The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert beneficial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. We performed a monocenter, single-blind randomized, placebo-controlled trial comparing cognitive training to concurrent anodal tDCS (target intervention) with cognitive training to concurrent sham tDCS (control intervention), registered at ClinicalTrial.gov (Identifier NCT03838211). The primary outcome (performance in trained task) and secondary behavioral outcomes (performance on transfer tasks) were reported elsewhere. Here, underlying mechanisms were addressed by pre-specified analyses of multimodal magnetic resonance imaging before and after a three-week executive function training with prefrontal anodal tDCS in 48 older adults. Results demonstrate that training combined with active tDCS modulated prefrontal white matter microstructure which predicted individual transfer task performance gain. Training-plus-tDCS also resulted in microstructural grey matter alterations at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.

The combination of repeated behavioral training with transcranial direct current stimulation (tDCS) holds promise to exert benefial effects on brain function beyond the trained task. However, little is known about the underlying mechanisms. This was adressed by multimodal magnetic resonance imaging (MRI) before and after a three-week executive function training with prefrontal excitatory tDCS in 48 older adults. Results demonstrate that training combined with active tDCS enhanced prefrontal white matter microstructure which predicted individual performance gain. Training-plus-tDCS also resulted in microstructural grey matter reductions at the stimulation site, and increased prefrontal functional connectivity. We provide insight into the mechanisms underlying neuromodulatory interventions, suggesting tDCS-induced changes in fiber organization and myelin formation, glia-related and synaptic processes in the target region, and synchronization within targeted functional networks. These findings advance the mechanistic understanding of neural tDCS effects, thereby contributing to more targeted neural network modulation in future experimental and translation tDCS applications.

IntroductionBreast cancer is the most common form of cancer in women. A considerable number of women with breast cancer who have been treated with chemotherapy, subsequently develop neurological symptoms such as concentration and memory difficulties (also known as ‘chemobrain’). Currently, there are no validated therapeutic approaches available to treat these symptoms. Cognitive training holds the potential to counteract cognitive impairment. Combining cognitive training with concurrent transcranial direct current stimulation (tDCS) could enhance and maintain the effects of this training, potentially providing a new approach to treat post-chemotherapy cognitive impairment (PCCI). With this study, we aim to investigate the effects of multi-session tDCS over the left dorsolateral prefrontal cortex in combination with cognitive training on cognition and quality of life in women with PCCI.Methods and analysisThe Neuromod-PCCI trial is a monocentric, randomized, double-blind, placebo-controlled study. Fifty-two women with PCCI after breast cancer therapy will receive a 3-week tDCS-assisted cognitive training with anodal tDCS over the left dorsolateral prefrontal cortex (target intervention), compared to cognitive training plus sham tDCS (control intervention). Cognitive training will consist of a letter updating task. Primary outcome will be the performance in an untrained task (n-back task) after training. In addition, feasibility, safety and tolerability, as well as quality of life and performance in additional untrained tasks will be investigated. A follow-up visit will be performed one month after intervention to assess possible long-term effects. In an exploratory approach, structural and functional magnetic resonance imaging (MRI) will be acquired before the intervention and at post-intervention to identify possible neural predictors for successful intervention.Ethics and disseminationEthical approval was granted by the ethics committee of the University Medicine Greifswald (BB236/20). Results will be available through publications in peer-reviewed journals and presentations at national and international conferences.Trial registrationThis trial was prospectively registered at ClinicalTrials.gov (Identifier: NCT04817566, registered March 26, 2021).Strength and limitations of this study–This is the first randomized controlled trial to investigate the feasibility and effects of combined cognitive training and tDCS on cognitive outcomes and quality of life in patients with post-chemotherapy cognitive impairment–Results will help the development of treatment options for breast cancer patients with post-chemotherapy cognitive impairment–Results may not be generalizable to male cancer patients–Monocentric trial design may increase risk of bias

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