Neuromodulation through brain stimulation-assisted cognitive training in patients with post-chemotherapy cognitive impairment (Neuromod-PCCI): an explorative proof-of-concept randomized sham-controlled double-blind feasibility phase II trial

随着新的治疗方案的发展，乳腺癌患者的长期存活率正在增加。然而，这些患者中有50- 60%经历化疗后认知障碍（PCCI），也被称为“化疗脑”。PCCI可以持续多年，发生在不同的认知领域，如执行功能、记忆、处理速度和注意力。神经系统后遗症，如PCCI，是神经毒性化疗后癌症幸存者的主要健康负担，也具有重要的社会经济影响。因此，我们迫切需要探索临床相关的、创新的、有效的新治疗策略，以开发靶向神经康复治疗来逆转PCCI，提高患者的生活质量。目前尚无循证治疗方案，但初步研究发现，认知训练（CT）可能改善PCCI患者的认知能力。此外，非侵入性脑刺激（NIBS）是一种提高训练效果的方法，可以缩短训练时间，诱导向未训练功能的转移，并具有长期效果。经颅直流电刺激（tDCS）是应用最广泛的NIBS技术，它与CT相结合的结果令人鼓舞，不仅可以改善健康老年人的认知能力，还可以改善痴呆或轻度认知障碍患者的认知能力。该技术尚未在PCCI患者中进行检验。我们将在一项双盲随机对照II期临床试验中评估工作记忆功能多期CT联合tdcs干预是否可行，并对PCCI患者产生实质性的长期益处和转移效应。所有患者将在9次训练中完成CT，同时在左背外侧前额叶皮层上进行高清晰度的淋巴结tDCS。一半的样本将在进行CT时接受阳极tDCS，而另一半将在训练期间接受假刺激。干预将持续三周，每周进行三次培训。因此，本试验旨在评估使用tDCS治疗方案作为CT增强来改善认知功能的干预的可行性和有效性（概念验证）。具体目的是：(1)评估干预对PCCI患者的可行性；(2)收集首次疗效数据，通过直接训练效果进行操作，转移到非训练领域，以及在多个时间点对认知和生活质量的长期影响。关于可行性和行为结果，本研究的目的是(3)为未来的验证性随机对照试验（RCT）提供规划和指导方案制定（包括功率分析），以确定ct + tdcs在提高PCCI患者认知功能方面的疗效。

With the development of new treatment options, long-term survival rates of breast cancer patients are increasing. However, 50-60 % of these patients experience post-chemotherapy cognitive impairment (PCCI), also referred to as “chemobrain”. PCCI can persist for many years and occurs in various cognitive domains, such as executive functions, memory, processing speed, and attention. Neurological sequelae such as PCCI present a major health burden for cancer survivors following a neurotoxic chemotherapy, and also have important socioeconomic impact. Thus, we are faced with the pressing need to explore clinically relevant, innovative and effective new treatment strategies with the long-range aim of developing targeted neuro-rehabilitative therapy which can reverse PCCI and improve quality of life of the patients. No evidence-based treatment options are available, but first studies have found preliminary evidence that cognitive training (CT) may improve cognitive abilities of patients with PCCI. In addition, non-invasive brain stimulation (NIBS), an approach to boost training gains, allows for shorter training periods, induction of transfer to untrained functions, and long-term effects. Promising results of combining transcranial direct current stimulation (tDCS), the most widely used NIBS technique, with CT, have shown benefit for improving cognitive performance in healthy aging, but also in patients with dementia or mild cognitive impairment. This technique has not yet been examined in patients with PCCI. We will assess in a double-blind randomized controlled phase II clinical trial if a combined multi-session CT of working memory functions-plus-tDCS intervention is feasible and yields substantial long-term benefits and transfer effects in patients with PCCI. All patients will complete CT over nine training sessions with concurrent high-definition anodal tDCS over left dorsolateral prefrontal cortex. Half of the sample will receive anodal tDCS while performing the CT, whereas the other half will undergo sham stimulation during training. The intervention will span three weeks, with three training sessions per week. The present trial thus aims to assess the feasibility and efficacy (proof-of-concept) of an intervention for improving cognitive function using a tDCS treatment protocol as augmentation to CT. Specific aims are to (1) assess feasibility of the intervention for patients with PCCI, (2) collect first efficacy data, operationalized by direct training effects, transfer to untrained domains, and long-term effects on cognition and quality of life at multiple time points. With regard to both feasibility and behavioral outcomes, the purpose of the present study is to (3) inform planning and guide protocol development (including power analysis) in relation to future, confirmatory randomized controlled trials (RCT) on the efficacy of CT-plus-tDCS in increasing cognitive functions in patients with PCCI.