Globally, more than 10 million new stroke cases occur annually, of which post-stroke aphasia (PSA) accounts for about one-third (Stefaniak et al., 2020). About 21–40% of stroke patients have persistent language impairment symptoms, which seriously affect the quality of life (Cichon et al., 2021). Research has shown that aphasia is an independent predictor of functional dependence and death after stroke, which has led to aphasia, an acquired language defect, becoming a clinical problem to be solved urgently (Stefaniak et al., 2020). At present, speech-language therapy (SLT) in behavioral science is still the mainstream treatment for aphasia (Fridriksson and Hillis, 2021). High-dose and high-intensity SLT is beneficial to the functional recovery of PSA (Breitenstein et al., 2017), but when SLT is more than 2 h per day, the benefit does not increase significantly (Rehabilitation and Recovery of People with Aphasia after Stroke, 2022). In the context of limited medical resources, treatment strategies need to be reconsidered based on the existing evidence to maximize language recovery and cost-effectiveness.

The closed-loop rehabilitation is a treatment paradigm designed based on the central-peripheral-central concept, which organically combines central nervous system regulation with peripheral therapy to compensate for the limitations of simple peripheral or central intervention. In closed-loop rehabilitation that can activate functional pathways, the central intervention represented by non-invasive brain stimulation (NIBS) can promote the activation of corresponding brain functional areas and enhance neuroplasticity, and peripheral intervention represented by behavioral therapy strengthens positive feedback through continuous input of motor and sensory signals, and some scholars believe that neuroimmunology mechanisms may also be involved (Jia, 2022). Several studies provide clues to closed-loop treatment strategies that boost functional recovery in aphasia (Vines et al., 2011; Wang et al., 2014; Fridriksson et al., 2018a,b; Cichon et al., 2021; Sheppard and Sebastian, 2021). However, the combination of peripheral and central interventions requires more evidence of randomized controlled trials to support its clinical implementation.

Multi-center cross-sectional study shows that there is a positive correlation between upper limb motor function and language function in the stroke population (Xu et al., 2021), which may suggest giving priority to treatment models involving both upper limb movement and language. Melodic Intonation Therapy (MIT) can be applied to aphasia, especially non-fluent aphasia caused by ischemic damage in the left dominant hemisphere (American Academy of Neurology, 1994; Cichon et al., 2021). MIT mainly emphasizes the use of external features of speech, such as intonation, rhythm, stress, etc., to recite polysyllabic words, high-frequency phrases, long sentences, and complex sentences musically, and finally to communicate in a normal rhythm and intonation (Cichon et al., 2021). During the treatment, allow the patient to clap according to the rhythm (Haro-Martinez et al., 2019). Compared with conventional speech therapy, MIT, as a behavioral therapy, has shown its advantages in the functional recovery of spontaneous, comprehension, repetition, naming, communication, and other aspects (Kasdan and Kiran, 2018; Huang et al., 2021; Zhang X. Y. et al., 2021; Zhang X. et al., 2021; Siponkoski et al., 2023). With the onset of PSA, the earlier MIT gets involved, the more significant this advantage will be (van der Meulen et al., 2014, 2016). The researches show that MIT is an intervention that is expected to improve language ability in the long run and is effective for many language families (Cortese et al., 2015; Martzoukou et al., 2021; Zhang X. Y. et al., 2021; Zhang X. et al., 2021).

In addition, NIBS has become an important auxiliary means for the treatment of PSA. There is evidence that NIBS is effective for aphasia symptoms and augments the effect of behavioral therapy through a neural plasticity mechanism (Fridriksson and Hillis, 2021). Transcranial direct current stimulation (tDCS), as a technology in NIBS, has great potential in central regulation (Duncan et al., 2020). The results of the systematic review and meta-analysis show that the most effective intervention of tDCS in improving language function may be to stimulate the inferior frontal gyrus (IFG) of the left dominant hemisphere with the anode (Elsner et al., 2020). Its mechanism is that the tDCS anode depolarizes the neuron cell membrane, thereby enhancing cortical activity (Duncan et al., 2020; Cichon et al., 2021). It is generally believed that tDCS is a therapeutic method with minimal risk and may be one of the most promising therapeutic methods besides language training (Bikson et al., 2016).

To optimize the outcome of rehabilitation, this trial was designed to verify whether tDCS anode stimulation of left IFG combined with MIT can augment the positive effect and provide a more evidence-based basis for aphasia rehabilitation.

