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

Schizophrenia is one of the most common severe mental disorders which can seriously affect human health all over the world. The lifetime prevalence rate of schizophrenia is 7.81‰ in China, leading to serious deficiencies or loss of social functions and general life and working skills [1]. This disorder not only causes mental disability, but also brings heavy mental and economic burden of patients, families, and society. Among the causes for disability, cognitive deficit (CD) is one of the most important ones, which has a serious impact on patients’ daily life, work, and disease outcomes [2].

The cognitive impairment of patients with schizophrenia is complicated, among which working memory (WM) deficit is one of the most core and critical cognitive impairments suffered by these patients [3]. Studies have confirmed that central control components play a critical role in working memory system, which are mainly related to dorsolateral prefrontal cortex (DLPFC) function. Meanwhile, the basal ganglia and hippocampus are also involved in working memory processing [4, 5]. The abnormal functional connection between the prefrontal lobe and other working memory-relevant areas may be a vital neurological basis for the deficit of working memory in schizophrenia [6, 7]. MRI shows that the thickness of the left DLPFC cortex and the volume of gray matter decreased in schizophrenic patients [8], and the volume of gray matter decreased in the prefrontal lobe [9] was significantly correlated with the performance of working memory. In addition, diffusion-weighted imaging (DTI) reveals impaired white matter in uncinate fasciculus, the main area of frontotemporal junction in schizophrenic patients, which is significantly correlated with impaired working memory and daily function [10].

Large-scale multi-center trials have shown that cognitive deficits in schizophrenia patients can be improved by repeated intensive and targeted cognitive training, such as cognitive remediation therapy (CRT) [11, 12]. Although a mass of research has confirmed that cognitive remediation therapy and other neuropsychological trainings can significantly improve the cognitive function of schizophrenia patients, the overall effect value is about 0.4, which amounts to a moderate effect level, especially for working memory, which is the core basic cognitive deficit. The improvement effect is lower than that of general cognition, only about 0.35. The recent systematic review of the effects of cognitive training shows that the overall effect of cognitive training is 0.38 and the working memory effect is 0.29 in schizophrenia [13]. Hence, it can be seen that the clinical effect of cognitive training needs to be improved.

Numerous studies have shown that cognitive training plays a role by altering the brain structural and functional plasticity [14]. Brain structural plasticity includes improved cortical thickness [15] or increased white matter integrity [16]. And the functional plasticity includes brain functional changes [17] and cerebral blood flow [18]. So far, repetitive transcranial magnetic stimulation (rTMS) is deemed to be one of the most effective and safe non-drug methods to improve cerebral neural plasticity. It can change the activity of cortical nerve temporarily or continuously and enhance the neural plasticity. However, the recent results are inconsistent. A large sample, multi-center, randomized controlled study recently has found that rTMS at 10 Hz for three consecutive weeks can improve some aspects of cognitive performance, but there is no significant improvement compared with the Sham-stimulation group. It is suggested that the improvement of cognitive function by simple conventional rTMS is limited [19]. At the same time, the clinical conventional rTMS is relatively long-time, generally takes about 20–30 min each session, and the clinical efficiency on cognitive function is not clear, which limits its application on improving cognition of schizophrenia.

However, with regard to recent scientific literature, a newer form of rTMS called intermittent theta burst stimulation (iTBS) has been developed, which simulates burst discharges of physiological action potentials in the central nervous system by cluster stimulation. Compared with conventional rTMS, it can regulate the activity of potential regions in a shorter time and produce stronger and more lasting post-stimulation effects [20]. Theta burst stimulation (TBS), a new stimulation method based on repetitive stimulation, can better simulate the true action potential of human neurons. By regulating synaptic plasticity, TBS produces a rapid and efficient response to the human motor cortex. The major long-term forms of synaptic plasticity, referred to as long-term potentiation (LTP) and long-term depression (LTD), are induced by changes in the postsynaptic Ca2+ concentration [21]. Short bursts of iTBS stimulation, mimicking a common pattern of hippocampal pyramidal neuronal discharge, induce LTP in the hippocampus only when the stimulation is repeated at intervals less than 2 s [22]. And intermittent TBS, which denotes short trains of intermittent bursts, leads to the Ca2+ influx-related excitatory effect (through postsynaptic NMDA receptors) and produces the LTP-like effect [23]. There is less research about iTBS, a new model, compared with conventional rTMS in psychiatric disorder. A retrospective study conducted by Bakker in 2014 found that iTBS (expending 6 min) and conventional rTMS (expending 30 min) had similar effects on the dorsal prefrontal cortex [24]. In the RCT study with higher evidence intensity, Blumberger team has found that iTBS improved depression in patients with treatment-resistant depression and was not inferior to conventional 10-Hz rTMS, which was more efficient in time efficiency (4 min vs 37.5 min). Both treatments have lower shedding rates and similar side effects, with both good safety and tolerability [25].

