Granger causality analysis, as a time series analysis technique derived from econometrics, has been applied in an ever-increasing number of publications in the field of neuroscience, including fMRI, EEG/MEG, and fNIRS. The present study mainly focuses on the validity of "signed path coefficient Granger causality," a Granger-causality-derived analysis method that has been adopted by many fMRI researches in the last few years. This method generally estimates the causality effect among the time series by an order-1 autoregression, and defines a positive or negative coefficient as an "excitatory" or "inhibitory" influence. In the current work we conducted a series of computations from resting-state fMRI data and simulation experiments to illustrate the signed path coefficient method was flawed and untenable, due to the fact that the autoregressive coefficients were not always consistent with the real causal relationships and this would inevitablely lead to erroneous conclusions. Overall our findings suggested that the applicability of this kind of causality analysis was rather limited, hence researchers should be more cautious in applying the signed path coefficient Granger causality to fMRI data to avoid misinterpretation.

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.

Beneficial effects of repetitive transcranial magnetic stimulation (rTMS) on left dorsolateral prefrontal cortex (DLPFC) have been consistently shown for treating various neuropsychiatrical or neuropsychological disorders, but relatively little is known about its neural mechanisms. Here we conducted a randomized, double-blind, SHAM-controlled study to assess the effects of high-frequency left DLPFC rTMS on resting-state activity. Thirty-eight young healthy subjects received two sessions of either real rTMS (N = 18, 90% motor-threshold; left DLPFC at 20 Hz) or SHAM TMS (N = 20) and functional magnetic resonance imaging scan during rest in 2 days separated by 48 h. Resting-state bran activity was measured with the fractional amplitude of low-frequency fluctuation (fALFF) and functional connectivity (FC). Increased fALFF was found in rostral anterior cingulate cortex (rACC) after 20 Hz rTMS, while no changes were observed after SHAM stimulation. Using the suprathreshold rACC cluster as the seed, increased FC was found in left temporal cortex (stimulation vs. group interaction). These data suggest that high-frequency rTMS on left DLPFC enhances low-frequency resting-state brain activity in the target site and remote sites as reflected by fALFF and FC.

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.

Transfer entropy from non-uniform embedding is a popular tool for the inference of causal relationships among dynamical subsystems. In this study we present an approach that makes use of low-dimensional conditional mutual information quantities to decompose the original high-dimensional conditional mutual information in the searching procedure of non-uniform embedding for significant variables at different lags. We perform a series of simulation experiments to assess the sensitivity and specificity of our proposed method to demonstrate its advantage compared to previous algorithms. The results provide concrete evidence that low-dimensional approximations can help to improve the statistical accuracy of transfer entropy in multivariate causality analysis and yield a better performance over other methods. The proposed method is especially efficient as the data length grows.

Anatomical and functional abnormalities in the cortico-cerebellar-thalamo-cortical circuit have been observed in schizophrenia patients and their unaffected siblings. However, it remains unclear to the relationship between anatomical and functional abnormalities within this circuit in schizophrenia patients and their unaffected siblings, which may serve as potential endophenotypes for schizophrenia.Anatomical and resting-state functional magnetic resonance imaging data were acquired from 49 first-episode, drug-naive schizophrenia patients, 46 unaffected siblings, and 46 healthy controls. Data were analyzed by using voxel-based morphometry and Granger causality analysis.The patients and the siblings shared anatomical deficits in the left middle temporal gyrus (MTG) and increased left MTG-left angular gyrus (AG) connectivity. Moreover, the left MTG-left AG connectivity negatively correlates to the duration of untreated psychosis in the patients.The findings indicate that anatomical deficits in the left MTG and its increased causal connectivity with the left AG may serve as potential endophenotypes for schizophrenia with clinical implications.

Sensorineural hearing loss (SNHL), sometimes accompanied with tinnitus, is associated with dysfunctions within and outside the classical auditory pathway. The salience network, which is anchored in bilateral anterior insula and dorsal anterior cingulate cortex, has been implicated in sensory integration. Partial auditory deprivation could alter the characteristics of the salience network and other related brain areas, thereby contributing to hearing impairments-induced neuropsychiatric symptoms. To test this hypothesis, we performed fMRI scanning and neuropsychological tests on 32 subjects with long-term bilateral hearing impairment and 30 well-matched Controls. Non-directional functional connectivity and directional Granger causality analysis were used to identify aberrant spatial and temporal patterns of connections targeting bilateral anterior insula and dorsal anterior cingulate cortex. We found that the left anterior insula showed decreased connectivity with right precentral gyrus and superior frontal gyrus. The connections between the dorsal anterior cingulate cortex and middle frontal gyrus, superior parietal gyrus and supplementary motor area (SMA) were also reduced. Relative to Controls, SNHL patients showed abnormal effective connectivity of the salience network, including inferior temporal gyrus, cerebellum lobule VI, lobule VIII, precentral gyrus, middle frontal gyrus and SMA. Furthermore, correlation analysis demonstrated that some of these atypical connectivity measures were correlated with performance of neuropsychiatric tests. These findings suggest that the inefficient modulation of the salience network might contribute to the neural basis of SNHL and tinnitus, as well as associated cognition and emotion deficits.

