Monaural-driven Functional Changes within and Beyond the Auditory Cortical Network: Evidence from Long-term Unilateral Hearing Impairment

Accepted Manuscript Monaural-driven Functional Changes Within and Beyond the Auditory Cortical Network: Evidence from Long-term Unilateral Hearing Impairment Yanyang Zhang, Zhiqi Mao, Shiyu Feng, Xinyun Liu, Jun Zhang, Xinguang Yu PII: DOI: Reference:

S0306-4522(17)30887-4 https://doi.org/10.1016/j.neuroscience.2017.12.015 NSC 18185

To appear in:

Neuroscience

Received Date: Accepted Date:

29 April 2017 11 December 2017

Please cite this article as: Y. Zhang, Z. Mao, S. Feng, X. Liu, J. Zhang, X. Yu, Monaural-driven Functional Changes Within and Beyond the Auditory Cortical Network: Evidence from Long-term Unilateral Hearing Impairment, Neuroscience (2017), doi: https://doi.org/10.1016/j.neuroscience.2017.12.015

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Monaural-driven Functional Changes Within and Beyond the Auditory Cortical Network: Evidence from Long-term Unilateral Hearing Impairment

Author names: Yanyang Zhang 1, Zhiqi Mao1, Shiyu Feng 1, Xinyun Liu 2, Jun Zhang1, Xinguang Yu 1 1

Department of Neurosurgery, PLA General Hospital, Beijing (100853), China

2

Department of Radiology, PLA General Hospital, Beijing (100853), China

First Author: Yanyang Zhang Correspondence to: Xinguang Yu, Department of Neurosurgery, PLA General Hospital, Beijing (100853), China Tel: 13501097965 Fax: +86-010-68150287 E-mail: [email protected]

Abbreviations: AN, auditory network; DMN, default mode network; FEW, familywise error rate; LHI, left-sided hearing impairment; PTA, pure tone average; RHI, right-sided hearing impairment; RSFC, resting-state functional connectivity; ROI, region of interest; SMN, somatomotor network; UHI, unilateral hearing impairment; VAN, ventral attention network; VMHC, voxel-mirrored homotopic connectivity; VN, visual network.

1

Abstract Long-term unilateral hearing impairment (UHI) results in changes in hearing and psychoacoustic performance that are likely related to cortical reorganization. However, the underlying functional changes in the brain are not yet fully understood. Here, we studied alterations in inter- and intra-hemispheric resting-state functional connectivity (RSFC) in 38 patients with long-term UHI caused by acoustic neuroma. Resting-state fMRI data from 17 patients with left-sided hearing impairment (LHI), 21 patients with right-sided hearing impairment (RHI) and 21 healthy controls (HCs) were collected. We applied voxel-mirrored homotopic connectivity analysis to investigate the interhemispheric interactions. To study alterations in between-network interactions, we used four cytoarchitectonically identified subregions in the auditory cortex as “seeds” for whole-brain RSFC analysis. We found that long-term imbalanced auditory input to the brain resulted in (1) enhanced interhemispheric RSFC between the contralateral and ipsilateral auditory networks and (2) differential patterns of altered RSFCs with other sensory (visual and somatomotor) and higher-order (default mode and ventral attention) networks among the four auditory cortical subregions. These altered RSFCs within and beyond the auditory network were dependent on the side of hearing impairment. The results were reproducible when the analysis was restricted to patients with severe-to-profound UHI and patients with hearing-impairment durations greater than 24 months. Together, we demonstrated that long-term UHI drove cortical functional changes within and beyond the auditory network, providing empirical evidence for the association between brain changes and hearing disorders. Keywords: Unilateral hearing impairment; Resting-state fMRI; Functional connectivity; Auditory network Introduction Unilateral hearing impairment (UHI), characterized by asymmetric hearing input, is frequently observed in newborns (1/1000 newborns) (Dalzell et al., 2000), and its incidence increases with age (Niskar et al., 1998). In individuals with long-term hearing impairment of only one ear, imbalanced auditory input to the brain triggers cortical reorganization and contributes to not only hearing problems but also behavioral and psychosocial deficits, such as poor sound localization, difficulties in directional hearing and speech recognition in noise (Firszt et al., 2017; Lieu et al., 2012; Pross et al., 2015; Schmithorst et al., 2014). An emerging body of literature suggests that the hearing and psychoacoustic deficits in UHI may be partially derived from abnormal interactions between intrinsic brain networks (Schmithorst et al., 2014; Zhang et al., 2015). The cascading causal effect of UHI on the auditory network could result in altered functional network interconnections and systematically impact multiple large-scale networks involved in sensory and higher-level cognitive functions. Thus, understanding intra- and inter-network interactions as a window into brain dysfunction mechanisms in long-term UHI is crucial. From a network perspective, auditory and auditory-related cortical areas work together as a large-scale brain auditory network (Bressler and Menon, 2010; Liang et al., 2013), which displays functional lateralization in a wide variety of domains, notably in the contexts of speech (Giraud et al., 2007; Obleser et al., 2008) and tonal processing (Zatorre and Gandour, 2008). Interhemispheric functional interactions within the auditory network are fundamental to integrative auditory processing (Andoh et al., 2015). In normal hearing, monaural stimulation produces a pattern of asymmetrical neuronal activation over the brain auditory network, which can be explained by the fact that the contralateral projection pathway is dominant both anatomically and functionally (Chang et al., 2016). In UHI, although this contralateral dominance of auditory projections is considerably preserved, auditory cortex activation 2

