Discussion
BRAIN ATROPHY, CORTEX
In this re-analysis of previously published data, we tested the influence of biological sex on tDCS-supported enhancement of cognitive control training in healthy females and males who underwent a challenging 2-week training paradigm (PASAT). For the whole study group, including all stimulation conditions (anodal, cathodal, sham), we found a larger training benefit in females compared to males over the course of the training phase. More precisely, females had consistently higher training gains compared to males when anodal tDCS (but not cathodal or sham) was applied to the prefrontal cortex during training. Consistently, the comparison of stimulation conditions within sexes demonstrated a beneficial effect of anodal over sham tDCS in females, but no such effect in males. No effects were found in either sex for cathodal over sham tDCS. Thus, our analysis indicates that the enhancement of cognitive control training by anodal tDCS is critically modulated by biological sex, with females being more susceptible for beneficial effects than males. A similar level of performance at baseline and the lack of differential effects in the sham group underline the specificity of this effect: the absence of differences in educational levels and expectation towards the task as assessed via questionnaire indicate comparable performance prerequisites in both sexes, and both groups had similar math abilities and motivation to perform well in the task.So far, the available data on the interaction between biological sex and tDCS are highly inconsistent with some studies reporting effects only in one sex while being absent, or even opposite, in the other [As diverse as the outcomes of anodal tDCS alone are, so are the results from studies focusing on cathodal tDCS. For example, some research has found excitatory effects of cathodal tDCS over the motor cortex. This effect however, was only prominent for certain current intensities. More strikingly, the magnitude, duration, and direction of these non-linear effects were dependent on stimulation intensity [It seems reasonable to assume that the sex-dependent variability in our study is at least partially explained by anatomical differences for instance in volume of cerebrospinal fluid, skull thickness, gyrus orientation, or the individual location of the dlPFC. It should be noted that the relevance of sex differences in brain architecture for cognitive functions and mental health are still under debate. Two recent analyses based on MRI data [Besides anatomical variability, variations in task-specific activation of brain networks exist and reinforce the significance of the task being conducted during the application of tDCS. Sex-specific activation patterns have been found in various cognitive tasks as well as in the processing of emotional information [More specifically, and in addition to the aforementioned differences, variability between the sexes in challenging cognitive tasks might be linked with the fact that females and males show different brain activity particularly in response to cognitive stress, which then in turn affects performance during those stressful tasks [Within our sample we found an age difference of approximately 2 years between males and females. Previous studies have shown that age seems to be related to tDCS efficacy. Supposedly, this effect can be related to brain atrophy and that the aging brain, with its accompanying changes in morphology, requires different tDCS parameters to be effective [Conclusively, structural and functional anatomy of cognitive control training likely varies between males and females. Indeed, recent studies allow the assumption that individual components of cognitive control may be altered differently in the sexes (yet without systematic advantage) and that these effects depend on the modality of testing and respective parameters [A limitation of this retrospective analysis is the unequal distribution of sexes in our sample. While the applied statistical models are robust enough to account for the numerical distribution, the smaller number of male subjects did not allow to analyse the influence of sex on stimulation intensity and laterality. Another challenge is that the hormonal states of individual subjects can influence tDCS and should therefore be monitored thoroughly: oestradiol is known to enhance cortical excitability and should be considered when excitability is modified via tDCS, while at the same time, progesterone can decrease excitability [Another aspect to consider is the question whether the observed effects are actually related to biological sex or whether they are mostly correlated to anatomical differences. However, as certain anatomical features and sex heavily correlate with each other, this is more a matter of perspective and phrasing and hence the critical interaction between sex and tDCS intervention outcomes remains.Finally, in an adult human sample effects of sex can hardly be disentangled from effects of gender and gender roles. Self-concepts and personality traits, such as neuroticism and conscientiousness, that are more expressed in females [In sum, we can conclude that research is picking up on the importance of sex differences in the neuromodulation of the human cortex. With this study we shed further light on the variable impact of tDCS on performance in a cognitive task and whether this is influenced by biological sex. Most likely, sex-related diversities are not binary but lie on a complex spectrum composed of morphological, hormonal, and neurobiological factors. Researchers should harness the knowledge on sex differences to stratify and personalise brain stimulation interventions. Especially in the light of tDCS being a viable tool for the treatment of various illnesses, it is vital to further uncover the (biological) characteristics that have a bearing on tDCS efficacy and hence contribute to the high variability we currently see in the study landscape. By doing so, personalised interventions may prove to surpass standardised paradigms soon.