Abstract
We recently showed that constraining eye contact leads to exaggerated increase of amygdala activation in autism. Here, in a proof of concept pilot study, we demonstrate that administration of bumetanide (a NKCC1 chloride importer antagonist that restores GABAergic inhibition) normalizes the level of amygdala activation during constrained eye contact with dynamic emotional face stimuli in autism. In addition, eye-tracking data reveal that bumetanide administration increases the time spent in spontaneous eye gaze during in a free-viewing mode of the same face stimuli. In keeping with clinical trials, our data support the Excitatory/Inhibitory dysfunction hypothesis in autism, and indicate that bumetanide may improve specific aspects of social processing in autism. Future double-blind placebo controlled studies with larger cohorts of participants will help clarify the mechanisms of bumetanide action in autism.
Highlights
Eye-contact is experienced as stressful, or threatening in autism[1], and the brain mechanisms underlying this reaction are beginning to be understood
These observations raise the possibility that high chloride levels and excitatory actions of GABA prevail in these brain regions leading to adverse response to eye contact in autism
Supporting our hypothesis, we found a significant decrease in amygdala activation compared with the baseline during constrained eye gaze (CROSS condition) following bumetanide treatment according to a nonparametric Wilcoxon signed ranks test (z = −2.100, p = 0.036, 2-tailed)
Summary
We show that bumetanide treatment in autism normalizes amygdala activation in response to eye contact, and that it increases the time spontaneously spent in the eyes of dynamic emotional faces. In addition to the reduction in amygdala activation, visible in whole brain analysis, other areas involved in social, cognitive or somatic (preparation for action) responses showed reduced activation after bumetanide, probably modulated by the amygdala reduction, as would be expected based on the data by[46] These areas overlapped to a great extent with areas were we have previously demonstrated an eye-contact effect in typical individuals (see Fig. 1 in[38]). Our results demonstrate that bumetanide reduces threat response to eye contact and increase time spontaneously spent looking in the eyes, potentially allowing acquisition of the necessary information to improve social processing. Whether the actions of bumetanide are due to alterations of [Cl−]I levels in amygdala neurons in patients with autism is beyond direct demonstration, but both the exquisite selectivity of the diuretic to the NKCC1 chloride importer and the converging experimental data are strongly suggestive that this is the underlying mechanism
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