following stimulation of the unaffected ear is known to shift toward a more symmetrical and synchronous pattern (Burton et al., 2012; Chang et al., 2016; Eggermont, 2017; Khosla et al., 2003; Pross et al., 2015). Moreover, previous studies demonstrated that the side of hearing impairment (left versus right ear) significantly affected the pattern of auditory cortical lateralization (Burton et al., 2012; Khosla et al., 2003). We hypothesized that monaural hearing impairment might affect interhemispheric functional interactions within the auditory network, contributing to the loss of cortical lateralization and exhibiting differential ear effects. Importantly, studies on macaques and humans have revealed that the auditory cortical network contains several heterogeneous subregions, and each subregion exhibits distinct connectivity profiles and specialized functions (Hackett, 2011; Leaver and Rauschecker, 2016; Morosan et al., 2001; Woods et al., 2010). The auditory cortex is proposed to be subdivided into tonotopically organized core fields, surrounding belts, and lateral parabelt fields (Woods et al., 2010) that are specialized to process complex sound features (Rauschecker and Scott, 2009). Cytoarchitectonically, based on quantitative and objectively defined criteria, the auditory cortex is parcellated into three primary subregions (core area Te1.0, and belt areas Te1.1 and Te1.2) and one higher auditory subregion (Te3.0) (Burton et al., 2012; Morosan et al., 2005, 2001). Although a few neuroimaging studies (Liu et al., 2015; Zhang et al., 2015, 2016) have demonstrated UHI-related alterations of auditory network connectivity, whether the auditory network subregions exhibit differentially altered connectivity patterns responding to monaural input impairment remains largely unknown. Beyond the auditory network, the default mode network (DMN) is a key network altered in long-term UHI (Schmithorst et al., 2014; Zhang et al., 2015, 2016). The DMN is most active when an individual is not engaged in any externally driven tasks (Fransson et al., 2007) and is thought to play a crucial role in cognitive processing (Fox et al., 2005; Menon, 2011). The DMN is dynamically associated with several other sensory and cognitive networks, including the executive and salience networks (Menon, 2011; Menon and Uddin, 2010). Currently, few studies have reported altered inter-network functional connectivity between the DMN and the auditory network in UHI patients (Schmithorst et al., 2014; Zhang et al., 2015), which is the proposed mechanism underlying the association between hearing impairment and cognitive deficits. However, whether alterations in inter-network communication are related to the side of hearing impairment and specific auditory subregions has not yet been studied. In this study, we aimed to systematically explore the functional reorganization within and beyond the auditory network in 38 long-term patients with UHI caused by acoustic neuroma using resting-state fMRI (rs-fMRI), a promising imaging technique that measures the brain’s resting-state functional connectivity (RSFC) (Bertolero et al., 2015; Biswal et al., 1995). First, to explore the lateralization of interhemispheric interaction in patients with left-sided hearing impairment (LHI) and right-sided hearing impairment (RHI), we examined homotopic RSFC using a recently validated approach, voxel-mirrored homotopic connectivity (VMHC) (Zuo et al., 2010). VMHC measures the RSFC between each voxel in one hemisphere and its mirrored voxel in the opposite hemisphere. Second, given that the primary and higher auditory cortex were cytoarchitectonically parcellated into four subregions (Te1.0, Te1.1, Te1.2 and Te3.0), we separately used the four subregions as seed regions and mapped whole-brain RSFC patterns associated with each subregion separately to examine alterations in between-network interactions in UHI. Considering the loss of cortical lateralization as measured by a more symmetrical activation of the left versus right auditory cortex in response to monaural stimulation in UHI patients, it is reasonable to expect the presence of enhanced homotopic connectivity within the auditory network. Furthermore, the auditory and psychoacoustic symptoms associated with UHI led us to hypothesize altered functional connectivity between multiple brain networks ranging from sensory processing to higher-order cognitive functions dependent on the auditory cortex subregions. Finally, given the known hemispheric asymmetry and specialization in auditory processing, we predicted that the side of hearing impairment would result in differential patterns of functional connectivity within 3

functional networks. Materials and methods Participants Thirty-eight participants with long-term UHI caused by primary ipsilateral acoustic neuroma were included in this study. Specifically, 17 patients (7 with moderate UHI and 10 with severe-to-profound UHI) had left-sided UHI, and 21 patients (7 with moderate UHI and 14 with severe-to-profound UHI) had right-sided UHI. All UHI patients had post-lingual hearing impairment. Previous studies have suggested that cortical reorganization in UHI patients occurs until approximately 2 years (Schmithorst et al., 2014). We attempted to restrict inclusion to participants with hearing impairments lasting at least 2 years. Consequently, the duration of hearing impairment was verified as 2 years or greater for 34 of the UHI participants, whereas the duration was less than 2 years (22 months) for 4 participants (3 LHI and 1 RHI). See Table 1 for complete details. In addition, we recruited 21 healthy controls (HCs) with no previous history of neurological dysfunction and normal findings on neurological examination. The pure tone average (PTA) was calculated by averaging the hearing thresholds measured by standard pure tone audiometry at the frequencies of 0.5, 1.0, 2.0 and 4.0 kHz to reflect the participants hearing level. All patients in this study were diagnosed with UHI at least moderate hearing impairment in the affected ear (PTA ≥ 40 dB HL) and normal hearing in the unaffected ear (PTA ≤ 20 dB HL). All control subjects were normal-hearing individuals with PTAs less than 20 dB for both ears, and all participants were right-handed. This study was approved by the local ethics committee of Chinese People's Liberation Army (PLA) General Hospital, and written informed consent was obtained from each participant. Image acquisition Imaging data were acquired using a GE750 3.0 T scanner (Department of Radiology at PLA General Hospital). Participants were fitted with soft earplugs and an MRI-compatible electrostatic headphone to attenuate acoustic scanner noise. High-resolution anatomical images were acquired using a sagittal Fast Spoiled Gradient-Echo (FSPGR) T1-weighted sequence with the following parameters: repetition time = 6.7 ms, echo time = 2.9 ms, flip angle = 7°, thickness = 1 mm, slices = 192, field of view = 256 × 256 mm2 and voxel size = 1 × 1 × 1 mm3. Functional images were obtained using an echo-planar imaging (EPI) sequence with the following parameters: repetition time = 2000 ms, echo time = 30 ms, flip angle = 90°, thickness/gap = 3.5 mm/0.5 mm, slices = 36, field of view = 224 × 224 mm2 and voxel size = 3.5 × 3.5 × 3.5 mm3. During the scan, participants were instructed to keep their eyes closed, remain motionless, and not think of anything specific. After scanning, a simple questionnaire indicated that no participants had fallen asleep. Data preprocessing Image preprocessing was performed using Statistical Parametric Mapping (SPM12, http://www.fil.ion.ucl.ac.uk/spm) and Data Processing & Analysis for (Resting-State) Brain Imaging (DPABI) (Yan et al., 2016). The first ten images were discarded to ensure steady-state longitudinal magnetization, and the remaining images were then corrected for temporal differences and head motion. After subject selection, neither translation nor rotation parameters in any given data exceeded ± 2 mm or ± 2°. T1-weighted images were then co-registered to the mean functional image after motion correction using a linear transformation and segmented into 4

