Balance is one of the most a critical function that supports the normal activities of daily life in humans. Maintaining balance requires a complex integration and coordination of multiple systems (such as the vestibular system, visual system and auditory system) in the body (Ataullah and Naqvi, 2021). The cerebellum is strongly involved in the integration process associated with balance in the central nervous system (CNS) (Nashef et al., 2019), as demonstrated by previous functional magnetic resonance imaging studies and clinical trials (Maurer et al., 2016; Esterman et al., 2017). According to the functional divisions of the cerebellum, the three functional areas include the cerebrocerebellum, the spinocerebellum and the vestibulocerebellum. These three functional areas all play a vital role in the process of maintaining balance and motor control. In the spinocerebellum, the cerebellar vermis plays a key role in balance and motor control. Recent evidence suggests that the cerebellar vermis is critical for maintaining equilibrium and coordinating speech, eye and body movement because the vermis provides information regarding sensations along the extremities, as well as the different stimuli that pertain to balance, visual and auditory processes (Fujita et al., 2020). In addition, the cerebellar vermis participates in anticipatory postural adjustment and compensatory postural adjustment to maintain balance during functional activities (Richard et al., 2017). Study has displayed patients with lesions in the vermis mainly exhibit balance dysfunction (Harris et al., 2018), while patients with lesions in the cerebellar hemispheres mainly exhibit global coordination dysfunction (Carass et al., 2018; Maas et al., 2020).

Except for the important role of cerebellum in balance, cerebral cortex is also involved. Previous studies illustrated that the supplementary motor area (SMA) and the dorsal lateral prefrontal cortex (DLPFC) are crucial during balance tasks (Richard et al., 2017; Harris et al., 2018; Fernandez et al., 2020). Richard et al. (2017) pointed out that the SMA plays an important role in the initiation of gait and the initiation of standing on one leg, which is related to maintaining stability during change of posture. Other studies have also confirmed the results obtained by Richard et al. (Mihara et al., 2012; Dale et al., 2019). Moreover, the increase in HbO₂ related to postural disturbance in the contralesional SMA is significantly correlated with the increase in balance function measured by the Berg balance scale, and the postural disturbance-related changes in HbO₂ signals in the bilateral SMA in stroke patients are positively correlated (Fujimoto et al., 2014). Studies also demonstrated that increased HbO₂ was positively correlated with cortical excitability and functional improvement (Liu et al., 2018; Kinoshita et al., 2019). In addition, studies have demonstrated that intercortical connections exist between the DLPFC and primary motor cortex (M1). The connections from the DLPFC to the M1 transfer crucial information for the execution of motor output (Cao et al., 2018). The results from Teo et al. (2018) highlighted the involvement of the DLPFC in maintaining postural control. Study also demonstrated that the prefrontal cortex (PFC) and temporal-parietal regions were engaged during active balancing process, which was thought to be involved with allocation of attentional demands in standing postural control (Mihara et al., 2008). The non-invasive brain stimulation (NIBS) was applied to the DLPFC in patients with Parkinson’s disease and balance dysfunction, and balance function improved after intervention (Lattari et al., 2017). The results of a fNIRS study demonstrate that after external disturbances in healthy subjects, the bilateral DLPFC undergoes significant activation, which also indicates that the DLPFC also participates in maintaining balance (Mihara et al., 2012).

In current understandings, the process of maintaining balance involves the close cooperation between cerebellum and the cerebral. Some studies have established a strong anatomical and functional connections between cerebellum and M1 cortex through cerebellar-thalamus-M1 circuit (Coffman et al., 2011; Maurer et al., 2016). It is well worthy noted that previous study showed that the cerebellar vermis is a target of extensive projections from motor areas of cerebral cortex, which are involved in the regulation of whole-body posture and locomotion (Coffman et al., 2011). Additionally, anatomical experiment on monkey brains have shown that some cortical regions, especially the prefrontal cortex, receive projections from the cerebellum (Dale et al., 2019). Furthermore, Cho et al. (2012) pointed that the cerebellum connects not only to the M1 area and SMA but also to the DLPFC.

