Four pairs of nuclei (fastigial nuclei, emboliform nuclei, globose nuclei and the dentate nuclei) exist in the cerebellum. The cerebellar fastigial nucleus (FNS) is located at the top of the fourth ventricle. According to one MRI study, the FN is approximately 3 × 3 × 3 mm in size (in width, height and length, respectively) (Dimitrova et al., 2002). The FN is well known for its essential role in motor control and the non-motor system (Al-Afif et al., 2019; Zhang X. Y. et al., 2016). It carries out extensive projections to many motor structures, which control the body’s movement by projecting to the reticular structure of the medulla oblongata/brainstem and the primary motor cortex (MC). Eye movement, for example, is governed by the projection of the cranial nucleus in the brainstem. The FN also regulates the cardiovascular system by sending projection fibers to the solitary tract and the paramedian reticular nucleus. In the 1990s, a study discovered a fastigial pressor response (FPR) in cats, whereby the arterial pressure was observed to increase upon stimulation of the FN (Miura and Reis, 1969).

Electrical stimulation of the cerebellar FNS has been proven to improve brain cortical blood perfusion effectively (Golanov and Reis, 1996). It is also effective against cerebral ischemia. Cerebral ischemia can evoke an inflammatory response and secondary brain injury. Researchers found that FNS contributes to decreased infarction volumes, elicits suppression of periinfarction depolarizing waves, promoting axonal regeneration, and inhibiting inflammatory response (Golanov and Reis, 1999; Wang et al., 2019; Xia et al., 2019). Xia et al. (2019) observed that FNS treatment could affect the expression of some inflammatory factors such as caspase-1 and interleukin 1β, besides inhibiting cell apoptosis and promoting neuronal repair and regeneration (Wang et al., 2019). Several basic animal experiments have proven that FNS is involved in regulating activity in other brain regions and modulate vascular activity (Zhang C. et al., 2016; Golanov et al., 2017; Gao et al., 2018). However, clinical applications of this treatment are relatively few, and relevant clinical treatment evidence are still lacking.

Functional imaging technology can be applied to detect brain metabolism, cerebral blood flow (CBF) and other indicators to determine the level of cerebral cortex activity, thus providing a clear image of a person’s state of brain function. Traditional functional imaging methods include functional magnetic resonance imaging (fMRI) (Buxton, 2013) and positron emission tomography (PET) (Hooker and Carson, 2019). Nevertheless, these techniques cannot provide dynamic observation of brain function changes during electrical stimulation. Recently, functional near-infrared spectroscopy (fNIRS) has been widely used in the evaluation of brain function because of its portability, repeatability, and for being non-radiation. fNIRS is a hemodynamics-based neuroimaging technique that provides a non-invasive method for the detection of relative changes in cerebral oxygenated hemoglobin (ΔHBO) at the cortical surface (Lloyd-Fox et al., 2010; Obrig, 2014; Scholkmann et al., 2014). This method is commonly used to detect changes in cerebral hemodynamics during electrical stimulation and rehabilitation tasks in stroke, depression, Parkinson’s and various mental diseases (Noda et al., 2012; Wang et al., 2020; Conceição et al., 2021; Zhang et al., 2021). Kozel et al. (2009) and Li et al. (2019) acquired fNIRS when their subjects were receiving transcranial magnetic stimulation, and they found decreased levels of activation and functional connectivity within the cerebrum. In addition, the simultaneous application of transcranial electrical stimulation or peripheral nerve electrical stimulation combined with fNIRS to explore the mechanism of CBF is an essential innovation in therapeutic interventions (Di Rosa et al., 2019; Huo et al., 2019). The integration of fNIRS and transcranial electrical stimulation therapy also brings great potential for neuroscience research and clinical application of the brain related diseases. All these advantages make fNIRS a suitable technique for detecting activity changes in the brain cortex during FNS.

FNS is a non-invasive brain stimulation technique that transmits bionic low-frequency biological current to the cerebellar FNS through a bilateral mastoid process to modulate CBF and brain function (Hu et al., 2017). This study aims to detect brain functional connectivity changes in stroke patients, and investigate the cortical activation caused by FNS through measuring the concentration of HBO in the cerebral cortex of stroke patients and healthy controls (HCs), respectively.