gray matter (GM), white matter (WM), and cerebrospinal fluid using a unified segmentation algorithm (Ashburner and Friston, 2005). Next, the motion-corrected functional volumes were spatially normalized to the Montreal Neurological Institute (MNI) space and resampled to 3-mm isotropic voxels. Subsequently, the global signal, WM signal, cerebrospinal fluid signal and 24 head motion parameters (6 motion parameters for the current volume, 6 motion parameters for the previous volume and 12 corresponding squared items) were regressed from the data. Finally, to reduce the effects of low-frequency drift and high-frequency physiological noise, linear detrending and temporal bandpass filtering (0.01–0.08 Hz) were performed. Analysis of voxel-mirrored homotopic connectivity The VMHC computation was performed using the DPABI package. Briefly, all normalized GM images were averaged to create a mean normalized GM image. Subsequently, this image was then averaged with its left-right mirrored version to generate a group-specific symmetrical template. Then, the normalized GM images were registered to the symmetric template, and nonlinear transformation was applied to the normalized functional images. Specifically, in the symmetrical brain space, we calculated the VMHC value as the Pearson’s correlation coefficient (Fisher z-transformed) between the residual time-series data of every pair of symmetrical interhemispheric voxels (Canna et al., 2017; Zuo et al., 2010). Analysis of auditory cortical subregions RSFCs The auditory cortex has been cytoarchitectonically parcellated into primary (Te1.0, Te1.1, Te1.2) and a higher auditory subregion (Te3.0) (Morosan et al., 2005, 2001), and we performed whole-brain RSFC analysis on each subregion. Briefly, along the lateral-to-medial direction, a region of interest (ROI) mask for each subregion (ROI1, Te3.0; ROI2, Te1.2, ROI3, Te1.0; ROI4, Te1.1) was defined within the custom space based on SPM12 Anatomy Toolbox (Eickhoff et al., 2005) (first column of Fig. 2 and Fig. 3A). Subsequently, the regional mean time course within the ROI was extracted by averaging the time courses of all the voxels belonging to the ROI. The regional mean time course was then used to compute correlation coefficients with the time courses of all GM voxels. Notably, the computation was constrained within a GM mask, which was generated by thresholding (threshold of 0.2) a prior GM probability map in SPM12. The resulting correlation coefficients were further converted to z scores using Fisher’s r-to-z transformation to improve normality. For each subject, we obtained 4 z-score maps indicative of intrinsic RSFC patterns of the four auditory cortical subregions. Statistical analysis To examine between-group VMHC and auditory subregions related to RSFC differences in the UHI and HC groups, we performed nonparametric permutation tests based on 10000 permutations. This procedure was conducted using the Statistical nonParametric Mapping (SnPM) toolbox (http://www.nitrc.org/projects/snpm/) in SPM12. SnPM uses a general linear model to construct pseudo t-statistic images, which are then assessed for significance using a standard nonparametric multiple comparisons procedure test (Nichols and Holmes, 2002). A recent study (Eklund et al., 2016) reported the reliability of the nonparametric permutation method in controlling false-positive rates in cluster-level inference. In this study, we set the significance level as the cluster-forming threshold of 0.01 with a familywise error rate (FWE)-corrected cluster of P < 0.05, controlling for age, gender and education level. Next, to investigate the relationships of RSFC alterations with hearing impairment degree and duration, we 5

first explored the relationships of hearing impairment degree and duration with mean VMHC values within regions exhibiting group differences. Second, to investigate relationships between hearing impairment degree and duration with subregion-based RSFC strength, we separately performed correlation analysis (dependent variable: RSFC strength; independent variables: hearing-impairment duration and PTA) within regions exhibiting group differences in the subregion-based RSFC analysis, controlling for age, gender and education level (FWE corrected, P < 0.05). Additional analyses involving subpopulations Due to the heterogeneity of the LHI and RHI populations, we further performed additional analyses involving subpopulations to evaluate the robustness of our main results. We separately compared normal-hearing HCs with subsets of (1) only patients with severe-to-profound UHI (10 LHI and 14 RHI) and (2) only patients with hearing-impairment durations greater than 24 months (14 LHI and 20 RHI). The between-group differences in the VMHC values and RSFCs of the auditory cortical subregions were recomputed in the selected LHI and RHI subsets. Results Demographic and clinical data No significant differences in age (P = 0.106), gender composition (P = 0.666), or education level (P = 0.376) existed between the UHI and HC groups. In addition, no significant differences were identified between the LHI and RHI groups for PTA thresholds or hearing-impairment duration (Table 2). Voxel-mirrored homotopic connectivity The VMHC maps are presented in Fig. 1. Visual examination of VMHC demonstrated remarkable regional differences in homotopic RSFC in both patients (Fig. 1A and Fig. 1B) and HCs (Fig. 1C). Robust homotopic connectivity was observed in the motor, somatosensory, and visual areas, as well as in subcortical regions (thalamus, basal ganglia and brainstem). These findings are consistent with those of previous studies (Canna et al., 2017; Zuo et al., 2010). Further statistical analysis revealed that compared with HCs, only patients with LHI exhibited stronger VMHC within and around the bilateral auditory cortex (Fig. 1D and Table 3), and no significant difference in VMHC was observed between RHI and HCs. Between-group differences in the RSFCs of auditory cortical subregions in the LHI group Significant between-group differences in RSFCs with each auditory cortical subregion between the LHI and HCs groups are illustrated in the second column of Fig. 2 and in Table 3. Both the Te3.0 and Te1.0 regions exhibited significantly decreased RSFC with the inferior parietal lobe (IPL), a component of DMN. Te1.1 also exhibited significantly decreased RSFC with the IPL. Moreover, Te1.1 exhibited further increased RSFC with the right inferior precentral gyrus and the anterior insula, which are core components of the ventral attention network (VAN). Additionally, we observed increased RSFC between the Te1.2 and bilateral supplementary motor area (SMA) regions, which belong to the somatomotor network (SMN). Between-group differences in the RSFCs of auditory cortical subregions in the RHI group 6

