Citation: Hamel, R.; Oyler, R.; Harms, E.; Bailey, R.; Rendeiro, C.; Jenkinson, N. Dietary Cocoa Flavanols Do Not Alter Brain Excitability in Young Healthy Adults. Nutrients 2024, 16, 969. https://doi.org/10.3390/ nu16070969 Academic Editor: Abdelouahed Khalil Received: 21 February 2024 Revised: 21 March 2024 Accepted: 26 March 2024 Published: 27 March 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). nutrients Article Dietary Cocoa Flavanols Do Not Alter Brain Excitability in Young Healthy Adults Raphael Hamel 1,2, *, Rebecca Oyler 1 , Evie Harms 1 , Rosamond Bailey 1 , Catarina Rendeiro 1,2 and Ned Jenkinson 1,2 1 School of Sports, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham B15 2TT, UK 2 Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham B15 2TT, UK * Correspondence: r.hamel@bham.ac.uk Abstract: The ingestion of dietary cocoa flavanols acutely alters functions of the cerebral endothelium, but whether the effects of flavanols permeate beyond this to alter other brain functions remains unclear. Based on converging evidence, this work tested the hypothesis that cocoa flavanols would alter brain excitability in young healthy adults. In a randomised, cross-over, double-blinded, placebo- controlled design, transcranial magnetic stimulation was used to assess corticospinal and intracortical excitability before as well as 1 and 2 h post-ingestion of a beverage containing either high (695 mg flavanols, 150 mg (−)-epicatechin) or low levels (5 mg flavanols, 0 mg (−)-epicatechin) of cocoa flavanols. In addition to this acute intervention, the effects of a short-term chronic intervention where the same cocoa flavanol doses were ingested once a day for 5 consecutive days were also investigated. For both the acute and chronic interventions, the results revealed no robust alteration in corticospinal or intracortical excitability. One possibility is that cocoa flavanols yield no net effect on brain excitability, but predominantly alter functions of the cerebral endothelium in young healthy adults. Future studies should increase intervention durations to maximize the acute and chronic accumulation of flavanols in the brain, and further investigate if cocoa flavanols would be more effective at altering brain excitability in older adults and clinical populations than in younger adults. Keywords: cocoa flavanols; paired-pulse transcranial magnetic stimulation (ppTMS); brain excitability; corticospinal excitability (CSE); corticospinal silent period (CSP); short intracortical facilitation (SICF); short intracortical inhibition (SICI); intracortical facilitation (ICF); long intracortical inhibition (LICI) 1. Introduction Observational studies suggest that a high intake of dietary flavonoids results in im- proved cognitive evolution later in life [1–4]. In addition to their capacity to alleviate neuroinflammation [5,6], flavonoids have also been suggested to enhance cognition by improving the regulation of blood flow to the brain [7–11]. Namely, in healthy adults, the ingestion of a single dose of cocoa flavanols acutely improves cognitive performance at counting backwards in steps of three [12], as well as at visually identifying target items [13] and motion direction [14] (see [15,16] for meta-analyses). Further work has associated these cognitive enhancements with the capacity of cocoa flavanols to acutely increase cortical blood perfusion [7,11], cortical oxygenation [8,9], and neurovascular coupling [10], suggesting that flavanols improve cognitive performance through their vascular effects. Interestingly, converging lines of evidence now suggest that cocoa flavanols also alter brain excitability (see below), implying that the effects of flavanols permeate beyond the cerebral endothelium. This possibility is compelling and important to address, as it could reveal novel mechanisms by which flavanols alter brain health and cognition. The overarching objective of this study was to examine whether cocoa flavanols alter brain excitability, which is supported by at least two possibilities. A first possibility is that cocoa flavanols cross the brain–blood barrier (BBB) and di- rectly alter brain excitability. Namely, extensive in vitro and vivo animal work shows that Nutrients 2024, 16, 969. https://doi.org/10.3390/nu16070969 https://www.mdpi.com/journal/nutrients