Beta-Adrenergic Antagonism Modulates Default Mode Network Coherence in Autism Spectrum Disorder

Background: Altered functional connectivity (FC) and network coherence is implicated in autism spectrum disorder (ASD) with the majority of studies suggesting local hyper-connectivity and long distance hypo-connectivity. Beta-adrenergic antagonism, such as the use of propranolol, benefits social and communication domains in ASD and performance benefits on language tasks following propranolol administration have been associated with increased FC. These cognitive and behavioral benefits following propranolol administration may be due to pharmacological effects on network coherence improving cognitive processing. 

Objectives: We propose that the cognitive and behavioral benefits from propranolol may be partially mediated by changes in network coherence in the brain, which is especially relevant for ASD given the known alterations in FC. Resting-state fMRI data was acquired to assess drug-related changes in network coherence.

Methods: Participants attended three counterbalanced sessions separated by at least 24 hours in which propranolol, nadolol, a peripheral beta-adrenergic antagonist, or placebo were administered in a double-blinded manner. Utilizing a graph theoretical approach, we assessed the effects of beta-adrenergic antagonism on resting state network coherence in individuals with ASD compared to unaffected individuals, with particular emphasis on the default mode network (DMN). DMN regions (ROIs) were also segregated into subnetworks using the Louvain algorithm for community detection. This process was repeated for 1000 iterations to determine the most representative functional network structure. 

Results: Regardless of diagnosis, beta-adrenergic antagonism decreased FC and network efficiency in the dorsal medial prefrontal cortex (dMPFC) subnetwork of the DMN and increased connectivity and network efficiency in the medial temporal lobe (MTL) subnetwork. However, these alterations in network coherence appeared to be due to diagnostic group specific effects on functional organization. ROIs comprising the dMPFC subnetwork decreased co-occurrence in the ASD group but increased co-occurrence in the control group; whereas ROIs comprising the MTL subnetwork increased lateralized co-occurrence in the ASD group but decreased lateralized co-occurrence in the control group. Furthermore, network coherence and functional organization effects were primarily not seen with nadolol, a peripheral beta-adrenegic antagonist that does not cross the blood-brain barrier, suggesting these findings were not due to peripheral cardiovascular effects on the BOLD signal. 

Conclusions: Our findings suggest that beta-adrenergic antagonism may be able to up- or down- regulate specific subnetworks in the brain and differentially affect functional organization of the DMN in individuals with ASD as compared to controls. Network coherence and functional organization in the brain modulates information processing. Beta-adrenergic effects on network coherence altering information processing may underlie the previously reported propranolol-mediated benefits to the social and language domains in ASD.