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
41 citations
"A causal study of bumetanide on a m..." refers background in this paper
...During development, the polarity of GABAergic action transitions from excitatory (depolarizing) to inhibitory (hyperpolarizing) 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]....
[...]
40 citations
"A causal study of bumetanide on a m..." refers background or methods or result in this paper
...See [31] for more details....
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...This finding stands in contrast to studies showing that GABAA and GABAB modulators increase perceptual suppression during rivalry [31]....
[...]
...5 inhibition [31, 36, 37]....
[...]
...Binocular rivalry replay trial stimuli were identical to those used in the main rivalry experiment, and the paradigm was identical to our previously published studies [31, 33]....
[...]
...Indeed, the effects we 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]....
[...]
39 citations
"A causal study of bumetanide on a m..." refers background in this paper
...Bumetanide, a loop diuretic, has proven hopeful in rectifying GABA polarity in valproic acid and Fragile X animal models of autism [16, 19]....
[...]
37 citations
"A causal study of bumetanide on a m..." refers methods in this paper
...We 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]....
[...]
33 citations
"A causal study of bumetanide on a m..." refers background in this paper
...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]....
[...]