This study was conducted at the Rehabilitation Medicine Department of Sun Yat-sen Memorial Hospital. This study was performed adhering to the Declaration of Helsinki on biomedical research involving stroke patients and healthy subjects. The research protocol was approved by the Sun Yat-sen Memorial Hospital Ethics Committee (SYSEC-KY-KS-2021-251). All participants provided written informed consent before their inclusion in this study. The comprehensive testing lasted for 10 min, including resting and stimulation.

In this study, the fNIRS approach was used to study cortex functional connectivity and activation characteristics in the stroke patient and HCs. From the functional connectivity perspective, the correlation coefficients between bilateral MC and left OC were found to decrease in stroke patients compared with the HCs during the resting state; from the cortex activation perspective, significant activation was observed in the PFC and MC of stroke patients during FNS. Moreover, FN was also found to activate part of the LPFC in the HCs.

Based on the results of this study, the functional connectivity strength between RMC and LMC, RMC and LOC, and LMC and LOC were significantly decreased in stroke patients compared with participants in the HCs. And the strength of functional connection in both hemispheres decreased asymmetrically. Neural plasticity is an important factor that reflects cortical reorganization after stroke, and functional connection is one of the main indicators of neural plasticity. The MC is the core of the brain that plans and executes volitional movements (Svoboda and Li, 2018), whereas the OC is associated with peripheral sensory information (Song et al., 2017). The results of this study are consistent with previous studies that reported a high correlation between decreased sensorimotor connectivity and clinical motor functional defect assessment (Volz et al., 2016). Studies found that focal cerebral ischemic injury can lead to a decline in the complete network of sensorimotor connections, especially in the early stage of stroke (Park et al., 2011). It can also affect functional connections between the hemispheres of the undamaged lateral cortex (Green et al., 2018). Although all patients in the stroke patient group of this study suffered from long-term unilateral ischemic brain injury and most of the infarcts are located in the left basal ganglia, with only a few patients that had large frontal parietal and temporal lobe infarction on left hemisphere, results showed weakened intra-hemispheric and inter-hemispheric brain functional connectivity. The results of our study suggest that our stroke patients still need rehabilitation therapy to improve the motor function of the affected limbs and improve the level of motor functional connection between the hemispheres.

Results also showed that the HBO of the bilateral PFC and bilateral MC significantly increased during the FNS period in stroke patients and HCs. This outcome indicates that FNS can activate parts of the brain in the PFC and MC. HBO in the MC increased with FNS but gradually returned to baseline when FNS was stopped (Figure 4). These results are in line with those of previous studies (Steriade, 1995; Golanov and Reis, 1996; Watson et al., 2009, 2014), where EEG examination showed that the brain-electric activity began to increase after FNS. CBF was also found to increase in 4 s, peaked around 8 s, and then gradually dropped to the baseline level. A plausible explanation to these results may be the ability of FNS in increasing CBF by evoking vasodilation neurons. The HBO signal could reflect the dynamic changes in the neural and functional activity of the cerebral cortex due to the neurovascular coupling mechanism (Claassen et al., 2021). Besides the influence of CBF, FNS also activates the intrinsic neurons in the cerebral cortex through neural pathways (Reis et al., 1997). Fibers from the FNS cross to the opposite side of the cerebellar vermis to form an uncinate cerebellar bundle (Haroian et al., 1981). This nerve bundle projects to the dorsal tegmental area of the midbrain, continues to rise into the thalamus, and finally terminates in the ventromedial nucleus of the thalamus dorsal medial nucleus. Due to the extensive relationship between the dorsal medial thalamic nucleus and the prefrontal cortex (PFC), the FNS could activate the PFC (Steriade, 1995). The present results are significant as the activation of PFC and MC by FNS provides a certain therapeutic basis and plays a guiding role in the rehabilitation of stroke patients.

This study illustrated that FNS induced activation in the brain regions of PFC and MC, with the FC values between bilateral MC and left OC being significantly decreased in stroke patients. The results of this study provide evidence for the clinical application and curative effect guidance of FNS treatment in the rehabilitation of patients with stroke and brain injury.

Due to the limitation of the fNIRS technology, it was not possible to measure the subcortical structures and cerebellum. In the future, the mechanisms related to the neural conduction pathways between cerebellar FN and cortex should be further explored to provide more accurate evidence that would be critical for potential clinical application. Besides, the sample size in this study was not large enough as well.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Sun Yat-sen Memorial Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

HM and YZ performed the experiment and wrote the manuscript. ZX collected the data. SF and XW contributed significantly to the data analysis. JX contributed to data processing. CM and SW contributed equally to design the experiment. All authors read and approved the final version of the manuscript.