To our knowledge, this is the first retrospective cohort study to investigate the efficacy and safety of MNS in patients with cognitive impairment. The results showed that MNS improved cognitive function in patients with cognitive impairment, and no adverse effects were observed with the MNS preformation.
Cognitive impairment is caused by stroke, TBI, and CO poisoning. It affects patient’s quality of life and poses a major burden to caregivers and healthcare systems. Cognitive impairment often manifests as memory loss, impaired orientation, and computational dysfunction. However, its underlying mechanism is uncertain. Many factors such as lesions on neuroanatomical structures, neuronal apoptosis, synaptic dysfunction, brain volume, and myelinated neuron reduction may cause cognitive dysfunction (10, 25). Some antidementia drugs have been shown to have positive effects on cognitive impairment (26). Cholinesterase inhibitors such as donepezil, rivastigmine, and galantamine have been approved for clinical use to treat cognitive dysfunction caused by Alzheimer’s disease (27). Following clinical trials, cholinesterase inhibitors have proven to be promising agents for treating cognitive impairment after stroke, with donepezil being the most effective. A double-blind, placebo-controlled, randomized clinical trial showed that donepezil improved cognitive function in post-stroke patients; however, the improvement in overall cognitive function was inconsistent (28). Additionally, more randomized clinical trials have shown that memantine improves cognitive function (29, 30). Studies have shown that these drugs significantly improve some cognitive domains, such as executive function; however, the uncertainty of global and daily function makes it difficult to evaluate the value of the drugs in the clinic.
Neuromodulation, both invasive and noninvasive, has been the most rapidly developed neuroscience technology in recent years. A randomized, double-blind, parallel-group study revealed that anodal transcranial direct current stimulation is a promising therapeutic option which can significantly improve cognitive performance, such as episodic memory, attention, working memory, and visuospatial skills, in patients with multiple sclerosis (31). Another controlled trial found that deep brain stimulation of the anterior thalamic nucleus may positively influence executive function, leading to better performance in verbal learning (32). Additionally, a clinical trial showed that auricular vagus nerve stimulation can improve cognitive performance and increase the overall Montreal cognitive assessment-basic (MOCA-B), N5, and N7 scores in patients with mild cognitive impairment (33). Cognitive function is an important part of consciousness, and our previous study demonstrated that vagus nerve stimulation may be an effective and safe method for promoting the recovery of consciousness (34, 35) and MNS can promote awareness recovery in TBI-induced comatose rats (17). This study revealed that MNS may be a safe and effective approach to improve the MMSE scores, ADL scores, and amplitude of P300 event-related potential, and decrease the latency of P300 event-related potential in patients with cognitive impairment. However, the mechanism of MNS-induced cognitive enhancement effect is still not fully understood.
A possible mechanism by which MNS improves cognitive function is as follows. First, the modulation of related neuroendocrine activity and neurotransmitters, such as orexin-A, norepinephrine, and glutamic acid, may be key factors in behavioral changes and abnormalities in cognition. According to our previous studies, MNS increases the expression levels of excitatory orexin-A and its receptor OX1R in the hypothalamic region of TBI rats (36), which can promote cognitive recovery (37, 38). Second, boosting cerebral blood flow may be another potential mechanism. Following MNS preformation, regional cerebral perfusion in the contralateral motor and somatosensory areas improved, and enhanced blood flow improved neural survival and promoted cognitive recovery (39). Changes in cortical excitability after stimulation may also be key factors. MNS can enhance low motor cortex excitability in patients with spinocerebellar ataxia (40).
The common complications of MNS include seizures, gastrointestinal bleeding, and increased sympathetic activity (41). In this study, we observed that the incidence of side effects in the standard treatment group was similar, and no new adverse effects were observed during the MNS period, suggesting that MNS may be a safe approach for patients with cognitive impairment.
However, this study has some limitations. First, although we did not observe a difference between the two treatment groups at baseline, this retrospective cohort study has a potential bias. For example, the treatment for which patients received MNS and the specific regimen of standard treatment were not controlled. Second, the results are less persuasive because of the small sample size and lack of more accurate evaluation criteria, such as the MOCA and auditory verbal learning test. Third, additional factors affecting cognition, such as education level, sex, age and etiology, should be considered. Therefore, a standard MNS intervention with an accurate assessment method and a larger sample size is required for future investigations.