Intermittent theta burst stimulation (iTBS) combined with working memory training to improve cognitive function in schizophrenia: study protocol for a randomized controlled trial

BACKGROUND: Working memory deficit is one of the most critical complex cognitive impairments in schizophrenia. Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy, but not still unsatisfactory. Intermittent theta burst stimulation (iTBS), which has recently been used in clinical practice, may have faster and stronger effects comparing the traditional model (10-Hz high-frequency rTMS). A large number of studies have showed that rTMS, especially iTBS, can enhance the neural plasticity of the brain, and cognitive training can improve the cognitive function of schizophrenia. Is there any facilitation effect of iTBS add on cognitive training (such as working memory training, WMT) on cognitive function enhancement in schizophrenia is still unknown. METHODS/DESIGN: The proposed study is designed of a double-center, double-blinded, randomized controlled trial that will include 200 schizophrenia patients between 18 and 45 years of age. The patients will be randomized to four groups, i.e., the study group (iTBS+WMT), WMS control group (iTBS+ Simple Response Training (SRT)), iTBS control group (sham iTBS+WMT), and placebo control (sham iTBS+SRT). The patients will receive 3 min 20 s of real or sham stimulation, followed by a short 1–2-min rest and 40 min of WMT training or SRT immediately. Neuropsychological and clinical symptom assessments, with functional and structural MRI, will be performed on baseline, post-treatment, and 3- and 6-month follow-up periods. The primary outcome is cognitive function measured by the MATRICS Consensus Cognitive Battery (MCCB). The secondary outcomes are changes in neuroplasticity, as measured by MRI and other behavioral assessments. DISCUSSION: The aim of our study is to explore the facilitation effects of iTBS added on WMT in improving cognitive function of schizophrenia. That means, patients with schizophrenia will benefit more in cognitive function improvement from the combination training mode of “preheating (iTBS stimulation changes the neural activity of working memory-related brain regions) and ironning (working memory training).” And the long-term effects of this combined training model will be assessed at a 6-month follow-up period. In case of a significant improvement of working memory with a prolonged effect, the iTBS combined with WMT protocol could be considered as a first-line clinical protocol in schizophrenia treatment. More broadly, the potential for increased universality and efficiency of rTMS with the iTBS model to enhance the neural plasticity of the brain should have a more positive effect on cognitive function in schizophrenia. TRIAL REGISTRATION: chictr.org.cn ChiCTR1900023405. Registered on 25 May 2019