Between-group differences in the RSFCs of auditory cortical subregions in the RHI group are illustrated in the last column of Fig. 2 and in Table 4. All subregions exhibited significantly decreased RSFCs with typical components of DMN, including the medial prefrontal cortex (mPFC) and the dorsolateral prefrontal cortex (DLPFC). In addition, Te1.1 exhibited further increased RSFC with the right inferior precentral gyrus and anterior insula, a core component of VAN. Additionally, we observed increased RSFC between the Te1.2 and medial occipital area regions belonging to the visual network (VN). Relationship of RSFC alterations with hearing impairment degree and duration First, in the LHI group, we observed a significant positive correlation between PTA and mean VMHC values within the regions exhibiting group differences (Fig. 3B; r = 0.48, P < 0.05). Second, in the LHI group, a higher PTA was significantly associated with higher RSFC between the ROI 3 seed and left IPL (Fig. 4; r = 0.70, P < 0.05). No significant correlations between RSFC and hearing-impairment duration were identified in the LHI group. Furthermore, no significant associations between RSFC alterations and hearing impairment degree and duration were observed in the RHI group. Additional analysis involving subpopulations Our main results were reproducible when analysis was restricted to patients with severe-to-profound UHI (Fig. 5 and Fig. 6) or patients with hearing-impairment durations greater than 24 months (Fig. 5 and Fig. 7), indicating that our findings were indeed due to left/right ear differences rather than differences in clinical factors. In these additional analyses, stronger VMHC values within and around the bilateral auditory cortex were exclusively identified in the LHI group. The LHI and RHI groups exhibited differential patterns of altered functional connectivity in multiple brain networks with the four subregions of the auditory network. Notably, in analysis of patients with severe-to-profound UHI, more widespread regions exhibiting altered RSFC were observed in the RHI group (Fig. 6 vs. Fig. 2). For example, the posterior cingulate cortex (PCC), a core component of the DMN, exhibited decreased RSFC with the Te3.0 and Te1.2 ROIs. Discussion We demonstrated the following: (1) long-term imbalanced auditory input results in enhanced interhemispheric connectivity within the bihemispheric auditory network, (2) UHI patients exhibited differential patterns of altered functional connectivity with other sensory and higher-order networks among the four subregions of the auditory network, and (3) the altered RSFCs within and beyond the auditory network were dependent on the side of hearing impairment. Together, we demonstrated monaural-driven functional changes with altered RSFCs within and beyond the auditory network. Enhanced interhemispheric RSFC within the auditory network in UHI Using a VMHC approach, we demonstrated increased interhemispheric connectivity within the bihemispheric auditory network that was specific to the LHI group. This interhemispheric hyperconnectivity likely contributed to the increased symmetry of response latency and the amplitude strength between contra and ipsilateral auditory cortices in both neurophysiological and imaging studies on adult-onset UHI (Eggermont, 2017; Langers et al., 2005; 7

Ponton et al., 2001). Moreover, this phenomenon is particularly true when hearing impairment occurs in the left ear (Hanss et al., 2009; Khosla et al., 2003). This finding together with our finding of differential ear effects on interhemispheric connectivity are consistent with the theoretical framework proposed by Zatorre and Belin (Zatorre and Belin, 2001), which emphasizes hemispheric asymmetries for auditory processing such that temporal resolution is better in left auditory cortices and spectral resolution is better in right auditory cortices. Moreover, the PTA and interhemispheric RSFC were correlated, suggesting that hearing levels impact brain functional changes. Remarkably, previous studies reported that higher interhemispheric connectivity between bihemispheric auditory cortices induced by transcranial magnetic stimulation was associated with better performance in a melody discrimination task (Andoh et al., 2015; Andoh and Zatorre, 2011). Thus, a reasonable hypothesis is that increased interhemispheric connectivity within the bihemispheric auditory network might mirror homeostatic plasticity in compensation for binaural input loss, which is specific to LHI patients. This finding was consistent with previous studies reporting that compared with LHI patients, RHI patients suffered from significantly poorer functions of sound recognition and localization in noise (Gustafson and Hamill, 1995; Hartvig et al., 1989). Further studies combining extensive auditory-related profiling and RSFC analysis in UHI are of great interest to explore the relationship between neuroplasticity and changes in auditory ability, which may in turn facilitate advances in intervention. Specifically, previous studies demonstrated that interhemispheric interactions within the auditory network were highly likely mediated by callosal connections (Andoh et al., 2015; Westerhausen and Hugdahl, 2008). We hypothesized that such reorganization within the bihemispheric auditory network in patients with LHI might be related to anatomical changes in corresponding commissural fibers in the corpus callosum, but this hypothesis must be specifically tested in further structural studies. Altered RSFC between the auditory network and multiple brain networks in UHI In addition to functional changes in interhemispheric interactions within the auditory network, we observed that long-term monaural input resulted in widespread alterations in connectivity with other sensory and higher-order brain functional networks, mainly including the DMN, VAN, SMN and VN (Fig. 8). To our knowledge, this is the first study specifically examining altered RSFC between architectonically defined subregions of the auditory network and other multiple large-scale brain networks in long-term UHI. In both the LHI and RHI groups, subregions Te3.0 (ROI1) and Te1.0 (ROI3) exhibited equally reduced RSFC, exclusively with regions of the DMN. Previous rs-fMRI studies (Wang et al., 2014; Zhang et al., 2015, 2016) reported changes in entropic RSFCs and nodal topological properties in the DMN of UHI patients but did not emphasize the influence of auditory cortical subregions. As a non-primary parabelt auditory area, subregion Te3.0 is involved in the integration of different auditory features and interacts with higher-order brain areas (Barrett and Hall, 2006; Morosan et al., 2005; Scott and Johnsrude, 2003). With the highest density of granular layer IV, subregion Te1.0 is considered a koniocortical core auditory area (Burton et al., 2012; Morosan et al., 2001). Moreover, Te1.0 was related to frequencies that characterize human speech (Morosan et al., 2005), and the DMN is associated with nongoal-directed cognition, memory, and semantic processing (Raichle and Snyder, 2007). Thus, the decreased RSFCs of non-primary and core primary auditory subregions with DMN regions suggested that UHI is associated with alterations in a neural system that subserves cognitive functions, which might be related to cognitive bias. Another major finding in this study was altered RSFC in the lateral (Te1.2, ROI2) and medial (Te1.1, ROI4) belt subregions of auditory cortices with multiple brain networks, ranging from sensory (SMN and VN) to higher-order functional networks (DMN and VAN). Cytoarchitectonically, subregions Te1.1 and Te1.2 are less 8

