Tinnitus, a common hearing disease, can be subdivided into subjective tinnitus and objective tinnitus. Subjective tinnitus is often observed in clinical settings, while objective tinnitus is rare. Without any corresponding external auditory source, tinnitus can be expressed by affected patients in a variety of ways including ringing, buzzing, hissing, or clicking. Additionally, tinnitus can be accompanied by different degrees of hearing loss. The prevalence of tinnitus is about 10% to 15% in humans [1] and the incidence rate of tinnitus increases with age, so it is more common among adults older than 65 years [2]. Tinnitus has become the third most harmful otological disease after deafness and vertigo. According to the 2014 United States tinnitus Clinical Application Guidelines, acute subjective tinnitus (AST) refers to tinnitus with an onset time of no more than six months. Long-term tinnitus can have a serious impact on patients, who may also suffer from sleep disorder, inattention and emotional disorder. As compared with chronic tinnitus, patients with AST are more motivated to seek clinical help. Currently, the pathogenesis of tinnitus remains unclear, and effective objective examinations and tailored medicines for tinnitus are rare, causing difficulties for clinical treatment and nursing.

The mechanism of tinnitus has been studied for many years but has yet not been fully elucidated. Previously, it was generally believed that tinnitus occurs when the peripheral auditory system was acutely or chronically damaged or underwent pathological changes. Recently it has been found that tinnitus may continue to exist even if the auditory nerve is severed to block the input of sound to the ear, so tinnitus is not only linked to a damaged cochlea [1]. More recently, with the progression of basic research using tinnitus animal models, an updated theory of tinnitus centralization has been put forward: abnormal central neuronal activity and reorganization of the central cortex or subcortical structure may be the cause of tinnitus. Furthermore, nonauditory centers including the limbic system and autonomic nervous system may also participate in tinnitus.

The rapid development of neuroimaging and neuroelectrophysiology has made it possible to gather detailed evidence verifying recently updated theory. Resting-state functional magnetic resonance imaging (fMRI) has the advantages of being an objective and repeatable data acquisition technique. It displays the brain function activities of specific areas and is a powerful tool for observing auditory activities. The amplitude of low-frequency fluctuations (ALFF) is one type of fMRI data that measures the internal average response of the brain to indicate the intensity of local neuron activity. Specifically, it reflects the level of spontaneous activity of each single voxel from the perspective of energy and has been demonstrated to be an effective method for the evaluation of spontaneous changes in brain activity associated with various neurological or mental diseases [3]. The degree centrality (DC) value is the most direct index available to describe node centrality in a network analysis. The higher the DC value of a node, the more important that node is in the network. The DC method reflects the functional connection of the human brain at the voxel level. It has been successfully used to assess the pathological mechanisms of many diseases, such as primary open-angle glaucoma [4], schizophrenia with auditory hallucinations [5] and Parkinson’s disease [6].

Previous studies have shown that tinnitus might be correlated with abnormal spontaneous neuronal activity in the auditory and nonauditory centers (frontal lobe, marginal lobe and cerebellum) [7, 8, 9]. However, previously published results have varied widely, due to differences in the fMRI techniques and calculation methods applied. In the current study, ALFF and DC were used to analyze the brain function activities of patients with tinnitus. These two techniques can directly measure the intensity and connection state of neural activity between brain regions, and have high test-retest reliability. Therefore, the combination of these two methods may be more realistic than using either method alone. the ALFF and DC methods were employed to detect spontaneous brain activity in patients with AST to clarify the neuropathological mechanism of tinnitus-related symptoms.

The current study revealed findings of altered brain activity related to AST patients for the first time by combining ALFF and DC analyses. Specifically, extensive brain regions were identified that belonged to the auditory network, default mode network and visual network that presented remarkably different ALFF and DC values in the study population. More generally, the reported findings support that neuroimaging may be useful for detecting the characteristics of neural network modifications in patients with AST by indicating the neuropathological mechanism of tinnitus.

