Clinical And Animal Research On The Neural Mechanism Of Tinnitus By Using Resting-State FMRI Technique

Part 1:Aberrant amplitude of low-frequency fluctuations in chronic tinnitus patients revealed by resting-state functional MRIObjective:The neural mechanisms that give rise to the phantom sound of tinnitus are poorly understood. This study aims to investigate whether aberrant spontaneous brain activity exists in chronic tinnitus patients using resting-state functional magnetic resonance imaging (fMRI) technique.Methods:A total of 31 patients with chronic tinnitus and 32 age-, sex-, and education-matched healthy controls were prospectively examined. Both groups had normal hearing thresholds. We calculated the amplitude of low-frequency fluctuations (ALFFs) of fMRI signals to measure spontaneous neuronal activity and detect the relationship between fMRI information and clinical data of tinnitus.Results:Compared with healthy controls, we observed significant increased ALFF within several selected regions including the rightmiddle temporal gyrus (MTG), right superior frontal gyrus (SFG), and right angular gyrus; decreased ALFF was detected in the left cuneus, right middle occipital gyrus and bilateral thalamus. Moreover, tinnitus severity correlated positively with increased ALFF in right MTG and right SFG; tinnitus duration correlated positively with higher ALFF values in right SFG.Conclusions:The present study confirms that chronic tinnitus patients have aberrant ALFF in many brain regions, which is associated with specific clinical tinnitus characteristics. ALFF disturbance in specific brain regions might be used to identify the neuro-pathophysiological mechanisms in chronic tinnitus patients.Part 2:Abnormal resting-state regional homogeneity and functional connectivity in chronic tinnitus patientsObjective:Subjective tinnitus is hypothesized to arise from aberrant neural activity; however, its neural bases are poorly understood. To identify aberrant neural networks involved in chronic tinnitus, we compared the resting-state functional magnetic resonance imaging (fMRI) patterns of tinnitus patients and healthy controls.Methods:Resting-state fMRI measurements were obtained from a group of chronic tinnitus patients (n=29) with normal hearing and well-matched healthy controls (n=30). Regional homogeneity (ReHo) analysis and functional connectivity analysis were used to identify abnormal brain activity; these abnormalities were associated with tinnitus distress.Results:Relative to healthy controls, tinnitus patients had significant greater ReHo values in several brain regions including the bilateral anterior insula (AT), left inferior frontal gyrus, and right supramarginal gyrus. Furthermore, the left AI showed enhanced functional connectivity with the left middle frontal gyrus (MFG), while the right AI had enhanced functional connectivity with the right MFG; these measures were positively correlated with Tinnitus Handicap Questionnaires (r= 0.459, P= 0.012 and r= 0.479, P= 0.009, respectively).Conclusions:Chronic tinnitus patients showed abnormal intra-and interregional synchronization in several resting-state cerebral networks; these abnormalities were correlate ed with clinical tinnitus distress. These results suggest that tinnitus distress is exacerbated by attention networks that focus on internally generated phantom sounds.Part 3:Aberrant Interhemispheric Functional Connectivity in Chronic Tinnitus PatientsObjective:Recent studies suggest that tinnitus may be due in part to aberrant callosal structure and interhemispheric interaction. To explore this hypothesis we use a novel method, voxel-mirrored homotopic connectivity (VMHC), to examine the resting-state interhemispheric functional connectivity and its relationships with clinical characteristics in chronic tinnitus patients.Methods:Twenty-eight chronic tinnitus patients with normal hearing thresholds and 30 age-, sex-, education-, and hearing threshold-matched healthy controls were included in this study and underwent the resting-state fMRI scanning. We computed the VMHC to analyze the interhemispheric functional coordination between homotopic points of the brain in both groups.Results:Compared to the controls, tinnitus patients showed significantly increased VMHC in the middle temporal gyrus, middle frontal gyrus, and superior occipital gyrus. In tinnitus patients, a positive correlation was found between tinnitus duration and VMHC of the uncus. Moreover, correlations between VMHC changes and tinnitus distress were observed in the transverse temporal gyrus, superior temporal pole, precentral gyrus, and calcarine cortex.Conclusions:These results show altered interhemispheric functional connectivity linked with specific tinnitus characteristics in chronic tinnitus patients, which may be implicated in the neuropathophysiology of tinnitus.Part 4:The rat model of salicylate-induced tinnitus:a resting-state fMRI studyObjective:Salicylate-induced tinnitus is one of the most classical animal models of tinnitus. To identify the neural substrates for tinnitus, we induced the tinnitus with salicylate and used electrophysiological and resting-state functional magnetic resonance imaging (fMRI) techniques to observe the tinnitus-related neural network.Methods:The SD rats were injected with 300 mg/kg salicylate to induce tinnitus. Electrophysiological recordings were performed to show the local field potentials in the auditory cortex (ACx), medial geniculate body (MGB) and inferior colliculus (IC); Resting-state fMRI method was used to observe the abnormal functional connectivity of tinnius rats. We set the ACx, MGB and IC as seed regions and computed the seed-based functional connectivity to show the whole brain network.Results:After injecting salicylate for two hours, the ACx, MGB and IC showed enhanced amplitude of local field potential. Through the resting-state fMRI, with the seed located in the ACx, we observed significantly increased functional connectivity in the MGB, IC, amygdala, reticular nucleus, and cerebellum; with the seed located in the MGB, we observed significantly increased functional connectivity in the ACx and hippocampus; when the seed region was located in the IC, there were significant increases of functional connectivity in the MGB and hippocampus.Conclusions:Salicylate-induced tinnitus appears to arise from enhanced central gain and increased functional connectivity in an auditory network with four side branches. The core of the network is composed of auditory structures extending from the IC, through the MGB to the ACx plus branches to the amygdala, reticular nucleus, cerebellum and hippocampus. These side branches presumably contribute to the emotional significance, arousal, motor response, gating, and memories associated with tinnitus.