosci Biobehav R 17
Node definition – Brain parcellation
Cortical areas have traditionally been defined based on the idea that a cortical area
should exhibit distinct function, architectonics, connectivity, and topography
Individual voxels Cytoarchitectonic atlas for macaque and human
Anatomical parcellation Random parcellation Connectivity profile Task-related

variations activation peaks
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Node definition Random parcellation
Influence of node sizes
• Validity of boundaries: Constraint from a coarse structural/functional parcellation

• Reliability of the findings: repeat the analyses based on a few random parcellations
Zalesky et al. (2010) NeuroImage 19
Node definition Random parcellation
• Validity of boundaries: Constraint from a coarse structural/functional parcellation

• Reliability of the findings: repeat the analyses based on a few random parcellations
Zalesky et al. (2010) NeuroImage; Hagmann et al. (2008) PLoS Biol 20
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Node definition
Detecting boundary of functional connectivity profiles

Diagram of anatomical fingerprints Seed-based functional
for two prefrontal areas connectivity
Macaque tracer data
21
Passingham et al. (2002) Nat Rev Neurosci; Buckner et al. (2014) Nat Neurosci
Node definition
• Detects transitions between whole-brain correlation maps of nearby cortical seeds

• Translates these abrupt transitions into boundaries between cortical regions
Cohen et al. (2008) NeuroImage

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Node definition
Edge detection
Focus on local gradients in the whole-brain FC patterns
Cohen et al. (2008) NeuroImage 23
Node definition
Borders of similarity in resting-state functional connectivity profiles

or functional activation during tasks
Strong relationship between the connectivity fingerprint of an area and its functional role
Cohen et al. (2008) NeuroImage 24
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Node definition
Fan et al. (2016) Cereb Cortex 25
Node definition Multivariate decomposition of functional MRI signals
Incorporate a spatial constraint into the clustering method (Global similarity)

Inter-voxel similarity in the voxel time series (rt) or functional connectivity maps (rs)
Craddock et al. (2012) Human Brain Mapp 26
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Schaefer et al. (2018) Cereb Cortex 27
Nodes obtained from the independent component analysis (ICA)
Allen et al. (2014) Cereb Cortex 28
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The HCP’s multi-modal parcellation, version 1.0
Glasser et al. (2016) Nature

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q Node definition (MRI studies) ← Brain area ~ 100-1000 nodes
Ø Parcellation approaches in two dimensions: features and algorithms
Brain parcellation is fundamental for understanding brain organization and function

Eickhoff et al. (2018) Nat Rev Neurosci 30
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Whole-brain cortical parcellations available
Macroanatomy
More information can be found in Eickhoff et al. (2018) Nat Rev Neurosci
31
Resting-state fMRI
Population level Individual specific
Schaefer et al. (2018)
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Other modalities
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Commonly used parcellation for brain node definition
Brodmann-82 AAL-90 HOA-112 Dosenbach-160 Craddock-200 Power-264 Random-1024

Brodmann, Tzourio- Frazier et Dosenbach et al., Craddock et Power et al., Zalesky et al.,
1909 Mazoyer N et al., 2005 2010 al., 2012 2011 2010
al., 2002
Random
Structural parcellation Functional parcellation
parcellation
Different parcellations can influence the estimation of network properties

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Notes:
It is still an open question regarding how to choose the most appropriate node
definition while addressing a specific scientific question
Ø Structural networks: structurally constrained schemes are preferred
Ø Functional networks: functional defined schemes are preferred
Ø Structure-function relationship: multi-modal parcellations or randomized
parcellations are appropriate
Ø Cross-validation using different parcellations is encouraged to address
whether the findings are not driven by a specific brain parcellation
Liao et al. (2017) Neurosci Biobehav R 35
Notes:
One critical aspect: the issue of selecting the number of clusters or parcels
Ø Brain has a multilevel organization
Ø Internal information criteria: an objective function
Ø Reproducibility: re-sampling and reproducibility across independent samples
In the absence of apparent ground truth, current parcellation work capitalizes on

replication, robustness and convergence as proxies for biological validity
Eickhoff et al. (2018) Nat Rev Neurosci

