Bumetanide for autism: more eye contact, less amygdala activation

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.

Figure 1

Working hypothesis: At birth, babies instinctively attend to ‘protofaces’, through the subcortical face processing system. Protofaces and faces activate the pathway going from SC to PUL and AMY. In autism (ASD), this pathway becomes over connected because of E/I imbalance. Later, eye contact activates the subcortical system, and helps normal maturation of the cortical face processing in neurotypicals (NT); but in ASD, eyes over-activate the system, in particular the amygdala, and provoke over-arousal, resulting in aversion to eye contact, and reduced experience with eyes and faces, which ultimately leads to an abnormal maturation of the “social brain”, (that includes e.g. the FFA, superior temporal sulcus (STS), intraparietal sulcus (IPS), prefrontal cortex and insula (INS)). – NT: neurotypicals; AMY: amygdala; PUL: thalamus pulvinar nucleus SC: superior colliculus; LGN: lateral geniculate nucleus; FFA: Fusiform Face Area; V1: primary visual cortex. E/I: excitatory/inhibitory.

Figure 2

Descriptive plots of amygdala (left and right combined) activation at baseline (purple) and after 10 months of bumetanide treatment (green) in constrained eye contact (CROSS) and free viewing (NO CROSS) conditions. Data are shown as mean ± SEM.

Figure 3

Descriptive plots of time spent in the eyes AOI at baseline (purple) and after bumetanide treatment (green) during free viewing showing that participants with ASD spontaneously spend more time looking at the eye region after treatment. Data are shown as mean ± SEM.