granular than the core auditory subregion Te1.0, serving as a transitional zone between primary auditory areas and non-primary areas (Morosan et al., 2001). By combining microelectrode recordings with anatomical tract-tracing, previous studies found that the belt auditory cortex of primates was reciprocally connected with multiple domains in the following principal directions: rostral, caudal, medial, and lateral (Hackett, 2011; Romanski et al., 1999). Thus, these features provided anatomical support for altered RSFC between belt auditory cortices and multiple brain networks in UHI patients. UHI patients experience difficulties in listening to speech in noise (Gordin et al., 2009) and localizing sound (Litovsky et al., 2006). Thus, to limit the consequence of hearing deficits, increased RSFC might occur to compensate for maintaining perceptional and cognitive abilities, reflecting a cross-modal plasticity in UHI. Our results were consistent with those of previous studies, which revealed that deprivation of sensory input after hearing damage results in cross-modal plasticity in sensory and higher-order cortices (Wang et al., 2014). Moreover, a positive correlation was noted between the PTA and RSFC in the LHI group and was not observed in the RHI group, raising the possibility that the hearing level had disparate effects on functional reorganization between the LHI and RHI groups. In the current study, no significant correlation between RSFC alterations and the duration of hearing impairment was observed in UHI patients. The null findings are potentially explained as follows: the duration of hearing impairment reported by the patients might have been subjectively biased or the duration unit (months) may not have provided sufficient temporal resolution to detect significant correlations. Moreover, because the development of brain plasticity over time is biologically complex, the relationship between brain changes and the duration of hearing impairment may be more complicated and not linear. Differential effects of the side of hearing impairment on RSFC patterns in UHI In our study, the results of divergent RSFC patterns in patients with LHI and RHI provide empirical evidence

that the effects of UHI on the brain are related to the side of hearing impairment. These differential patterns highlight the specialization and interhemispheric lateralization of auditory cortical functions, such as language (Scott and Johnsrude, 2003) and spatial cognition (Spierer et al., 2009), and may thus have differential connectivity patterns involving specific sensory and higher-order areas. This asymmetry has been supported by numerous neuroimaging studies demonstrating hemispheric differences in spectral and temporal resolution (Boemio et al., 2005; Hyde et al., 2008; Jamison et al., 2006). Notably, since input from the right ear is predominantly processed in the left hemisphere of the brain, it is widely accepted that the so-called right ear advantage reflects left-hemisphere dominance for language processing (Giraud et al., 2007; Obleser et al., 2008; Schmithorst et al., 2013; Westerhausen and Hugdahl, 2008). In patients with RHI, the main left ear input, which is predominantly conveyed to the right hemisphere, needs to be further transferred to language processing centers. Moreover, by top-down (instruction-driven) regulation (Westerhausen and Hugdahl, 2008), patients with RHI must constantly attend to the left ear (forced-left attention) to decrease the effect of the right ear advantage and thus require additional cognitive control resources (Kompus et al., 2012; Zhang et al., 2017). Consistently, we observed more distributed regions with altered RSFCs in patients with RHI than in patients with LHI. Further investigations are required to assess the extent to which this divergent RSFC pattern represents disparate hearing and psychoacoustic abilities in patients with LHI and RHI. Limitations and further considerations Several issues need to be addressed. First, because the subjects were relatively heterogeneous, and the sample 9

size in each cohort was small, generalization of our current results warrants further validation using a larger cohort that includes a homogeneous population. Indeed, this study included both LHI and RHI patients with a broad range of hearing levels (e.g., moderate, severe, profound), and our study was too underpowered to detect this influence on RSFC patterns. Nonetheless, our main results were reproducible when the analysis was restricted to patients with severe-to-profound UHI or patients with hearing-impairment durations greater than 24 months, indicating that our findings were indeed due to left/right ear differences rather than the heterogeneity of clinical factors. Moreover, the reported results of divergent altered RSFC patterns within and beyond the auditory networks in patients with LHI and RHI were highly consistent with previous studies on UHI children (Schmithorst et al., 2014) and post-lingual UHI adults (Zhang et al., 2015). Second, in the context of fMRI research, the possible confounding effect of acoustic scanner noise (ASN) on intrinsic connectivity networks can represent a technological issue (Andoh et al., 2017). In our study, all participants were fitted with soft earplugs and an electrostatic headphone to attenuate ASN. To further circumvent concerns regarding ASN, studies on evoked potentials and evoked magnetic fields without ASN are clearly warranted to draw firm conclusions. Third, future studies are needed to understand the interplay among large-scale neural networks and their associations with psychoacoustic and behavior dimensions in UHI patients. Finally, since the anatomical structure has constraints on functional connectivity, we employed priori cytoarchitectonic-identified subdivisions in the auditory cortex. The use of subfields based on the functional topography of the auditory cortex will be important to characterize brain functional changes responding to long-term monaural input. Conclusion In this study, we found that long-term UHI resulted in enhanced interhemispheric connectivity within the bihemispheric auditory network and altered functional connectivity with other sensory and higher-order networks among the auditory network subregions. Together, our findings indicated that although the functional changes in UHI might be rooted around the common auditory network, monaural auditory deprivation could also be associated with altered connectivity within cortico-cortical networks that also support other sensory and higher-order functions. Understanding the underlying brain changes following the deprivation of unilateral auditory input may facilitate the formulation of a comprehensive clinical treatment plan for patients with hearing disorders. Conflicts of interest There are no conflicts of interest in this study.

References Andoh J, Ferreira M, Leppert IR, Matsushita R, Pike B, Zatorre RJ (2017) How restful is it with all that noise? Comparison of Interleaved silent steady state (ISSS) and conventional imaging in resting-state fMRI. Neuroimage 147:726-735. Andoh J, Matsushita R, Zatorre RJ (2015) Asymmetric Interhemispheric Transfer in the Auditory Network: Evidence from TMS, Resting-State fMRI, and Diffusion Imaging. J Neurosci 35:14602-14611. Andoh J, Zatorre RJ (2011) Interhemispheric Connectivity Influences the Degree of Modulation of TMS-Induced Effects during Auditory Processing. Front Psychol 2:161. Ashburner J, Friston KJ (2005) Unified segmentation. Neuroimage 26:839-851. 10