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q Edge Definition
Ø Structural network Structural networks
Ø Functional network
Functional networks
Park and Friston (2013) Science; Hagmann et al. (2008) PLoS Biology; Raichle (2009) J Neurosci 37
q Edge Definition
Ø Structural network: anatomical pathways between brain regions
ü White-matter structural connectivity: interregional white matter fiber tracts
Diffusion MRI: measure the anisotropic diffusion of water molecules in brain tissues
White matter fiber tracts reconstructed through deterministic or probabilistic
tractography methods
Tensor model
Lynn and Bassett (2019) Nat Rev Phys 38
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q Edge Definition
ü White-matter structural connectivity: interregional white matter fiber tracts
Note: the selection of appropriate seed points for the initiation of the tracking algorithm
usually seed voxels along the interface of gray and white matter
Individual level
Connectivity strength:
number of streamlines; diffusion-based measures (fractional anisotropy)
q Edge Definition
ü Structural covariance connectivity: inter-regional structural covariance across
individuals
Structural MRI: measure regional morphological measures
Population level
See Tijms et al. (2012) for

individual level construction
Evans (2013) NeuroImage

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q Edge Definition
Ø Functional connectivity:
interregional statistical coherence (e.g., synchronization likelihood, Pearson's
correlation)
EEG measures the electrical activity via electrodes placed on the scalp surface
MEG measures the weak magnetic fields that are generated by neuronal currents
High temporal resolution (~ 1000 Hz), poor spatial resolution
Sensor as nodes
Source localization
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q Edge Definition
correlation; partial correlation)
Functional MRI: measure blood-oxygenation-level-dependent signal
High spatial resolution, poor temporal resolution (0.5-1.5 Hz)
Series of 3D volumes (i.e., 4D data)

… (e.g., every 2 sec for 8 min)
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Intrinsic functional organization during resting state
q Theoretical motivation: understanding of brain energy metabolism
Ø Human brain: only 2% of total body mass, 20% of body’s energy
Ø Task-related increases in neuronal metabolism is small (< 5%)
q Empirical motivation: Intrinsic temporal correlation during rest
Activation Correlation High correlation

in task in rest
Correlation between low-frequency (<0.1Hz) oscillations of bilateral motor cortices
Biswal et al. (1995) MRM; Fox and Raichle (2007) Nat Rev Neurosci
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q Edge Definition
correlation; partial correlation)
Trade-off between spatial and temporal resolution

• Temporal structure: EEG or MEG
• Anatomical localization or large-scale organization: functional MRI
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q Brain networks
Too small to resolve with the naked eye

q Multi-scales Need microscopic techniques
Ø Microscopic
Ø Mesoscopic
Ø Macroscopic Can be resolved
with without
microscopic
methods
Each scale has distinct advantages and disadvantages

The benefits of a coarser mapping:
“It makes no sense to read a newspaper with a microscope”
------Valentino Braitenberg
45
q Edge definition
Ø Structural network
q Network thresholding strategy: connectivity matrix to adjacency matrix
Ø Use a threshold to exclude weak or spurious connections potentially induced by
noisy signals
Ø Generate a binary or weighted network

Connectivity matrix Weighted adjacency matrix Binary adjacency matrix
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q Edge definition
Ø Structural network
q Network thresholding strategy: connectivity matrix to adjacency matrix
Ø Use a threshold to exclude weak or spurious connections potentially induced by
noisy signals
White matter structural connectivity

can be weighted according to:
Fiber length, fiber number, fractional
anisotrophy, connectivity probability, etc
Deco and Kringelbach (2014) Neuron

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Rubinov and Sporns (2010) NeuroImage

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Different ways of visualizing an 82-region human structural connectivity matrix
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Brain network analysis
Deco and Kringelbach (2014) Neuron

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Perspectives
q Novel definitions of brain nodes and connectivities

Ø Node: multi-modal, individualized
Ø Connectivity: co-activation, time-varying (dynamic)
q Inter-subject variability: network, cognition, and populations
q Incorporating multi-dimensional data
q Parcellations for different periods of the human lifespan
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Individual variability in functional organization
q Functional networks/systems in individuals
Ø Exhibit topological features distinct from the group-level system organization
Ø Dramatically varies across individuals
q The capacity to identify the unique functional architecture of an individual’s brain
is a crucial step toward personalized medicine and understanding the neural basis
of variation in human cognition and behavior
Example of idiosyncratic patterns of functional connectivity in an individual
Laumann et al. (2015) Neuron; Liao et al. (2017) NeuroImage; Wang et al. (2015) Nat Neurosci 53
Novel node definitions
Inter-individual variability in functional parcellation
Network-level Network-level Area-level Network-level
Eickhoff et al. (2018) Nat Rev Neurosci

