A causal study of bumetanide on a marker of excitatory-inhibitory balance in the human brain
Summary (2 min read)
Introduction
- Excitatory and inhibitory (E/I) activity is balanced in neural systems at multiple spatial scales [1, 2], and this balance is thought to be critical for typical neural function [3–5].
- In particular, studies in both humans and in animal models suggest that altered inhibitory signaling, mediated by the neurotransmitter GABA, may characterize the condition [10, 11].
- During development, the polarity of GABAergic action transitions from excitatory to inhibitory due to a progressive reduction in intracellular chloride (Cl-) concentration in principal neurons [14, 15] -- a developmental sequence that may be disrupted in animal models of autism [16, 17].
- Importantly, to date, direct evidence that bumetanide increases inhibition in the human brain is lacking, which complicates linking the reported symptomatic benefits to the drug’s predicted physiological effects.
- The authors tested this hypothesis in a within-subjects drug-placebo, crossover design pharmacological study of rivalry dynamics in neurotypical adults.
Materials and Methods
- Written consent was obtained from all participants, and all studies were approved by the Massachusetts Institute of Technology Institutional Review Board.
- Bumetanide is an FDAapproved loop-diuretic known to antagonize sodium-potassium-chloride cotransporters, NKCC1 and NKCC2, which modulate intracellular chloride concentration.
- For each participant and trial, the frequency of perceptual transitions as well as the duration of any perceptual event (red, green, or mixed) were calculated.
- Binocular rivalry replay trial stimuli were identical to those used in the main rivalry experiment, and the paradigm was identical to their previously published studies [31, 33].
Results
- The authors predicted that bumetanide, a drug known to alter intracellular Cl- concentration and, by proxy, posited to increase GABAergic inhibition, would increase perceptual suppression during rivalry.
- The authors also assessed performance on rivalry replay control trials to establish whether any observed changes were due to non-perceptual effects on response latencies or response criteria [39, 40].
- To test whether bumetanide affects the depth of perceptual suppression during rivalry, the authors calculated the drug effect on the proportion of suppression for each individual (Proportion of Suppression on Drug - Placebo days) using a Wilcoxon signed-rank test.
- Drug effects are not confounded by shifts in response latency or response criteria.
Test-retest reliability
- To examine the stability of their primary measure, perceptual suppression, the authors calculated test-retest reliability by correlating performance on drug versus placebo days across individuals in each study.
- Bumetanide does not affect self-reported drowsiness Participants did not report significant differences in drowsiness between placebo and drug days (mean: 0.35 questionnaire points +/- 1.69 points, p = 0.367).
Discussion
- The authors have shown that acute administration of bumetanide does not alter binocular rivalry dynamics in neurotypical adult individuals.
- Indeed, the effects the authors observed (lower perceptual suppression) here trended in the opposite direction as predicted from previous studies of the impact of GABA modulators on rivalry dynamics [31, 32].
- Previous studies examining the longitudinal effects of bumetanide in individuals with autism have often demonstrated success in modulating social processing.
- It is thought that bumetanide may affect neural processing by modulating E/I balance in the brain.
- By this measure (and excluding self-citations to the and last authors of their current paper), their references contained 3.8% woman/ woman(last), 3.8% man/woman, 22.6% woman/man, 69.8% man/man, and 0% unknow n categorization.
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References
67 citations
"A causal study of bumetanide on a m..." refers background in this paper
...Additionally, recent neuroimaging studies report increased neural response to emotional faces, and normalization of amygdala activation in response to eye-contact in individuals with autism following bumetanide administration [22, 44]....
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65 citations
"A causal study of bumetanide on a m..." refers background in this paper
...One recent MRS study suggests that bumetanide may, as predicted, modulate E/I balance in adults, as evidenced through changes in the GABA-Glutamate ratio in visual and insular cortex pre- relative to post- 3-months of bumetanide administration in children with autism [46]....
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64 citations
60 citations
"A causal study of bumetanide on a m..." refers background in this paper
...right eye percepts governs the strength of perceptual suppression during rivalry [36, 37]....
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...5 inhibition [31, 36, 37]....
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...The potential for sensory tasks to provide such markers is particularly high, given their suitability for translational research [56] and presence in conditions such as autism in some [57–60], although not all studies [36, 61]....
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59 citations
"A causal study of bumetanide on a m..." refers background or methods in this paper
...Further, some studies of bumetanide in humans, specifically children with autism, have shown evidence for attenuation of social symptom severity and improvement of emotion recognition [21–23], although, notably, these benefits are not universally observed [24]....
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...15 respectively, and only minor reductions in repetitive behaviors, measured by the Repetitive Behavior Scale Revised (RBS-R) [24]....
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