Subsystem organization of axonal connections within and between the right and left cerebral cortex and cerebral nuclei (endbrain)

Abstract

The endbrain (telencephalon) is at the rostral end of the central nervous system and is primarily responsible for supporting cognition and affect. Structurally, it consists of right and left cerebral hemispheres, each parceled into multiple cortical and nuclear gray matter regions. The global network organization of axonal macroconnections between the 244 regions forming the endbrain was analyzed with a multiresolution consensus clustering (MRCC) method that provides a hierarchical description of community clustering (modules or subsystems) within the network. Experimental evidence was collated from the neuroanatomical literature for the existence of 10,002 of a possible 59,292 connections within the network, and they cluster into four top-level subsystems and 60 bottom-level subsystems arranged in a 50-level hierarchy. Two top-level subsystems are bihemispheric: One deals with auditory and visual information, and the other corresponds broadly to the default mode network. The other two top-level subsystems are bilaterally symmetrical, and each deals broadly with somatic and visceral information. Because the entire endbrain connection matrix was assembled from multiple subconnectomes, it was easy to show that the status of a region as a connectivity hub is not absolute but, instead, depends on the size and coverage of its anatomical neighborhood. It was also shown numerically that creating an ultradense connection matrix by converting all "absent" connections to a "very weak" connection weight has virtually no effect on the clustering hierarchy. The next logical step in this project is to complete the forebrain connectome by adding the thalamus and hypothalamus (together, the interbrain) to the endbrain analysis.

Macroscale intrinsic network architecture of the hypothalamus

“…Combining the ipsilateral and contralateral macroconnection data, it follows that each side of the hypothalamus generates ∼3,991 intrinsic macroconnections (8,385 × macroconnection density ratio of 0.476) and, thus, ∼7,982 intrinsic macroconnections (of 16,770 possible) are generated in the complete hypothalamus. We also applied a metric for the validity of pathway-tracing methods (as described previously) (8,9). The average validity of the pathway-tracing methods was 6.6 [on a scale of 1 (lowest) to 7 (highest)] for macroconnection reports of present intrahypothalamic macroconnections selected for network analysis, and the average validity was 6.2 for selected reports of macroconnections that do not exist (absent) (SI Appendix, Fig.…”

“…Centrality Metrics and Additional Network Attributes. In addition to MRCC analysis, we investigated hypothalamic network properties using four common network centrality metrics (measures that indicate the dominance/"importance" of each node in the network): degree, strength, betweenness, and closeness (8)(9)(10). The centrality metric of degree measures the number of input (in-degree) or output (out-degree) connections for each network node (here, each gray matter region); strength represents the total weight of each node's macroconnections; and the related centrality measures of betweenness and closeness take account of the shortest path between nodes and are considered to provide an indication of node centrality with respect to information flow.…”

“…We investigated two additional network properties: the attributes of "small-world" and "rich-club." Previously, we investigated these for macroscale cerebral hemisphere subconnectomes (8)(9)(10). The small-world attribute is characteristic of networks with clustered nodes connected via short paths, whereas rich-club, in network theory parlance, refers to a group (subgraph) of well-connected network nodes that are also densely connected with one another.…”

“…Using data-driven approaches, we recently investigated the macroscale network of the cerebral hemispheres (8) and their principle parts: the cerebral cortex (9) and cerebral nuclei (10). This led to novel network models for two of the four major divisions of the forebrain that play an essential role in the cognitive control of behavior.…”

“…This is complemented with comparative analysis of gene markers associated with inhibitory [glutamic acid decarboxylase 65 (GAD65)] and excitatory [vesicular glutamate transporter 2 (VGLUT2)] neurotransmission. Network analysis is based on a weighted and directed connection matrix (for all 130 hypothalamic gray matter regions; 65 on each side), which is a macroscale intrahypothalamic subconnectome, and follows a strategy we have employed previously (8)(9)(10). on the same side (ipsilateral) or opposite sides (contralateral) of the hypothalamus.…”