The auditory cortex is divided into the primary and secondary cortices. This study reported increased ALFF values in the middle temporal gyrus (secondary auditory cortex) and decreased ALFF values in the superior temporal gyrus (primary auditory cortex) in both the AST-HL and AST-NHL groups. In a positron-emission tomography study, a correlation between higher brain metabolism in the middle temporal gyrus and tinnitus severity was confirmed [11]. Further, Chen et al. [9] recorded increased ALFF values in the right middle temporal gyrus of patients with chronic tinnitus. Additionally, a greater level of tinnitus disturbance was correlated with increased ALFF values in the middle temporal gyrus, suggesting that a change in the ALFF value may reflect an influence of tinnitus perceptions. Previous studies have demonstrated that the volume of the bilateral superior temporal gyrus in patients with unilateral pulsatile tinnitus was significantly larger than that in the normal control group, while FC in both the right superior temporal gyrus and left inferior temporal gyrus was abnormally increased [12, 13]. Contrary to the above results, the ALFF value of the superior temporal gyrus was significantly reduced in this study, suggesting dysfunction of the superior temporal gyrus. Therefore, it is speculated that the mechanism of tinnitus might be linked to activation of the secondary auditory center and inhibition of the primary auditory center.

The superior frontal gyrus and middle frontal gyrus may be key nodes in the tinnitus network responsible for receiving and integrating tinnitus sensory information and transmitting the impulses to maintain the overall coordination of the central nervous system. Geven [14] found an enhancement metabolism of the left middle frontal gyrus in tinnitus patients using 2-deoxy-2- (fluorine-18) fluoro-D-glucose positron-emission tomography. Additionally, a correlation between high neural activity in the middle frontal gyrus and the severity of tinnitus was observed [15]. The results of task-state fMRI also revealed an abnormal degree of activation of the superior frontal gyrus in tinnitus patients [16]. In chronic tinnitus patients, the FC of the left middle frontal gyrus was also significantly increased [17]. Consistent with previous studies, the findings reported here included significantly higher ALFF values from the superior and middle frontal gyrus in both AST-HL and AST-NHL patients. However, a previous study has shown that regional homogeneity (ReHo) values in several brain regions of the tinnitus group, including the inferior frontal gyrus, were increased [18]. Increased ALFF values were also observed in this study in the inferior frontal gyrus in the AST-NHL group Acting as the core brain area of the central inhibitory response, the inferior frontal gyrus might reflect the presence of long-term control of central attention allocation to tinnitus perception from the bottom to top. It has been hypothesized that a default mode network (DMN) exists in the human brain, with the prefrontal gyrus holding an important role [19]. The DMN is involved in scene memory, self-evaluation and internal expression. Schmidt et al. [20] have also reported specific changes in patients with tinnitus, including connectivity alterations in the DMN and dorsal attention network. They speculated that DMN might play a key role in the neurophysiological process of tinnitus. Taken together, tinnitus patients show extensive abnormally spontaneous brain activity in the frontal lobe, indicating that the frontal cortex may be a participant in the pathogenesis of tinnitus.

The limbic system and frontal lobe are the main brain areas that participate in emotion processing. However, studies are increasingly pointing to the fact that tinnitus is not only limited to the auditory system but also closely related to the psychological activities of emotion and memory. Boyen [21] contended that gray matter in the marginal lobe of tinnitus patients with hearing loss was increased. Significantly greater ReHo values were also found in tinnitus patients, related to the increased tinnitus duration and hearing threshold of tinnitus [22]. In this study, abnormal ALFF values were obtained in the marginal lobe, anterior uncinate gyrus and cingulate gyrus, which might be related to psychological problems linked to stress, anxiety, inattention and insomnia present in AST patients. From an anatomical perspective, there was an indirect fiber connection observed between the auditory cortex and the limbic system, which allowed for a new model for the pathophysiology of tinnitus. In this context, the abnormal activity of the auditory system is transmitted to the brain and experienced as tinnitus. Simultaneously, negative experiences such as fidgeting, insomnia, depression and fear are generated due to the involvement of the limbic system and induce the perception of tinnitus, resulting in an abnormal cycle between tinnitus and negative characteristics or feelings.

The cerebellum has always been considered as the center of coordination for the random movement and contraction of muscles in the whole body. However, a recent study showed that the cerebellum also plays an important role in auditory afferent processing [23]. Bauer [24] observed that the cerebellum might be an important and nonmandatory site of tinnitus in a rat model of noise-induced chronic tinnitus. Once cerebellum lesions occur, tinnitus signals might appear. Tinnitus patients additionally showed significantly decreased ReHo values in the anterior lobe of the cerebellum [25]. Han [26] recorded altered ALFF values in the posterior lobe of the right cerebellum in pulsatile tinnitus patients in a manner linked to the diversity and duration of tinnitus. The results reported here indicate that ALFF values in the left posterior cerebellar lobe and bilateral anterior lobe of cerebellum were decreased in patients with tinnitus, which confirmed that the integration of cerebellar functional processing of cochlear afferent signals might be involved in the occurrence and persistence of tinnitus.