Although rTMS improves the neuroplasticity of the brain, the improvement of cognitive function is frequently limited to some extent. It is necessary to combine other methods, such as cognitive training, to boost cognitive functions. A research about the combination of rTMS and motor rehabilitation has testified that the intervention based on improving cortical plasticity is more effective than other groups. However, a recent systematic review on the improvement of working memory in schizophrenia suggests that the combination of rTMS and working memory training (WMT) may improve the working memory ability [3].

So far, traditional cognitive training, especially working memory training, has small to medium effect on the improvement of cognitive function. Although standard rTMS can improve the neural plasticity, there are some limitations, such as inefficiency, time-consuming, and lack of strong evidence of cognition improvement. To sum up, we hypothesize that there is a joint enhancement effect of combination between iTBS and WMT, i.e., the combination training mode of “preheating (iTBS stimulation changes the activity of working memory-related brain regions) and ironning (working memory training).” At present, there is no relevant research report to explore whether and how the joint intervention will have a combined effect on improving cognitive function, especially working memory, in schizophrenic patients.

To our knowledge, this is the first study to test the efficacy of a combination of iTBS and WMT on working memory and other cognitive functions of schizophrenia using a double-blinded, randomized controlled trial design. In order to evaluate the efficacy of invention, we will use behavior outcomes (such as neuropsychological assessment) and neuroplasticity outcomes (such as brain microstructural index) combining with neuroimaging indexes. This study will provide scientific evidence for improving cognitive deficits, especially working memory deficits, and elucidate the neuroplasticity mechanism of iTBS stimulation combined with working memory training.

To our knowledge, this is the first trial aiming to solve the problem of limited overall effect and migration effect of working memory training in schizophrenia by performing professional training, which is based on changing the neuroplasticity of working memory-related brain areas through iTBS primitively.

This trial has several advantages. First, this study use iTBS stimulation, which is currently a well-evidentiary and efficient way to alter the plasticity of the brain, as a tool to regulate the functional state of brain regions before working memory training. The effects of iTBS on brain function and structural plasticity in schizophrenia were investigated by structural and functional MRI.

Second, we hypothesize that iBTS stimulation, which will be able to alter brain plasticity, will facilitate (enhance) the clinical effects of working memory training on improving cognitive function of schizophrenia? This is a key issue in the study of WMT mechanism, that is, whether the way of “preheating (iTBS stimulation activates local neuronal activity first) and then ironning (working memory training)” can make “iron better tempered” (the changes of brain function and structure are more significant). In our study, the WMT control group (iTBS+SRT) and iTBS control group (sham iTBS+WMT), were set up to compare with the study group, respectively, and to analyze the differences of brain plasticity, to explore whether the training of “preheating and then ironning” (iTBS+WMT) is superior to that of “ironning without preheating” (sham iTBS+WMT) and “ironning without preheating” (iTBS+SRT) in changing the neuroplasticity (function and structure) and to provide a scientific basis for exploring ways to enhance the neuroplasticity of the brain and improve its function.

Another advantage of this trial is to explore the migration effect, that is, whether training can improve untrained cognitive ability as well as related-cognitive processing ability, such as whether it can improve logical reasoning ability after working memory training? The training for the normal youngs suggests that working memory training alone can improve memory function and fluid intelligence, thus verifying the existence of migration effect of working memory training. However, there are few studies on whether the migration effect occurs in schizophrenia, and this study makes up for the shortcomings in this area.

This sample cannot entirely represent a population combining comorbidities with considerable treatment heterogeneity. However, we opted to the rigorous inclusion, exclusion, and dropping criteria in order to acquire fewer confusing variables and make trial more accuracy and truthfulness.

Patient recruitment is currently ongoing. This is the first version of this protocol (V1.0). If the protocol needs to be amended, we should notify firstly the sponsor and the centers. After passing the ethics committee review, a copy of the revised protocol will be sent to the managers of two centers and be added to the web for record accurately. The first patient has been enrolled on December 23, 2019, and it is expected to finish by the end of 2020. Due to the impact of COVID-19, our related researches have been severely affected, and the end time will be appropriately postponed.