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
96 citations
"A causal study of bumetanide on a m..." refers background in this paper
...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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95 citations
"A causal study of bumetanide on a m..." refers background in this paper
...Further, the direction of these changes was the opposite of what might be predicted if bumetanide were to increase MRS-based markers of inhibition [13]: bumetanide lowered the E/I ratio, resulting in greater excitation relative to inhibition....
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...One prominent developmental account of autism proposes a disruption of an important neurobiological milestone, known as the GABA-switch, as a potential explanation for disturbed inhibitory action in the autistic brain [13]....
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...In light of these accounts, it has been posited that augmenting GABAergic action might provide a promising therapeutic for some symptoms associated with autism [13, 18]....
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94 citations
"A causal study of bumetanide on a m..." refers background in this paper
...Rivalry is a simple visual phenomenon that is modeled to rely on the on the balance of inhibition and excitation in visual cortex [25–30]....
[...]
94 citations
"A causal study of bumetanide on a m..." refers result in this paper
...This finding is consistent with previous binocular rivalry studies which illustrate high test-retest reliability of rivalry dynamics within individuals [11, 31, 41]....
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93 citations