In the AST-NHL group, it was observed that the visual and extrapyramidal systems were activated. As an important part of the visual cortex, the inferior occipital gyrus is involved in logic analysis in the brain and the processing of visual memory. Based on the anatomic connection between auditory and visual areas, Ibrahim [27] suggested that the auditory cortex directly regulates the visual cortex. Therefore, the current authors speculated that higher ALFF values in the right suboccipital gyrus in AST-NHL patients might be the result of the activation of the visual center triggered by tinnitus. The above result was consistent with that of Zhou et al. [2]. However, it was found instead that the central visual system was not activated in the AST-HL group, which might be due to the time of onset or degree of hearing loss in the current study population. This study also reported increased ALFF values in the bilateral lenticular nucleus of the AST-NHL group. The lenticular nucleus belongs to the striatum, which receives almost all projections from the cerebral cortex and has direct fiber connections with the auditory cortex and the medial geniculate body. As such, changes in the cortical striatal pathway might constitute an important factor in tinnitus. However, the specific role of the lenticular nucleus in tinnitus requires further investigation.

The DC values in the right superior marginal gyrus/inferior parietal lobule/angular gyrus were increased in AST-HL patients, suggesting that the DMN plays an important role in tinnitus. The DMN influences negative emotions and attention disorders among patients. Therefore, it was speculated that the clinical manifestations of anxiety and insomnia in these patients might be correlated with increased activity of the DMN and limbic system network, causing a damaging cycle between tinnitus and negative events or feelings, as described above. The thalamus has also been found to be essential for the processing of tinnitus [28]. As an important component of many pathways of the brain, the thalamus transmits sensory information to the cerebral cortex and is the most important hub of sensory transmission. Except for olfaction, all other sensory pathway transmission neurons in the body are managed in the thalamus. Llinás proposed a model of thalamic cortical rhythm disorder that suggested that tinnitus was caused by the interruption of coherent oscillation between the thalamus and cortex [29]. Impaired white matter integrity involving thalamic connectivity was previously identified in tinnitus patients [30]. Other studies have also observed decreased short-range FC density and ALFF values in the thalamus [9, 31]. Consistent with the foregoing results, this study recorded significantly decreased DC values of the right thalamus in the AST-HL group, speculated to be caused by hearing loss—that is, in AST-HL patients, decreased auditory information stimulation caused weakened thalamo-cortical connections, thus leading to changes in the normal rhythm of the thalamo–cortical ring and ultimately, the generation of tinnitus.

As described above, the frontal gyrus was widely activated in tinnitus. Significantly higher DC values were obtained from the frontal gyrus of AST-NHL patients, which reinforced the fact that the frontal lobe plays an indispensable role in tinnitus. The posterior central gyrus, functioning as the primary somatosensory cortex, has been referred to as the joint area together with the frontal lobe and temporal lobe [32]. In this study, remarkably lower ALFF values were observed in the posterior central gyrus in AST-HL patients and decreased DC values were observed in the posterior central gyrus in AST-NHL patients. The dysfunction of the posterior central gyrus might be associated with sensory abnormalities in tinnitus patients.

The results reported here confirmed that the auditory and nonauditory centers of tinnitus patients showed abnormal ALFF and DC values, indicating that both the auditory center and nonauditory centers (limbic system, frontal lobe, cerebellum, posterior central gyrus) are crucial for tinnitus. The neural activity of tinnitus brain area is related to the disease stage, suggesting that we should pay attention to the different stages of tinnitus disease; The abnormality of tinnitus brain network is mainly manifested in the enhancement of frontal lobe centrality and the decrease of posterior central gyrus centrality. fMRI data was employed to compare the abnormal activity brain area of tinnitus patients in a resting state, which is proposed to reflect the neural mechanism of tinnitus relatively objectively. The relationship between tinnitus and spontaneous brain activity of the auditory cortex, DMN, limbic system and attention network was revealed first by combining the ALFF and DC methods. In short, the current study provides details on a comprehensive neurological pattern in patients with AST.

JC, LF, carried out the experiments and wrote the manuscripts. GC wrote and edited manuscript and performed f-MRI experiments. YX, ZZ conceived the study, designed experiments and wrote the manuscript. BH, JC performed the acquisition, analysis and interpretation of data.

Medical research ethics committee of the First Affiliated Hospital of Nanchang University (2019) Yi Yan Lun Shen No. (100).

The authors would also like to thank Yu Guo for helpful comments and lively discussion.

This research received no external funding.

The authors declare no conflict of interest.