Sex matters for the enhancement of cognitive training with transcranial direct current stimulation (tDCS)

BackgroundTranscranial direct current stimulation (tDCS) can influence brain network activity and associated cognitive and behavioural functions. In addition to the extensive variety in stimulation parameters, numerous biological factors drive these effects, however these are yet poorly understood. Here, we investigate one of the major biological factors by focusing on sex-dependent effects of tDCS on a challenging cognitive control task (adaptive paced auditory serial addition task [PASAT]) in healthy humans.MethodsThis sex-specific re-analysis was performed on data of 163 subjects who underwent a 2-week cognitive control training (6 sessions in total). Subjects received either verum (anodal/cathodal) or sham tDCS. Electrodes were placed over the left or right dorsolateral prefrontal cortex and the respective contralateral deltoid muscle. Cognitive control was measured as performance in the PASAT and was analysed in respect to stimulation conditions (sham, anodal, cathodal) and sex.ResultsRegardless of stimulation condition, performance gains between the sexes were higher in females compared to males (p = 0.0038). Female's performance during anodal tDCS exceeded male's (p = 0.0070), yet no effects were found for cathodal or sham tDCS. Moreover, in females we found a superior effect for anodal tDCS over sham stimulation (fanodal: p = 0.0354; fcathodal: p = 0.6181), but no such effect in males (manodal: p = 0.6882; mcathodal: p = 0.4822).ConclusionsThis study highlights the relevance of biological sex for the effects of tDCS on cognitive training. Thus, an increased attention to biological sex is advisable in future brain stimulation research to highlight and in consequence better understand potentially underlying sex-specific mechanisms. Considering biological sex will further advance customisation and individualisation of tDCS interventions.Trial registration ClinicalTrials.gov, NCT04108663.ConclusionsThis study highlights the relevance of biological sex for the effects of tDCS on cognitive training. Thus, an increased attention to biological sex is advisable in future brain stimulation research to highlight and in consequence better understand potentially underlying sex-specific mechanisms. Considering biological sex will further advance customisation and individualisation of tDCS interventions.Trial registration ClinicalTrials.gov, NCT04108663. This study provides evidence that tDCS affects females and males differently: females, compared to males, show higher performance gains in a demanding cognitive control task when tDCS is applied concurrently to the task.The performance altering effects of tDCS in females were observable for anodal, yet not cathodal stimulation. In males, we did not detect any differences in performance, suggesting that tDCS affects females and males differently and that sex-specific customisation can prove to enhance stimulation efficacy even further.Our study highlights that biological sex needs to be taken into account in order to further personalise and optimise the application of tDCS in humans. In previous studies, brain stimulation techniques like transcranial direct current stimulation (tDCS) have been shown to support cognitive trainings. However, these effects are rather small and vary between people. A key factor of variability is the biological sex. Hence, in this study we were interested in whether the effects of tDCS differ between females and males. To answer this research question, we analysed the data of 163 human subjects who underwent a 2-week cognitive control training program, which incorporates a challenging cognitive task (the adaptive paced auditory serial addition task [PASAT]). During the PASAT, subjects have to solve a stressful calculation exercise. Concurrently to solving this task, the subjects received either real (further divided into anodal [= enhancing] and cathodal [= inhibiting]) or placebo tDCS. We found that females had greater performance gains in the task than males, regardless of the type of tDCS they received. Furthermore, females performed particularly well when they received anodal tDCS, but there were no significant effects for cathodal or placebo tDCS. For males, we did not find any significant benefits of tDCS. These findings highlight the importance of considering biological sex in future brain stimulation research and suggest that biological sex is an important component to consider when studying the effects of tDCS. By paying more attention to this factor, researchers can better understand how tDCS works and develop more effective and personalised interventions.