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Auditory GABA levels and FC between Heschl's gyrus and ACC mediate the relationship between hearing loss and cognitive impairment in presbycusis1Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China, 2Philips Healthcare, Shanghai, China, 3Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Synopsis
Keywords: Aging, Brain
Motivation: The increasing evidence suggests a connection between presbycusis and cognitive impairment, yet the neurochemical mechanisms remain largely unexplored.
Goal(s): To compare auditory cortex metabolite levels and brain functional connectivity strength between presbycusis patients and healthy controls, and explore their potential associations with cognitive function and hearing.
Approach: We used Magnetic Resonance Spectroscopy (MRS) and resting-state functional Magnetic Resonance Imaging (rs-fMRI).
Results: We found reduced GABA levels in the auditory cortex (AC), and decreased connectivity between the AC and the ACC in presbycusis. Furthermore, the changes jointly mediated the association between hearing loss and declines in verbal memory and information processing speed.
Impact: These findings support the sensory deprivation hypothesis and highlight the role of GABA-induced inhibitory reduction and the dysconnectivity of AC and ACC in presbycusis-related cognitive impairment, providing new insights into the neurochemical mechanisms of hearing loss-associated cognitive impairment.
Methods
109 presbycusis patients and 63 healthy controls (HC) who have already auditioned and underwent a battery of neuropsychological tests were scanned with a 3.0 T scanner (Philips ‘Achieva’ TX, Best, The Netherlands) using an eight-channel phased-array head coil. The 3.0 ppm GABA and 3.75 ppm Glu were measured using a macromolecule (MM)-suppressed MEGA-PRESS sequence. Finally, partial correlation analyses of the cognitive performance, auditory GABA and Glu levels, and FC strengths were performed separately for patients with presbycusis and HCs, while controlling for age, gender, and education level.Results
Compared with the NH group, the FC between right HG and left fusiform gyrus, left superior temporal gyrus, left middle temporal gyrus, ACC, right insular lobe, right putamen, right middle cingulate gyrus, and bilateral posterior central gyrus were significantly decreased in PC group (p < 0.05, FDR correction). There was no significant difference in the FC between left HG and other voxels in the whole brain in the PC group compared with the HC group. Patients with PC performed worse on the MoCA, AVLT, SDMT, Stroop, TMT-A, and TMT-B tests. GABA level in the right AC and Glu level in the bilateral AC showed significant differences between the two groups, and all these metabolites exhibited higher levels in the HC group. Moreover, mediation analyses revealed the mediation effects of the functional connectivity of AC-ACC on the association between the right auditory GABA levels and auditory verbal learning Test (AVLT) scores of presbycusis patients.Discussion
In addition to alterations in FC, our study identified a significant correlation between the decline in GABA levels in the right HG and both AVLT and TMT-A scores. Present evidence indicates that defects in synaptic transmission mediated by GABA, the brain's principal inhibitory neurotransmitter, correlate with cognitive impairments (1-3). Research is scarce on how the decreased GABA levels in the AC can ultimately trigger cognitive impairment in patients with presbycusis. Recent animal experiments demonstrated that following hearing loss in mice, the GABAergic system within the AC becomes disrupted, subsequently leading to diminished spatial memory(4). Hence, it has been hypothesized that in patients with presbycusis, the GABAergic system may undergo a cascade of changes from the AC to the cognitive system, culminating in cognitive impairment (5). Additionally, some research indicates that a decrease in GABA levels might impair the brain's ability to regulate synchronized gamma oscillations in the AC, rendering patients incapable of distinguishing speech from background noise and subsequently affecting central auditory processing. Consequently, additional cognitive resources are necessitated to compensate for difficulties in understanding speech attributed to peripheral hearing loss (6). In this study, the decreased GABA levels in the right HG and the decrease in FC between the right HG and the SN served as two mediators, mediators, mediating the association between hearing loss and cognitive impairment. This reflects the bottom-up cascading reactions caused by hearing loss in patients with presbycusis.Conclusion
Our findings indicated that the auditory GABAergic system plays a crucial role in regulating AC - ACC functional connectivity, which is further associated with cognitive impairment in presbycusis patients.Acknowledgements
This work was supported by the National Natural Science Foundation of China (Nos. 81601479), Taishan Scholars Project (No. tsqn201812147), Shandong Provincial Natural Science Foundation of China (Nos. ZR2021MH030).References
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3. Reid MA, Salibi N, White DM, Gawne TJ, Denney TS, Lahti AC. 7T Proton Magnetic Resonance Spectroscopy of the Anterior Cingulate Cortex in First-Episode Schizophrenia. Schizophr Bull. 2019;45(1):180-9.
4. Beckmann D, Feldmann M, Shchyglo O, Manahan-Vaughan D. Hippocampal Synaptic Plasticity, Spatial Memory, and Neurotransmitter Receptor Expression Are Profoundly Altered by Gradual Loss of Hearing Ability. Cereb Cortex. 2020;30(8):4581-96.
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