Functional Connectivity in ASD with Pharmacological Modulation of the Beta-Adrenergic System

Background: Current behavioral interventions for autism focus on increasing quality of life and language development whereas pharmacological interventions are directed at managing the secondary manifestations such as anxiety and repetitive and obsessive behaviors. Pharmacological research directed at the core features of autism is limited. We have previously shown that propranolol, a beta-adrenergic antagonist, improved verbal problem solving in typically developing controls as well as people with autism. Current theories suggest that autism may be due to decreased network flexibility within cortical regions important for information processing, and we believe the previously noted propranolol effects may be due to increased flexibility within language networks. Functional magnetic resonance imaging, fMRI, allows for the measurement of a potential correlate of network flexibility, functional connectivity. We therefore wish to determine fcMRI alterations during language-based tasks when propranolol is administered. 

Objectives: Our objective was to examine the potential mechanism of the beneficial effects of a currently available pharmacotherapeutic agent, propranolol, on the core features of autism by assessing functional connectivity using fMRI. 

Methods: We examined a pilot sample of individuals with autism during administration of propranolol, nadolol, and placebo. Nadolol provides a control for general vascular effects on BOLD fcMRI since nadolol is a beta-adrenergic antagonist but does not cross the blood brain barrier. After drug administration, subjects were placed in a 3T magnetic resonance scanner at Ohio State University and asked to complete a cognitive flexibility task, the compound remote associates (CRA), and two verbal fluency tasks, one based on letters and the other based on categories. Structural T1-weighted images were acquired using a T1 weighted 3D FFE pulse sequence (TR=25 ms; TE=3.6 ms; 64 axial slices; 2.2 mm thick). BOLD contrast functional scans were acquired using a gradient echo EPI sequence (TR=3 s; TE=35 ms; 35 axial slices, 4mm thick; α = 90°). A priori regions of interest, ROIs, were used to extract region-specific activation in the inferior frontal cortex, fusiform gyrus, middle temporal gyrus, and posterior parietal cortex. Correlations between pairs of ROIs were computed by calculating the correlation coefficient between the time series for each ROI pair and then standardized using Fischer’s Z-transformation. 

Results: There was a significant effect of drug such that functional connectivity was significantly higher for propranolol trials compared to nadolol and placebo, which did not appear to significantly differ from each other. These results were most robust for the CRA task.

Conclusions: Although this is preliminary data, we begin to show the cognitive benefits of propranolol in autism may be due to increased network flexibility due to alterations of beta-adrenergic mechanisms. Theses alterations seem to be most beneficial for more difficult compared to easier tasks. Better understanding of the effects of the beta-adrenergic system on language processing, especially in the autism population, and modulation of the beta-adrenergic system pharamacologically could lead to development of additional treatments for the core features of autism. Additional research is required to fully understand these alterations and determine possible biomarkers, such as genetic status, of who may benefit most from beta-adrenergic intervention.