Brain network reorganization after targeted attack at a hub region

Abstract

The architecture of brain networks has been extensively studied in multiple species. However, exactly how the brain network reconfigures when a local region, particularly a hub region, stops functioning remains elusive. By combining chemogenetics and resting-state functional magnetic resonance imaging (rsfMRI) in an awake rodent model, we investigated the causal impact of acutely inactivating a hub region (i.e. the dorsal anterior cingulate cortex) on brain network properties. We found that suppressing neural activity in a hub could have a ripple effect that went beyond the hub-related connections and propagated to other neural connections across multiple brain systems. In addition, hub dysfunction affected the topological architecture of the whole-brain network in terms of the network resilience and segregation. Selectively inhibiting excitatory neurons in the hub further changed network integration. None of these changes were observed in sham rats or when a non-hub region (i.e. the primary visual cortex) was perturbed. This study has established a system that allows for mechanistically dissecting the relationship between local regions and brain network properties. Our data provide direct evidence supporting the hypothesis that acute dysfunction of a brain hub can cause large-scale network changes. These results also provide a comprehensive framework documenting the differential impact of hub versus non-hub nodes on network dynamics.

Keywords: Awake; DREADD; Graph theory; Rat; Resting-state fMRI.

Fig. 1.

Schematic diagram of the experimental paradigm.

Fig. 2.. Suppressing the dACC affects dACC FC strength, characteristic path length, and local efficiency.

A) dACC FC strength, B) dACC characteristic path length, and C) dACC local efficiency, with CNO or saline injection in the all-neuron DREADD group (top) and sham group (bottom). DREADD: n = 19, 78 scans; sham: n = 8, 41 scans. Linear mixed model; ***:p<0.05; NS: not significant. Error bar: standard error of the mean.

Fig. 3.. Suppressing the dACC changes RSFC in connections widespread the whole brain.

A) Top: averaged ROI-wise RSFC matrices after saline and CNO injections in the all-neuron DREADD group, respectively. Bottom: averaged ROI-wise RSFC matrices after saline and CNO injections in the sham group, respectively. B) Top: connections exhibiting significant RSFC changes after saline and CNO injections (two-way ANOVA, linear mixed model, p_interaction < 0.05, FDR corrected). RSFC changes between the CNO and saline conditions in the DREADD group were color coded with cold colors representing reduced RSFC and hot colors representing increased RSFC. Bottom: Connections with significant functional connectivity changes were grouped into multiple brain systems. Line thickness represents the total number of connections with significant RSFC changes between the two systems.

Fig. 4.. Suppressing a hub node changed whole-brain network topology.

A) Network resilience with CNO or saline injection in the all-neuron DREADD group and sham group; B) Network segregation with CNO or saline injection in the all-neuron DREADD group and sham group; C) Network integration with CNO or saline injection in the all-neuron DREADD group and sham group. Linear mixed model; all-neuron DREADD: n = 19, 78 scans; sham: n = 8, 41 scans. ***:p<0.005; NS: not significant. Error bar: standard error of the mean.

Fig. 5.. New hub emerged after the inactivation of an existing hub.

A) Hub scores without and with dACC inactivation, respectively; B) Centrality of the dACC and vRSC without and with dACC inactivation (linear mixed model; n = 19, 78 scans). **: p < 0.01; ***: p < 0.005. Error bar: standard error of the mean.

Fig. 6.. Suppressing dACC excitatory neurons affects dACC FC strength, characteristic path length, and local efficiency.

A) dACC FC strength with CNO or saline injection in the excitatory-neuron DREADD group. B) Characteristic path length of dACC with CNO or saline injection in the excitatory-neuron DREADD group. C) Local efficiency of dACC with CNO or saline injection in the excitatory-neuron DREADD group. Linear mixed model; excitatory-neuron DREADD group: n = 9, 56 scans. ***:p<0.005. Error bar: standard error of the mean.

Fig. 7.. Suppressing dACC excitatory neurons changes RSFC in widespread connections and whole-brain network topology.

A) Left: averaged ROI-wise RSFC matrices after saline and CNO injections in the excitatory-neuron DREADD group, respectively. Right: connections exhibiting significant RSFC changes after saline and CNO injections (two-way ANOVA, linear mixed model, p_interaction < 0.05, FDR corrected). RSFC changes between the CNO and saline conditions in the DREADD group were color coded with cold colors representing reduced RSFC and hot colors representing increased RSFC. These connections are grouped into B) multiple brain systems and overlaid on a glass rat brain. Line thickness represents the total number of connections with significant RSFC changes between the two systems. C) Suppressing dACC excitatory neurons changes whole-brain network topology including network resilience (left), network segregation (middle), and network integration (right). Linear mixed model; DREADD-CaMKII: n = 9, 56 scans. *: p<0.05; ***:p<0.005. Error bar: standard error of the mean.

Fig. 8.. Suppressing a non-hub node did not change whole-brain network topology.

A) Network resilience with CNO or saline injection; B) Network segregation with CNO or saline injection; C) Network integration with CNO or saline injection (linear mixed model; n = 8, 66 scans). NS: not significant. Error bar: standard error of the mean.