In recent years, NIBS of the cerebellum has also been a research hotspot (Benussi et al., 2020). There are a number of NIBS studies on the cerebellar hemisphere; however, studies of cerebellar vermis are relatively rare. Intermittent theta burst stimulation (iTBS), a type of repetitive transcranial magnetic stimulation (rTMS), which serves as a NIBS method, has been proved to have the positive effects on neuroplasticity and central nervous system excitability (Cotoi et al., 2019; Katagiri et al., 2020). It exhibits long lasting effects compared with traditional TMS with shorter stimulation period than traditional TMS (Kim et al., 2015; Hurtado-Puerto et al., 2020). Studies also demonstrated that iTBS can also modulate corticospinal excitability (Li et al., 2020). It is well known that regional hemodynamic responses are associated with cortical brain activation (Kinoshita et al., 2019). Recently, the use of fNIRS has become more widespread because the fNIRS system provides cortical brain activation information by measuring hemodynamic changes non-invasively (Kinoshita et al., 2019). Moreover, the cortical neural activity results obtained from fNIRS were similar to that from functional MRI (fMRI). The fNIRS is a useful tool that has been applied to record brain activation during balance tasks in previous study (Hoppes et al., 2020). Previous works by our research group have demonstrated that iTBS of the cerebellar hemisphere could improve balance and gait in patients with cerebral stroke. However, no significant changes in cortical excitability were observed (Liao et al., 2021).

Based on the extensive studies examining the relationship between cerebellum and cortex during balance tasks with the help of fNIRS, herein this study aimed to use fNIRS to explore the changes in cortical activation in the cerebral cortex (SMA and DLPFC) after iTBS of the cerebellar vermis during balance tasks. We hypothesized that activation of the SMA and DLPFC regions may increase after iTBS stimulation compared to baseline.

All subjects tolerated the trial, with no adverse events (Table 1). Mean HbO₂ significantly increased in channels S12-D14 (P = 0.043, Z = 2.028) and S15-D15 (P = 0.029, t = 2.849) at T2 compared with T1 (Table 2 and Figure 4). There was no difference in any channel in the DLPFC (P > 0.05) (Table 2 and Figure 4). In addition, we also found that the mean changes in HbO₂ in the bilateral brain region before and after stimulation were obvious through the distribution map of mean HbO₂ (Figure 5).

In this study, we found that single-session iTBS of the cerebellar vermis could increase the concentration of HbO₂ in the SMA region during the balance task, but no significant increase was found in the DLPFC.

After a single-session of iTBS on cerebellar vermis, the increments of HbO2 in the SMA region indicated an excitability increase in the SMA cortex. This result indicates a potential connection between the cerebellar vermis and the SMA, which is consistent with previous studies (Coffman et al., 2011; Franca et al., 2018). Animal study has demonstrated that cortical motor areas are a source of input to the cerebellar vermis, especially lobules VB–VIIIB (Coffman et al., 2011). One of these areas is the SMA. In our study, it was interesting that the excitability of the bilateral SMA increased during the balance task after iTBS on cerebellar vermis, which may indicate that the cerebellar vermis and bilateral SMA are involved in neuromotor control and balance processes. A study conducted by Fujimoto et al. (2014) showed that increased cortical excitability in the bilateral SMA regions was positively correlated with improved balance function (Fujimoto et al., 2014), some other studies obtained the same results (Kinoshita et al., 2019). Therefore, the cerebellar vermis may be a new target for iTBS stimulation to influence balance function and postural control in humans, but more formal studies are needed to prove this hypothesis.

In this study, we found no significant changes in HbO₂ in the DLPFC. However, previous studies have demonstrated that the DLPFC is also involved in postural control (Taube et al., 2015), coordinating with the cerebellar vermis (Farzan et al., 2016). Furthermore, the DLPFC participates in planning actions by providing flexibility among already acquired solutions (Torriero et al., 2007). Early results indicated that, in addition to the long-established role of the cerebellum in motor coordination, the cerebellum appears to be involved in the central integration of cognition and emotion (Demirtas-Tatlidede et al., 2011; Cho et al., 2012). The connection between the cerebellum and the contralateral motor cortex is close and important. In addition to the M1 area, the cerebellum also projects to the DLPFC (Maas et al., 2020). Our study result is inconsistent with the results of previous studies (Mihara et al., 2012). A possible explanation for this result might derived from the small sample size. The balance task is very simple, which does not involve much cognitive function or motor integration, may be another possible explanation (Torriero et al., 2007). Moreover, the DLPFC, along with its association connections, constitutes a potential cortical network for visual reaching (Johnson et al., 1996). However, in our study, subjects were required to open their eyes while standing on a single leg to maintain balance, which may account for the lack of significant differences in the data.