The insular cortex plays an important role in multimodal sensory processing, audio-visual integration and emotion; however, little is known about how the insula is affected by auditory deprivation due to sensorineural hearing loss (SNHL). To address this issue, we used structural and functional magnetic resonance imaging to determine if the neural activity within the insula and its interregional functional connectivity (FC) was disrupted by SNHL and if these alterations were correlated clinical measures of emotion and cognition. Thirty-five SNHL subjects and 54 Controls enrolled in our study underwent auditory evaluation, neuropsychological assessments, functional and structure MRI, respectively. Twenty five patients and 20 Controls underwent arterial spin labeling scanning. FC of six insula subdivisions were assessed and the FC results were compared to the neuropsychological tests. Interregional connections were also compared among insula-associated networks, including salience network (SN), default mode network (DMN), and central executive network (CEN). Compared to Controls, SNHL subjects demonstrated hyperperfusion in the insula and significantly decreased FC between some insula subdivisions and other brain regions, including thalamus, putamen, precentral gyrus, postcentral gyrus, mid-cingulate cortex, dorsolateral prefrontal cortex, rolandic operculum. Anxiety, depression and cognitive impairments were correlated with FC values. Abnormal interactions among SN, DMN, and CEN were observed in SNHL group. Our result provides support for the "inefficient high-order control" theory of the insula in which the auditory deprivation caused by SNHL contributes to impaired sensory integration and central deficits in emotional and cognitive processing.

Purpose. 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. Materials and 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.

Tinnitus, a phantom ringing, buzzing, or hissing sensation with potentially debilitating consequences, is thought to arise from aberrant spontaneous neural activity at one or more sites within the central nervous system; however, the location and specific features of these oscillations are poorly understood with respect to specific tinnitus features. Recent resting-state functional magnetic resonance imaging (fMRI) studies suggest that aberrant fluctuations in spontaneous low-frequency oscillations (LFO) of the blood oxygen level-dependent (BOLD) signal may be an important factor in chronic tinnitus; however, the role that frequency-specific components of LFO play in subjective tinnitus remains unclear. A total of 39 chronic tinnitus patients and 41 well-matched healthy controls participated in the resting-state fMRI scans. The LFO amplitudes were investigated using the amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF) in two different frequency bands (slow-4: 0.027-0.073 Hz and slow-5: 0.01-0.027 Hz). We observed significant differences between tinnitus patients and normal controls in ALFF/fALFF in the two bands (slow-4 and slow-5) in several brain regions including the superior frontal gyrus (SFG), inferior frontal gyrus, middle temporal gyrus, angular gyrus, supramarginal gyrus, and middle occipital gyrus. Across the entire subject pool, significant differences in ALFF/fALFF between the two bands were found in the midbrain, basal ganglia, hippocampus and cerebellum (Slow 4 > Slow 5), and in the middle frontal gyrus, supramarginal gyrus, posterior cingulate cortex, and precuneus (Slow 5 > Slow 4). We also observed significant interaction between frequency bands and patient groups in the orbitofrontal gyrus. Furthermore, tinnitus distress was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-4 band in left SFG, whereas tinnitus duration was positively correlated with the magnitude of ALFF in right SFG and the magnitude of fALFF slow-5 band in left SFG. Resting-state fMRI provides an unbiased method for identifying aberrant spontaneous LFO occurring throughout the central nervous system. Chronic tinnitus patients have widespread abnormalities in ALFF and fALFF slow-4 and slow-5 band which are correlated with tinnitus distress and duration. These results provide new insights on the neuropathophysiology of chronic tinnitus; therapies capable of reversing these aberrant patterns may reduce tinnitus distress.

Abnormal neural activity in the cerebellum has been implicated in hearing impairments, but the effects of long-term hearing loss on cerebellar function are poorly understood. To further explore the role of long-term bilateral sensorineural hearing loss on cerebellar function, we investigated hearing loss-induced changes among neural networks within cerebellar subregions and the changes in cerebellar-cerebral connectivity patterns using resting-state functional MRI. Twenty-one subjects with long-term bilateral moderate-to-severe sensorineural hearing loss and 21 matched controls with clinically normal hearing underwent MRI scanning and a series of neuropsychological tests targeting cognition and emotion. Voxel-wise functional connectivity (FC) analysis demonstrated decreased couplings between the cerebellum and other cerebral areas, including the temporal pole (TP), insula, supramarginal gyrus, inferior frontal gyrus (IFG), medial frontal gyrus, and thalamus, in long-term bilateral sensorineural hearing loss patients. An ROI-wise FC analysis found weakened interregional connections within cerebellar subdivisions. Moreover, there was a negative correlation between anxiety and FC between the left cerebellar lobe VI and left insula. Hearing ability and anxiety scores were also correlated with FC between the left cerebellar lobe VI and left TP, as well as the right cerebellar lobule VI and left IFG. Our results suggest that sensorineural hearing loss disrupts cerebellar-cerebral circuits, some potentially linked to anxiety, and interregional cerebellar connectivity. The findings contribute to a growing body showing that auditory deprivation caused by cochlear hearing loss disrupts not only activity with the classical auditory pathway but also portions of the cerebellum that communicates with other cortical networks.