Barrett DJ, Hall DA (2006) Response preferences for "what" and "where" in human non-primary auditory cortex. Neuroimage 32:968-977. Bertolero MA, Yeo BT, D'Esposito M (2015) The modular and integrative functional architecture of the human brain. Proc Natl Acad Sci U S A 112:E6798-6807. Biswal B, Yetkin FZ, Haughton VM, Hyde JS (1995) Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med 34:537-541. Boemio A, Fromm S, Braun A, Poeppel D (2005) Hierarchical and asymmetric temporal sensitivity in human auditory cortices. Nat Neurosci 8:389-395. Bressler SL, Menon V (2010) Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci 14:277-290. Burton H, Firszt JB, Holden T, Agato A, Uchanski RM (2012) Activation lateralization in human core, belt, and parabelt auditory fields with unilateral deafness compared to normal hearing. Brain Res 1454:33-47. Canna A, Prinster A, Monteleone AM, Cantone E, Monteleone P, Volpe U, Maj M, Di SF, Esposito F (2017) Interhemispheric functional connectivity in anorexia and bulimia nervosa. Eur J Neurosci 45:1129-1140. Chang JL, Pross SE, Findlay AM, Mizuiri D, Henderson-Sabes J, Garrett C, Nagarajan SS, Cheung SW (2016) Spatial plasticity of the auditory cortex in single-sided deafness. Laryngoscope 126:2785-2791. Dalzell L, Orlando M, MacDonald M, Berg A, Bradley M, Cacace A, Campbell D, DeCristofaro J, Gravel J, Greenberg E, Gross S, Pinheiro J, Regan J, Spivak L, Stevens F, Prieve B (2000) The New York State universal newborn hearing screening demonstration project: ages of hearing loss identification, hearing aid fitting, and enrollment in early intervention. Ear Hear 21:118-130. Eggermont JJ (2017) Acquired hearing loss and brain plasticity. Hear Res 343:176-190. Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25:1325-1335. Eklund A, Nichols TE, Knutsson H (2016) Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proc Natl Acad Sci U S A 113:7900-7905. Firszt JB, Reeder RM, Holden LK (2017) Unilateral Hearing Loss: Understanding Speech Recognition and Localization Variability-Implications for Cochlear Implant Candidacy. Ear Hear 38:159-173. Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME (2005) The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A 102:9673-9678. Fransson P, Skiöld B, Horsch S, Nordell A, Blennow M, Lagercrantz H, Aden U (2007) Resting-state networks in the infant brain. Proc Natl Acad Sci U S A 104:15531-15536. Giraud AL, Kleinschmidt A, Poeppel D, Lund TE, Frackowiak RS, Laufs H (2007) Endogenous cortical rhythms determine cerebral specialization for speech perception and production. Neuron 56:1127-1134. Gordin A, Papsin B, James A, Gordon K (2009) Evolution of cochlear implant arrays result in changes in behavioral and physiological responses in children. Otol Neurotol 30:908-915. Gustafson TJ, Hamill TA (1995) Differences in localization ability in cases of right versus left unilateral simulated conductive hearing loss. J Am Acad Audiol 6:124-128. Hackett TA (2011) Information flow in the auditory cortical network. Hear Res 271:133-146. Hanss J, Veuillet E, Adjout K, Besle J, Collet L, Thai-Van H (2009) The effect of long-term unilateral deafness on the activation pattern in the auditory cortices of French-native speakers: influence of deafness side. BMC Neurosci 10:23. Hartvig JJ, Johansen PA, Børre S (1989) Unilateral sensorineural hearing loss in children and auditory performance with respect to right/left ear differences. Br J Audiol 23:207-213. Hyde KL, Peretz I, Zatorre RJ (2008) Evidence for the role of the right auditory cortex in fine pitch resolution. Neuropsychologia 46:632-639. Jamison HL, Watkins KE, Bishop DV, Matthews PM (2006) Hemispheric specialization for processing auditory nonspeech stimuli. 11

Cereb Cortex 16:1266-1275. Khosla D, Ponton CW, Eggermont JJ, Kwong B, Don M, Vasama JP (2003) Differential ear effects of profound unilateral deafness on the adult human central auditory system. J Assoc Res Otolaryngol 4:235-249. Kompus K, Specht K, Ersland L, Juvodden HT, van Wageningen H, Hugdahl K, Westerhausen R (2012) A forced-attention dichotic listening fMRI study on 113 subjects. Brain Lang 121:240-247. Langers DR, van Dijk P, Backes WH (2005) Lateralization, connectivity and plasticity in the human central auditory system. Neuroimage 28:490-499. Leaver AM, Rauschecker JP (2016) Functional Topography of Human Auditory Cortex. J Neurosci 36:1416-1428. Liang X, Zou Q, He Y, Yang Y (2013) Coupling of functional connectivity and regional cerebral blood flow reveals a physiological basis for network hubs of the human brain. Proc Natl Acad Sci U S A 110:1929-1934. Lieu JE, Tye-Murray N, Fu Q (2012) Longitudinal study of children with unilateral hearing loss. Laryngoscope 122:2088-2095. Litovsky R, Parkinson A, Arcaroli J, Sammeth C (2006) Simultaneous bilateral cochlear implantation in adults: a multicenter clinical study. Ear Hear 27:714-731. Liu B, Feng Y, Yang M, Chen JY, Li J, Huang ZC, Zhang LL (2015) Functional Connectivity in Patients With Sensorineural Hearing Loss Using Resting-State MRI. Am J Audiol 24:145-152. Menon V (2011) Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci 15:483-506. Menon V, Uddin LQ (2010) Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct 214:655-667. Morosan P, Rademacher J, Palomero-Gallagher N, Zilles K (2005) Anatomical organization of the human auditory cortex: cytoarchitecture and transmitter receptors. The Auditory Cortex: A Synthesis of Human and Animal Research, eds R. König, P. Heil, E. Budinger and H. Scheich (Mahwah, NJ, US: Lawrence Erlbaum Associates Publishers) :27-50. Morosan P, Rademacher J, Schleicher A, Amunts K, Schormann T, Zilles K (2001) Human primary auditory cortex: cytoarchitectonic subdivisions and mapping into a spatial reference system. Neuroimage 13:684-701. Nichols TE, Holmes AP (2002) Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15:1-25. Niskar AS, Kieszak SM, Holmes A, Esteban E, Rubin C, Brody DJ (1998) Prevalence of hearing loss among children 6 to 19 years of age: the Third National Health and Nutrition Examination Survey. JAMA 279:1071-1075. Obleser J, Eisner F, Kotz SA (2008) Bilateral speech comprehension reflects differential sensitivity to spectral and temporal features. J Neurosci 28:8116-8123. Ponton CW, Vasama JP, Tremblay K, Khosla D, Kwong B, Don M (2001) Plasticity in the adult human central auditory system: evidence from late-onset profound unilateral deafness. Hear Res 154:32-44. Pross SE, Chang JL, Mizuiri D, Findlay AM, Nagarajan SS, Cheung SW (2015) Temporal Cortical Plasticity in Single-Sided Deafness: A Functional Imaging Study. Otol Neurotol 36:1443-1449. Raichle ME, Snyder AZ (2007) A default mode of brain function: a brief history of an evolving idea. Neuroimage 37:1083-1090; discussion 1097-1099. Rauschecker JP, Scott SK (2009) Maps and streams in the auditory cortex: nonhuman primates illuminate human speech processing. Nat Neurosci 12:718-724. Romanski LM, Tian B, Fritz J, Mishkin M, Goldman-Rakic PS, Rauschecker JP (1999) Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex. Nat Neurosci 2:1131-1136. Schmithorst VJ, Farah R, Keith RW (2013) Left ear advantage in speech-related dichotic listening is not specific to auditory processing disorder in children: A machine-learning fMRI and DTI study. Neuroimage Clin 3:8-17. Schmithorst VJ, Plante E, Holland S (2014) Unilateral deafness in children affects development of multi-modal modulation and default mode networks. Front Hum Neurosci 8:164. Scott SK, Johnsrude IS (2003) The neuroanatomical and functional organization of speech perception. Trends Neurosci 26:100-107. 12