In this trial, tDCS, as a central stimulus, activated the left dominant hemisphere language functional area through anodic stimulation, and MIT, as a peripheral stimulus, strengthened positive feedback through continuous input of signals including motion, vision, and hearing. Together, they formed the complete closed-loop treatment system for aphasia to explore the clinical efficiency of the closed-loop scheme on functional recovery and provide a clinical reference for linguistic rehabilitation. The results of this study revealed that, immediately after the intervention, both SG and TG improved in terms of language function, while CG was not significantly. Although SG and TG had a similar effect on spontaneous and repetition, SG was inferior to TG in comprehension and naming, and the overall efficiency of TG was better than SG.

Language recovery was related to nervous system reorganization (Stefaniak et al., 2020). The review showed that the closed-loop rehabilitation system could augment the positive effect of simple peripheral or central stimulation (Jia, 2022), which was related to a previous study that concluded that peripheral intervention combined with central intervention enhanced synaptic plasticity more strongly than any individual intervention (Fritsch et al., 2010). Based on extensive activation of the cerebral cortex by tDCS, TG, combined with behavioral training, enhanced the plasticity of synapses participating in specific tasks, which would appear in the short term and continue in the long term (Fridriksson and Hillis, 2021). This result provided an effective evidence basis for the clinical application of closed-loop rehabilitation of aphasia. Spontaneous neuroplasticity, which could be affected by therapy, was the norm in the early poststroke period (Dabrowski et al., 2019). Remarkably, the mean post-stroke duration of TG is about 8 months, which was longer than the other two groups in this trial, but the therapeutic efficacy of TG was stronger. It might be another piece of evidence supporting closed-loop rehabilitation. In the future, it is necessary to continue to carry out stratified research according to the course of the disease. Additionally, although SG was superior to CG, it had limitations in integrally improving communication. 112.5 h of MIT intervention promoted language output but not comprehension (Marchina et al., 2023). Moreover, due to previous studies focusing on behavioral indicators and insufficient imaging evidence, the neurological effect of MIT on aphasia patients was still unclear (Zhang X. Y. et al., 2021; Zhang X. et al., 2021). In this study, there was also a lack of neuroimaging detection, and the potential neural recovery mechanism of closed-loop rehabilitation also needed to be further supplemented.

The results of cognitive function analysis in this study showed that both SG and TG significantly improved after intervention, but CG was not. Moreover, the post hoc test supported the result that TG had the most significant effect on promoting cognitive function. The above results had a similar development tendency with the analysis of language function. Cognition is the general term for the process of recognizing and understanding objects, which belongs to the high-level activities of the cerebral cortex and interacts with language function (Norris et al., 2016; Ardila and Rubio-Bruno, 2018). Some studies had shown that the cognitive level of patients with aphasia after stroke was lower than that of non-aphasic patients, and there was a positive correlation between cognition and language (Fonseca et al., 2019; Yan et al., 2022b). These explained the experimental results and provided evidence for cognition-language integration intervention, which might be further explored in future research.

In language processing, language-related gestures might promote language performance (Grechuta et al., 2019). In our study, we found that although motor function improved in all three groups after treatment, SG and TG showed differences from CG in FMA and FMA-UE. In addition, a positive correlation between language and upper limb motor function was also found in the cross-sectional study (Xu et al., 2021). These suggested that the behavioral therapy paradigm in this trial might also facilitate motor function recovery, especially in the upper limbs, which needed to be verified by larger studies in the future.

The reason why the difference of BI was not statistically different among the three groups might be the lack of language components in BI, and the closed-loop rehabilitation program designed in this study mainly aimed at promoting the recovery of language function. In addition, the ability of daily living reflected by BI could be affected by other non-language factors, such as motor function, auxiliary appliance application, functional compensation, etc.

MIT combined with tDCS or sham stimulation is effective for patients with PSA, but the conventional treatment cannot significantly improve aphasia in the short term. Compared with sham stimulation, the closed-loop rehabilitation scheme combining MIT and tDCS can augment the positive effect on language and cognitive recovery in PSA and deserves promotion in clinical practice.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Third Affiliated Hospital of Xinxiang Medical University. The patients/participants provided their written informed consent to participate in this study.

ZY and JJ conceived and designed the analysis and writing – original draft. ZY, XH, MC, XF, and DW collected the data. ZY, XH, MC, XF, DW, SX, CL, XL, HX, and JJ contributed data or analysis tools, writing – review and editing, and discussed the results. ZY and XH performed the analysis. All authors contributed to the article and approved the submitted version.

This work was supported by the National Key R&D Program of China (2018YFC2002300), the National Natural Innovation Research Group Project of China (82021002), and the National Natural Major Research Program Integration Project of China (91948302).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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