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Novel node definitions
q Individualized functional parcellations

Ø Homogeneity of time courses and functional connectivity profiles
Ø Influence of intra- and inter-subject variability
Parcellating functional networks in an individual brain using an iterative adjusting approach

Wang et al. (2015) Nat Neurosci 55
Novel connectivity definitions
q Functional connectivity
Functional coactivation Inter-subject correlation
Crossley et al. (2013) PNAS; Bassett and Sporns (2017) Nat Neurosci 56
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q Structural connectivity
Desikan-Killiany
atlas
FA, fractional anisotropy; MD, mean diffusivity; MT, magnetization transfer; GM,
gray matter volume; SA, surface area; CT, cortical thickness; IC, intrinsic
(Gaussian) curvature; MC, mean curvature;
CI, curved index; FI, folding index
Seidlitz et al. (2018) Neuron 57
Seidlitz et al. (2018) Neuron 58
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10/10/22

Brain network construction

School of Systems Science

Suárez et al. (2020) Trends Cog Neurosci

Multi-scale spatial organization: Molecule, cell, system, behavior, cognition

突触囊 树突棘 神经过程 神经元 局部回路 全脑

Optical microscope Naked eyes

Mascaro et al (2015) J Biomed Opt 3

Too small to resolve with the naked eye

Researchers chart each neuron by tracing its thousands of projections

ü Main body of an individual neuron: optical/light microscopy (0.25-0.5 micrometer

Higher resolution means smaller fields of view and so more pictures.

Landhuis (2017) Nature 5

q Node and connectivity

• 7404 sections at 20-um thickness • Total data: 1 Tbyte

Tian et al. (2022) PNAS 8

q Node and connectivity

The concept of a cell assembly -- by Hebb (1949)

Amunts et al. (2013) Science 9

q Node and connectivity

Amunts et al. (2013) Science 10

Mapping the connectome of the fruit fly (~ 16,000 neurons)

Genetic labeling and

Functional connectivity networks estimated from local field potentials

Measuring functional connectivity with extracellular fields

White matter fiber tracts

Neural activity：BOLD signal

Nodes can be defined in various ways according to the neuroimaging data

Anatomical parcellation Random parcellation Connectivity profile Task-related

Influence of node sizes

• Validity of boundaries: Constraint from a coarse structural/functional parcellation

• Validity of boundaries: Constraint from a coarse structural/functional parcellation

Zalesky et al. (2010) NeuroImage; Hagmann et al. (2008) PLoS Biol 20

Detecting boundary of functional connectivity profiles

Macaque tracer data

Detecting boundary of functional connectivity profiles

• Detects transitions between whole-brain correlation maps of nearby cortical seeds

Cohen et al. (2008) NeuroImage

Detecting boundary of functional connectivity profiles

Focus on local gradients in the whole-brain FC patterns

Cohen et al. (2008) NeuroImage 23

Borders of similarity in resting-state functional connectivity profiles

Cohen et al. (2008) NeuroImage 24

Fan et al. (2016) Cereb Cortex 25

Incorporate a spatial constraint into the clustering method (Global similarity)

Craddock et al. (2012) Human Brain Mapp 26

Schaefer et al. (2018) Cereb Cortex 27

Allen et al. (2014) Cereb Cortex 28

The HCP’s multi-modal parcellation, version 1.0

Glasser et al. (2016) Nature

Brain parcellation is fundamental for understanding brain organization and function

Schaefer et al. (2018)

Commonly used parcellation for brain node definition

Brodmann-82 AAL-90 HOA-112 Dosenbach-160 Craddock-200 Power-264 Random-1024

Different parcellations can influence the estimation of network properties

Liao et al. (2017) Neurosci Biobehav R 35

In the absence of apparent ground truth, current parcellation work capitalizes on

Eickhoff et al. (2018) Nat Rev Neurosci

Lynn and Bassett (2019) Nat Rev Phys 38

Lynn and Bassett (2019) Nat Rev Phys 39

See Tijms et al. (2012) for

Evans (2013) NeuroImage

High temporal resolution (~ 1000 Hz), poor spatial resolution

突触囊树突棘神经过程神经元局部回路全脑