Spierer L, Bellmann-Thiran A, Maeder P, Murray MM, Clarke S (2009) Hemispheric competence for auditory spatial representation. Brain 132:1953-1966. Wang X, Fan Y, Zhao F, Wang Z, Ge J, Zhang K, Gao Z, Gao JH, Yang Y, Fan J, Zou Q, Liu P (2014) Altered regional and circuit resting-state activity associated with unilateral hearing loss. PLoS One 9:e96126. Westerhausen R, Hugdahl K (2008) The corpus callosum in dichotic listening studies of hemispheric asymmetry: a review of clinical and experimental evidence. Neurosci Biobehav Rev 32:1044-1054. Woods DL, Herron TJ, Cate AD, Yund EW, Stecker GC, Rinne T, Kang X (2010) Functional properties of human auditory cortical fields. Front Syst Neurosci 4:155. Yan CG, Wang XD, Zuo XN, Zang YF (2016) DPABI: Data Processing & Analysis for (Resting-State) Brain Imaging. Neuroinformatics 14:339-351. Zatorre RJ, Belin P (2001) Spectral and temporal processing in human auditory cortex. Cereb Cortex 11:946-953. Zatorre RJ, Gandour JT (2008) Neural specializations for speech and pitch: moving beyond the dichotomies. Philos Trans R Soc Lond B Biol Sci 363:1087-1104. Zhang GY, Yang M, Liu B, Huang ZC, Chen H, Zhang PP, Li J, Chen JY, Liu LJ, Wang J, Teng GJ (2015) Changes in the default mode networks of individuals with long-term unilateral sensorineural hearing loss. Neuroscience 285:333-342. Zhang GY, Yang M, Liu B, Huang ZC, Li J, Chen JY, Chen H, Zhang PP, Liu LJ, Wang J, Teng GJ (2016) Changes of the directional brain networks related with brain plasticity in patients with long-term unilateral sensorineural hearing loss. Neuroscience 313:149-161. Zhang Y, Mao Z, Feng S, Wang W, Zhang J, Yu X (2017) Convergent and divergent functional connectivity patterns in patients with long-term left-sided and right-sided deafness. Neurosci Lett 665:74-79. Zuo XN, Kelly C, Di MA, Mennes M, Margulies DS, Bangaru S, Grzadzinski R, Evans AC, Zang YF, Castellanos FX, Milham MP (2010) Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy. J Neurosci 30:15034-15043.

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Figure Legends Fig. 1. Interhemispheric functional connectivity within and between groups. Axial MR images reveal the mean interhemispheric functional connectivity in patients (A, RHI; B, LHI) and control (C) groups. D, Homotopic regions show increased functional connectivity in the LHI group (P < 0.05, corrected). LHI, left-sided hearing impairment; HC, healthy control; RHI, right-sided hearing impairment.

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Fig. 2. Between-group differences in RSFCs of the auditory cortical subregions. The first column shows the auditory cortical subregions. The second and third columns depict the between-group statistical RSFC maps of the LHI and RHI groups, respectively, with a corrected statistical threshold of P < 0.05. LHI, left-sided hearing impairment; HC, healthy control; RHI, right-sided hearing impairment; RSFC, resting-state functional connectivity.

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Fig. 3. (A) The auditory cortex was cytoarchitectonically parcellated into primary (Te1.0, Te1.1, Te1.2) and higher auditory (Te3.0) subregions. Region of interest (ROI) masks for each subregion were defined along the lateral-to-medial direction for further whole-brain RSFC analysis. (B) In the LHI group, the strength of the VMHC within the regions showing group differences correlated with the hearing level, as measured by PTA scores (r = 0.48, P < 0.05). LHI, left-sided hearing impairment; PTA, pure tone average; ROI, region of interest; VMHC, 16

voxel-mirrored homotopic connectivity.

Fig. 4. In the LHI group, the strength of the RSFC between ROI3 (Te1.0) and the left angular gyrus correlated with hearing level, as measured by the PTA (r = 0.70, P < 0.01). LHI, left-sided hearing-impaired; PTA, pure tone average; RSFC, resting-state functional connectivity.

Fig. 5. Homotopic regions show increased functional connectivity in the LHI group (P < 0.05, corrected) when the analysis was restricted to patients with severe-to-profound UHI (A) or to patients with hearing-impairment durations greater than 24 months (B). LHI, left-sided hearing impairment.

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Fig. 6. Differences in RSFC of the auditory cortical subregions between HCs and patients with severe-to-profound UHI (10 LHI and 14 RHI). The first column presents the auditory cortical subregions. The second and third columns depict the between-group statistical RSFC maps of the LHI and RHI groups, respectively, with a corrected statistical threshold of P < 0.05. LHI, left-sided hearing impairment; HC, healthy control; RHI, right-sided hearing impairment; RSFC, resting-state functional connectivity.

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Fig. 7. Differences in RSFC of the auditory cortical subregions between HCs and patients with a duration of hearing impairment greater than 24 months (14 LHI and 20 RHI). The first column shows the auditory cortical subregions. The second and third columns show the between-group statistical RSFC maps of the LHI and RHI 19

group, respectively, with a corrected statistical threshold of P < 0.05. LHI, left-sided hearing impairment; HC, healthy control; RHI, right-sided hearing impairment; RSFC, resting-state functional connectivity.

