Effect of propranolol on facial scanning in autism spectrum disorder: a preliminary investigation.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments and restricted, repetitive behaviors. Whereas current pharmacological interventions for ASD focus primarily on psychiatric symptoms, including agitation and obsessive behaviors, few agents target core symptomatology. It has been previously hypothesized that abnormalities in facial scanning, such as reduced eye contact or increased mouth fixation, contribute to social communication deficits in ASD. In addition, previous reports have suggested elevated stress and anxiety in ASD, symptoms that are believed to impact facial scanning patterns. OBJECTIVES: The present pilot study sought to explore the effects of pharmacological intervention via propranolol, a nonselective ß-adrenergic antagonist and known anxiolytic, on facial scanning in ASD. Specifically, we wished to determine whether there is an increase in eye contact and a decrease in mouth fixation with administration of propranolol. METHOD: A sample of 14 participants with ASD and 14 matched controls participated in two study sessions in which propranolol and placebo were administered in a counterbalanced, double-blinded manner. At each session, ocular fixation data were collected during presentation of video stimuli of 16 human faces. Fixation time on the eye, nose, and mouth regions of the face stimuli was analyzed. RESULTS: The baseline fixation patterns for the ASD and control groups did not significantly differ; however, administration of propranolol was associated with a significant reduction in mouth fixation for the ASD group. Additionally, mouth fixation was positively related to nonverbal communication impairment in the ASD group. CONCLUSIONS: Although eye fixation in ASD appears typical in the present study, the effect of propranolol in reducing mouth fixation suggests an important focus for further research. Future studies are needed to better characterize the relationship between stress and anxiety and facial scanning in ASD, as well as the effects of pharmacological intervention.

Noradrenergic moderation of working memory impairments in adults with autism spectrum disorder.

In addition to having difficulties with social communications, individuals with an autism spectrum disorder (ASD) often also experience impairment in higher-order, executive skills. The present study examined the effects of pharmacological modulation of the norepinephrine system on the severity of such impairments. A sample of 14 high-functioning adults with ASD and a demographically-matched comparison group of 13 typically developing individuals participated. An AX continuous performance test (AX-CPT) was used to evaluate working memory and inhibitory control. AX-CPT performance was assessed following administration of a single dose of propranolol (a beta adrenergic antagonist) and following placebo (sugar pill) administration. Individuals with ASD performed more poorly than non-ASD individuals in the working memory condition (BX trials). Importantly, administration of propranolol attenuated this impairment, with the ASD group performing significantly better in the propranolol condition than the placebo condition. Working memory performance of the non-ASD group was unaffected by propranolol/placebo administration. No group or medication effects were observed for the inhibition condition (AY trials). The present findings suggest that norepinephrine may play a role in some, but not necessarily all, cognitive impairments associated with ASD. Additional research is needed to fully understand whether this role is primarily causal or compensatory in nature.

Functional connectivity during language processing in acute cocaine withdrawal: a pilot study.

Recent research revealed decreased access to semantic and associative networks in acute cocaine withdrawal. In autism, such behavioral outcomes are associated with decreased functional connectivity using functional magnetic resonance imaging. Therefore, we wished to determine whether connectivity is also decreased in acute cocaine withdrawal. Eight subjects in acute cocaine withdrawal were compared to controls for connectivity in language areas while performing a task involving categorization of words according to semantic and phonological relatedness. Acute withdrawal subjects had significantly less overall connectivity during semantic relatedness, and a trend towards less connectivity during phonological relatedness. Of potential future interest is whether this might serve as an imaging marker for treatment in patients.

Effect of propranolol on word fluency in autism.

OBJECTIVE AND BACKGROUND: Autism is characterized by repetitive behaviors and impaired socialization and communication. Preliminary evidence showed possible language benefits in autism from the ß-adrenergic antagonist propranolol. Earlier studies in other populations suggested propranolol might benefit performance on tasks involving a search of semantic and associative networks under certain conditions. Therefore, we wished to determine whether this benefit of propranolol includes an effect on semantic fluency in autism. METHODS: A sample of 14 high-functioning adolescent and adult participants with autism and 14 matched controls were given letter and category word fluency tasks on 2 separate testing sessions; 1 test was given 60 minutes after the administration of 40 mg propranolol orally, and 1 test was given after placebo, administered in a double-blinded, counterbalanced manner. RESULTS: Participants with autism were significantly impaired compared with controls on both fluency tasks. Propranolol significantly improved performance on category fluency, but not letter fluency among autism participants. No drug effect was observed among controls. Expected drug effects on heart rate and blood pressure were observed in both the groups. CONCLUSIONS: Results are consistent with a selective beneficial effect of propranolol on flexibility of access to semantic and associative networks in autism, with no observed effect on phonological networks. Further study will be necessary to understand potential clinical implications of this finding.

Effect of propranolol on functional connectivity in autism spectrum disorder--a pilot study.

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.

Photic regulation of the mTOR signaling pathway in the suprachiasmatic circadian clock.

Here we analyzed the light-responsiveness of the mammalian target of rapamycin (mTOR) cascade, a key regulator of inducible translation, in the suprachiasmatic nuclei (SCN), the locus of the master circadian clock. Brief light exposure during the subjective night, but not during the subjective day, triggered rapid phosphorylation (a marker of catalytic activity) of the mTOR translation effectors p70 S6K, ribosomal S6 protein (S6) and 4E-BP1. In the absence of photic stimulation, marked S6 and 4E-BP1 phosphorylation was detected, indicating tonic mTOR activity in the SCN. Light stimulated the colocalized activation of p70 S6K and extracellular signal-regulated protein kinase (ERK), and pharmacological disruption of ERK signaling abolished light-induced mTOR activity, revealing that the MAPK cascade is an essential intermediate that couples light to mTOR. Together these data identify a light-responsive mTOR cascade in the SCN, and thus, raise the possibility that inducible translation contributes to the clock entrainment process.

Negative feedback regulation of nigrostriatal dopamine release: mediation by striatal D1 receptors.

The nigrostriatal dopamine system of the mammalian brain is necessary for normal voluntary motor activity. Dopamine exerts its effects by acting on two primary receptor subtypes: D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptors. Previous research has indicated that both subtypes are involved in the negative feedback regulation of dopamine release in the brain. However, the role of D1-like receptors localized within the striatum remains controversial. Using in vivo microdialysis, we report that infusions of the D1/D5 antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] (5-200 microM) directly into the striatum increased dopamine release in a concentration-dependent manner. Systemic administration of the novel, full D1/D5 agonist A-77636 [(-)-(1R,3S)-3-adamantyl-1-(aminomethyl)-3,4-dihydro-5,6-dihydroxy-1H-2-benzopyran] produced the opposite effect, a dose-dependent (0.75-3.0 mg/kg s.c.) decrease in striatal dopamine efflux. Infusions of SCH 23390 (5.0 microM) attenuated this decrease. These findings suggest that endogenous dopamine acts on D1-like receptors localized within the striatum to decrease nigrostriatal dopamine release. This negative feedback may be due to the activation of an inhibitory long-loop pathway. Knowledge of the circuitry underlying D1-mediated regulation of nigrostriatal neurons may have significance in current research on treatments for Parkinson's disease.