Effect of Propranolol on Functional Connectivity in Autism Spectrum Disorder—A Pilot Study

Ananth Narayanan 0 2 3 4 5 Catherine A. White 0 2 3 4 5 Sanjida Saklayen 0 2 3 4 5 Mary J. Scaduto 0 2 3 4 5 Allen L. Carpenter 0 2 3 4 5 Amir Abduljalil 0 2 3 4 5 Petra Schmalbrock 0 2 3 4 5 David Q. Beversdorf 0 2 3 4 5 0 Dr. Beversdorf has spoken for Pfizer, Eisai and Novartis in the past, unrelated to this work 1 ) Department of Radiology, University of Missouri, Thompson Center , 300 Portland St., Suite 122, Columbia, MO 65211, USA 2 D. Q. Beversdorf Department of Psychology, University of Missouri , Columbia, MO, USA 3 D. Q. Beversdorf Department of Neurology, University of Missouri , Columbia, MO, USA 4 A. L. Carpenter Neuroscience Graduate Studies Program, The Ohio State University , Columbus, OH, USA 5 C. A. White Departments of Psychiatry and Neurology, The Ohio State University , Columbus, OH, USA A decrease in interaction between brain regions is observed in individuals with autism spectrum disorder (ASD), which is believed to be related to restricted neural network access in ASD. Propranolol, a beta-adrenergic antagonist, has revealed benefit during performance of tasks involving flexibility of access to networks, a benefit also seen in ASD. Our goal was to determine the effect of propranolol on functional connectivity in ASD during a verbal decision making task as compared to nadolol, thereby accounting for the potential spurious fMRI effects due to peripheral hemodynamic effects of propranolol. Ten ASD subjects underwent fMRI scans after administration of placebo, propranolol or nadolol, while performing a phonological decision making task. Comparison of functional connectivity between pre-defined ROI-pairs revealed a significant increase with propranolol compared to nadolol, suggesting a potential imaging marker for the cognitive effects of propranolol in ASD. - Autism is a neurodevelopmental disorder characterized by impaired social interaction, impaired communication and repetitive and restricted behaviors (Lord et al. 1994). While varying degrees of mental retardation are common in autism (Lord et al. 1994), even those without global cognitive impairment encounter significant problems trying to function in society (Morgan 1996; Carpenter 1992). Autism spectrum disorder (ASD) is a term used to describe the spectrum of autism, Asperger syndrome and pervasive developmental disordernot otherwise specified (Beversdorf et al. 1998). Several theories have been proposed to explain the impairments in autism, including inability to comprehend the perspectives of others (theory of mind) (Baron-Cohen et al. 1985), inability to process emotional information (Hobson 1991, 1993; Fotheringham 1991) and impaired executive function (Rumsey 1985; Rumsey and Hamburger 1988, 1990). Individuals with autism are also known to have decreased central coherence, or difficulty with utilization of context to process its environmental relevance (Frith and Happ 1994; Happ 1994). This lack of central coherence is believed be related to restriction of semantic and associative networks, leading to the observed deficits in semantic clustering in verbal memory (Minshew and Goldstein 2001). This also relates to superior performance in recognition on false memory tasks (Beversdorf et al. 2000), proposed to be associated with increased neuronal density and decreased neuronal size in the hippocampus, among other atypical findings in the brain in autism (Bauman and Kemper 1985, 1994). More recently, a potential neural correlate of this phenomenon of network underconnectivity and decreased context utilization in autism has been revealed, with the demonstration of decreased functional connectivity, defined as the temporal correlation between spatially remote neurophysiological events (Friston 1994). This is demonstrated by decreased functional connectivity fMRI (fcMRI) during sentence comprehension and working memory in high functioning individuals with autism (Just et al. 2004), and during a range of other cognitive tasks (Koshino et al. 2005). Our recent pilot evidence has suggested a benefit in flexibility of access to networks on verbal problem solving tasks with propranolol in ASD (Beversdorf et al. 2008). In this study, subjects with ASD solved simple anagram tasks, which involved a search through the lexical/semantic network to find the solution (for example, BRICK is the solution to IRBCK), more quickly after administration of propranolol than after placebo. Therefore, we wished to determine whether propranolol might also result in an increase in functional connectivity in ASD. Propranolol, a -adrenergic antagonist, appears to affect flexibility of access to lexical, semantic and associative networks on verbal problem solving tasks in individuals without neurodevelopmental diagnoses (Beversdorf et al. 1999). In the initial work, anagram performance was better after propranolol, a -adrenergic antagonist, as compared to ephedrine, an adrenergic agonist (Beversdorf et al. 1999). In subsequent work, anagram performance was found to be significantly better after propranolol, which blocks both central and peripheral -adrenergic receptors, as compared to nadolol, which blocks only peripheral -adrenergic receptors, suggesting that noradrenergic modulation of cognitive flexibility is mediated by a central, rather than a peripheral mechanism (Beversdorf et al. 2002). However, in neither of these initial small studies in individuals without developmental diagnoses did the improvement with propranolol as compared to placebo reach significance. In order to better understand the effect of propranolol, a subsequent larger study was performed, which revealed a significant benefit from propranolol for the subjects slowest at solving the problems, as well as for the most difficult problems regardless of subject (Campbell et al. 2008). However, benefit was not observed for subjects best at solving the problems, or for simple problems regardless of subject, with a decline in performance occasionally observed with propranolol in these cases. This was true for anagrams as well as other verbal problem solving tasks requiring flexibility of access to lexical, semantic and associative networks. In contrast to the studies in individuals without neurodevelopmental diagnoses, in the study examining the effect of propranolol in ASD a benefit was observed for the simplest anagrams with propranolol as compared to placebo, despite a slight decline in performance with the same tasks with propranolol among control participants (Beversdorf et al. 2008). The effect of propranolol is believed to be due to the modulatory effect of norepinephrine on the signal-tonoise ratio (SNR) of neuronal activity within the cortex (Hasselmo et al. 1997). Increased SNR would be expected to increase the relative strength of dominant responses, but decreased SNR may allow greater access to more remote associative inputs, which may benefit cognitive flexibility in unconstrained tasks such as those involving search of semantic and (...truncated)