Fig. 8. Schematic layout of the altered RSFC model in patients with LHI and RHI. (A) LHI resulted in enhanced 20

interhemispheric FC within the bihemispheric auditory network and altered FC between auditory cortical subregions and multiple networks (DMN, VAN, and SMN). (B) RHI resulted in altered FC between auditory cortical subregions and multiple networks (DMN, VAN, VN, and SMN). In both patients with LHI and patients with RHI, the non-primary auditory subregion (ROI1, Te3.0) and core primary auditory subregion (ROI3, Te1.0) exhibited decreased FC exclusively with the DMN, whereas the belt primary auditory subregions (ROI2, Te1.2 and ROI4, Te1.1) exhibited altered FC with multiple networks (DMN, VAN, and SMN). AN, auditory network; DMN, default mode network; FC, functional connectivity; LHI, left-sided hearing impairment; RHI, right-sided hearing impairment; SMN, somatomotor network; VAN, ventral attention network; VN, visual network.

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Table 1. Audiologic information of all patients with unilateral hearing impairment Patient number

Gender

L01 L02 L03 L04 L05 L06 L07 L08 L09 L10 L11 L12 L13 L14 L15 L16 L17 R0I R02 R03 R04 R05 R06 R07 R08 R09 R10 R11 R12 R13 R14 R15 R16 R17 R18 R19 R20 R21

M F F M M F F M F F F F F F F M F M M F M M F M F F M F M F F F F F F F F F

(years)

PTA of affected ear (dB HL)

Disease duration (months)

Severity of hearing impairment

61 64 51 58 62 27 45 49 45 22 42 36 51 37 42 56 45 47 43 62 42 51 48 38 41 65 46 45 57 58 47 59 60 27 61 58 53 44

80 70 56 85 55 92 47 66 93 80 46 100 40 47 65 70 47 40 117 66 40 70 78 118 51 50 67 41 43 118 70 118 80 118 100 66 118 40

33 26 48 34 22 62 22 34 48 22 24 48 33 24 56 48 60 48 80 40 60 24 47 22 43 58 29 48 49 46 31 44 42 56 40 52 40 25

Severe Severe Moderate Profound Moderate Profound Moderate Severe Profound Severe Moderate Profound Moderate Moderate Severe Severe Moderate Moderate Profound Severe Moderate Severe Severe Profound Moderate Moderate Severe Moderate Moderate Profound Severe Profound Severe Profound Profound Severe Profound Moderate

Age

Note: L, left-sided hearing impairment; R, right-sided hearing impairment; F, female; M, male; PTA, pure tone average of the hearing thresholds at the frequencies of 0.5, 1.0, 2.0 and 4.0 kHz.

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Table 2. Clinical and demographic data of all participants Group

LHI (n = 17)

RHI (n = 21)

HCs (n = 21)

P value

Age (years)

46.6±11.9

50.1±9.5

43.8±7.0

0.106a

Male/Female

5/12

7/14

9/12

0.666b

Education (years)

9.88±2.8

11.43±3.3

11.2±4.3

0.376a

PTA (dB HL)

L: 67.0±18.9

R: 76.6±30.8

0.267c*

R: 15.1±3.0

L: 15.0±3.0

0.962c**

37.9±14.1

44.0±13.6

0.184c

UHI duration (months)

Note: LHI, left-sided hearing impairment; RHI, right-sided hearing impairment; HCs, healthy controls; PTA, pure tone average of the hearing thresholds at the frequencies of 0.5, 1.0, 2.0 and 4.0 kHz; HL, hearing level; UHI, unilateral hearing impairment. a P-value was obtained using one-way ANOVA (two-tailed);

b

P-value was obtained using a Pearson Chi-square test (two-tailed); c P-value was

obtained using the independent-sample t-test (two-tailed); * comparison of hearing level in the affected ears between LHI and RHI groups; ** comparison of hearing level in unaffected ears between LHI and RHI groups. Unless otherwise indicated, data are means ± standard deviation. Table 3. Brain regions showing altered RSFC between the LHI and HC groups Brain regions

BA

Cluster size

Peak MNI coordinate

Peak T

(voxels)

x

y

48

457

-51

0

0

4.43

40/39

282

-42

-51

42

-5.50

6

540

-12

-45

63

4.99

z

Interhemispheric RSFC STG/HG/Insula ROI_based RSFC ROI1

L.IPL/AG

RIO2

SMA

ROI3

L.IPL/AG

40/39

352

-30

-51

33

4.49

ROI4

L.IPL/AG

40/39

322

-45

-54

51

-4.12

R.ROL/Ins/ PreCG

48/6

332

42

-9

0

4.16

Note: Statistical threshold was set at P < 0.05, corrected. LHI, left-sided hearing impairment; HC, healthy control; ROI, regions of interest; BA, Brodmann areas; MNI, Montreal Neurological Institute; RSFC, resting-state functional connectivity; STG, superior parietal gyrus; HG, Heschl’s gyrus; IPL, inferior parietal lobule; AG, angular gyrus; SMA, supplementary motor area; ROL, Rolandic operculum; Ins, insula; PreCG, precentral gyrus; L, left; R, right.

Table 4. Brain regions exhibiting altered RSFC between the RHI and HC groups Brain regions ROI_based RSFC ROI1 RIO2

ROI3 ROI4

L. SFG/ MFG/dmPFC R.Cun L. SFG/ MFG/ dmPFC L.IPL/AG L. SFG/ MFG/ dmPFC L. SFG/ MFG/ dmPFC

BA

9/46/32 18 9/46/32 40/39 9/46/32 9/46/32 23

Cluster size (voxels) 1118 270 1842 299 333 1683

Peak MNI coordinate x

y

z

-21 12 -45 -42 9 -9

57 -75 15 -57 54 18

9 33 42 36 18 60

Peak T

-5.43 3.89 -5.45 -4.19 -4.20 -5.70

L.ROL/Ins/ PreCG R.ROL/Ins/ PreCG

48 48/6

473 1287

-60 51

-21 -36

12 60

4.99 4.77

Note: Statistical threshold was set at P < 0.05, corrected. RHI, right-sided hearing impairment; HC, healthy control; ROI, regions of interest; BA, Brodmann areas; MNI, Montreal Neurological Institute; RSFC, resting-state functional connectivity; SFG, superior frontal gyrus; MFG, middle frontal gyrus; dmPFC, dorsal medial prefrontal cortex; IPL, inferior parietal lobule; AG, angular gyrus; ROL, Rolandic operculum; Ins, insula; PrCG, precentral gyrus; L, left; R, right.

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Highlights

1. Long-term UHI resulted in enhanced interhemispheric connectivity within auditory network. 2. Auditory subregions showed differential patterns of RSFC with other sensory and higher-order networks. 3. The patterns of altered functional connectivity were dependent on the side of hearing impairment.

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