We already know that these inter-connections between cerebellum and cerebral tissue are mainly bundles of white matter fibers with the following connective pathways: the cortico-ponto-cerebellar pathway and cerebello-thalamo-cortical (CTC) pathway (Iwata and Ugawa, 2005; Opie and Semmler, 2020). These neural pathways are functionally involved in motor coordination and cognitive functions (Bonnì et al., 2014). Moreover, previous studies have demonstrated that fibers from the cerebellar hemispheres could project to the contralateral cerebral cortex (Tramontano et al., 2020; Solanki et al., 2021). In addition, in right-handed individuals, the connection between the right cerebellum and the left M1 is usually stronger than that of the contralateral network (Schlerf et al., 2015). This implicates that we can explore the differences in cortical excitatory activation on both sides in future studies.

In the studies we reviewed, NIBS of the cerebellar vermis could be traced back to 1995. Hashimoto et al. used TMS on cerebellar vermis of humans to explore the relationship between the cerebellar vermis and eye saccades (Hashimoto and Ohtsuka, 1995). The results of their study demonstrated that the posterior medial cerebellum in humans is involved in controlling the accuracy of visually guided saccades. Since then, due to neurophysiology of the connections between the cerebellum and different cortical layers of the cerebral cortex drew much attention, studies of NIBS of the cerebellum have gradually increased in different fields. For balance function and postural control in males, Cha YH indicated that cTBS on occipital cortex or the cerebellar vermis could effectively reduce the wobbling vertigo of Mal de Debarquement syndrome and may yield long-term benefits for patients (Cha et al., 2019). In 2020, a feasibility study found an association between cerebellar lobular mean electric field strength and changes in quantitative gait parameters after a single cerebellar transcranial direct-current stimulation (tDCS) session in chronic stroke patients (Kumari et al., 2020). In addition, the cerebellar vermis is involved in directing the postural response to a vestibular perturbation, which supports our hypothesis that the cerebellar vermis could be a target of NIBS to affect balance function and walking. Additionally, a study demonstrated that cTBS stimulating cerebellar vermis could lead to a significant influence on balance function as body sway increases (Colnaghi et al., 2017). For other effects on humans, Sasegbon et al. (2021) found that TMS on cerebellar vermis has an inhibitory effect on pharyngeal cortical activity and swallowing. Moreover, Argyropoulos et al. (2011) demonstrated that TBS of the right neocerebellar vermis can selectively disrupt the practice-induced acceleration of lexical decisions. As pointed out in neurophysiological research, the cerebellar vermis may be involved in the regulation of a series of non-physical functions (Van Overwalle et al., 2020). iTBS of the cerebellar vermis could result in the negative symptoms of schizophrenia patients. Similarly, non-invasive brain stimulation of the cerebellar vermis can also relieve symptoms of depression (Escelsior et al., 2019).

Regarding the coils we used, previous studies presented mostly used a figure-8 coil for iTBS (Franca et al., 2018). However, the latest research recommends a double-cone coil (Spampinato et al., 2020) because the use of a double-cone coil can achieve deeper stimulation effects in the cerebellar vermis. The safety of the double-cone coil in iTBS is guaranteed (Spampinato et al., 2020). In summary, stimulation of the cerebellar vermis with iTBS can increase the cortical excitability of the bilateral SMA, but the changes in the DLPFC are not significant and still need further exploration in formal studies.

There are some limitations of our pilot study. Firstly, the major limitation of our study is that we did not used behavioral assessments to prove whether iTBS could improve balance function. However, more behavioral assessments will be performed in our future formal studies to determine whether iTBS of the cerebellar vermis could improve balance function. Second, the study had a small sample size and was limited to healthy volunteers, and a larger sample size is needed in future studies. The focus of future trials should be the inclusion of more patients. Third, our trial did not use navigational equipment, which may have reduced the accuracy of iTBS processes. In future studies, we will include navigational devices in experiments to improve the accuracy of iTBS on cerebellar vermis. Besides, the statistical tests in our study were not Bonferroni-corrected, which may increase the probability of type I error. Furthermore, we used only a single-session of iTBS of the cerebellar vermis in this study, and the long-term effects of iTBS of the cerebellar vermis will be explored in formal experiments in the future.

In this study, we found that a single-session iTBS of the cerebellar vermis in healthy adults can increase the excitability of the cerebral cortex in the bilateral SMA during the balance tasks. Therefore, the iTBS on the cerebellar vermis may be a potentially effective intervention for improving balance function for the stroke patients with balance disorders.

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

The studies involving human participants were reviewed and approved by Institutional Review Board of West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study.

H-XT and Q-CW devised the project under the supervision of QG and drafted the manuscript. YC, Y-JX, Q-FG, and LH conducted the data collection and data analysis. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

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.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.