**3. Approach to mapping the human connectome**

As discussed in last section, the human connectome is a structural description of the neural network and connections across multiple spatial scales. In general, there are three scales of organization within the human brain [26]:


Mapping of the connectome at the first two levels usually occurs in animal models and is conducted in experimental trials. In this review, we will focus on the mapping of the human connectome at the macroscale.

At present, MRI has been used as a non-invasive tool for mapping of large-scale structural connections in the human brain [26, 27]. Both *structural* and *functional connectivity* need to be studied in detail.

*Structural connectivity* is usually assessed by diffusion-weighted MRI sequences, followed by probabilistic tractography, because water moves more freely along white matter fiber bundles than across them and so white matter pathways can be reconstructed, thereby identifying fibers that pass between various brain regions [27].

In contrast, resting state functional MRI (rfMRI) is frequently used to study *functional connectivity*. It examines the blood oxygen level dependent (BOLD) signal, which serves as an indirect marker of neuronal activity [27, 34]. When brain activity increases, blood flow and glucose consumption increase much more than oxygen consumption. Therefore, the amount of deoxygenated hemoglobin decreases in the region of increased activity and the BOLD signal is enhanced [40]. *Functional connectivity* is defined as the statistical association between time-series of anatomically distinct brain regions, which in functional MRI is typically calculated as zero-lag correlation. In other words, if two brain regions have BOLD signals that are correlated, they are functionally connected [34].

With the use of diffusion-weighted MRI and functional MRI, the functional human connectome can be mapped out at the macroscale [25, 27]. The approach to mapping the human connectome is outlined as follows (**Figure 1**) [25].

## **Step 1:**

First, diffusion-weighted MRI, followed by probabilistic tractography of thalamocortical tracts and corticocortical interareal pathways, should be performed to aid in the parcellation of the human brain, thereby creating a voxel-wise probabilistic all-to-all *structural connectivity* matrix.
