Functional Brain Regions Linked to Tinnitus Pathology and Compensation During Task Performance: A Systematic Review.

OBJECTIVE: To systematically search the literature and organize relevant advancements in the connection between tinnitus and the activity of different functional brain regions using functional magnetic resonance imaging (fMRI). DATA SOURCES: MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Web of Science, ProQuest Dissertations & Theses Global, Cochrane Database of Systematic Reviews, and PROSPERO from inception to April 2022. REVIEW METHODS: Studies with adult human subjects who suffer from tinnitus and underwent fMRI to relate specific regions of interest to tinnitus pathology or compensation were included. In addition, fMRI had to be performed with a paradigm of stimuli that would stimulate auditory brain activity. Exclusion criteria included non-English studies, animal studies, and studies that utilized a resting state magnetic resonance imaging or other imaging modalities. RESULTS: The auditory cortex may work to dampen the effects of central gain. Results from different studies show variable changes in the Heschl's gyrus (HG), with some showing increased activity and others showing inhibition and volume loss. After controlling for hyperacusis and other confounders, tinnitus does not seem to influence the inferior colliculus (IC) activation. However, there is decreased connectivity between the auditory cortex and IC. The cochlear nucleus (CN) generally shows increased activation in tinnitus patients. fMRI evidence indicates significant inhibition of thalamic gating. Activating the thalamus may be of important therapeutic potential. CONCLUSION: Patients with tinnitus have significantly altered neuronal firing patterns, especially within the auditory network, when compared to individuals without tinnitus. Tinnitus and hyperacusis commonly coexist, making differentiation of the effects of these 2 phenomena frequently difficult.

Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex.

BACKGROUND: Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. OBJECTIVE: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. METHODS: We quantified intracellular and extracellular antibody labelling of Aß42 in 6 regions of the central auditory system from p14 to p150. RESULTS: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aß42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. CONCLUSION: These results suggest that Aß42 accumulation, but not plaques, may impair gap detection.

Left hemispheric deficit in the sustained neuromagnetic response to periodic click trains in children with ASD.

BACKGROUND: Deficits in perception and production of vocal pitch are often observed in people with autism spectrum disorder (ASD), but the neural basis of these deficits is unknown. In magnetoencephalogram (MEG), spectrally complex periodic sounds trigger two continuous neural responses-the auditory steady state response (ASSR) and the sustained field (SF). It has been shown that the SF in neurotypical individuals is associated with low-level analysis of pitch in the 'pitch processing center' of the Heschl's gyrus. Therefore, alternations in this auditory response may reflect atypical processing of vocal pitch. The SF, however, has never been studied in people with ASD. METHODS: We used MEG and individual brain models to investigate the ASSR and SF evoked by monaural 40 Hz click trains in boys with ASD (N = 35) and neurotypical (NT) boys (N = 35) aged 7-12-years. RESULTS: In agreement with the previous research in adults, the cortical sources of the SF in children were located in the left and right Heschl's gyri, anterolateral to those of the ASSR. In both groups, the SF and ASSR dominated in the right hemisphere and were higher in the hemisphere contralateral to the stimulated ear. The ASSR increased with age in both NT and ASD children and did not differ between the groups. The SF amplitude did not significantly change between the ages of 7 and 12 years. It was moderately attenuated in both hemispheres and was markedly delayed and displaced in the left hemisphere in boys with ASD. The SF delay in participants with ASD was present irrespective of their intelligence level and severity of autism symptoms. LIMITATIONS: We did not test the language abilities of our participants. Therefore, the link between SF and processing of vocal pitch in children with ASD remains speculative. CONCLUSION: Children with ASD demonstrate atypical processing of spectrally complex periodic sound at the level of the core auditory cortex of the left-hemisphere. The observed neural deficit may contribute to speech perception difficulties experienced by children with ASD, including their poor perception and production of linguistic prosody.

The use of animal models to study cell transplantation in neuropathic hearing loss.

Auditory neuropathy (AN) is a form of sensorineural deafness specifically affecting the conduction of the nerve impulse from the cochlear hair cells to the auditory centres of the brain. As such, the condition is a potential clinical target for 'cell replacement therapy', in which a functioning auditory nerve is regenerated by transplanting an appropriated neural progenitor. In this review, we survey the current literature and examine possible experimental models for this condition, with particular reference to their compatibility as suitable hosts for transplantation. The use of exogenous neurotoxic agents such as ouabain or ß-bungarotoxin is discussed, as are ageing and noise-induced synaptopathy models. Lesioning of the nerve by mechanical damage during surgery and the neuropathy resulting from infectious diseases may be very relevant clinically, and we discuss whether there are good models for these situations. We also address genetic models for AN, examining whether the phenotypes truly model the clinical situation in their human counterpart syndromes - we use the example of the hyperbilirubinaemic Gunn rat as a particular instance in this regard.

Male rats exhibit higher pro-BDNF, c-Fos and dendritic tree changes after chronic acoustic stress.

Prolonged or intense exposure to environmental noise (EN) has been associated with a number of changes in auditory organs as well as other brain structures. Notably, males and females have shown different susceptibilities to acoustic damage as well as different responses to environmental stressors. Rodent models have evidence of sex-specific changes in brain structures involved in noise and sound processing. As a common effect, experimental models have demonstrated that dendrite arborizations reconfigure in response to aversive conditions in several brain regions. Here, we examined the effect of chronic noise on dendritic reorganization and c-Fos expression patterns of both sexes. During 21 days male and female rats were exposed to a rats' audiogram-fitted adaptation of a noisy environment. Golgi-Cox and c-Fos staining were performed at auditory cortices (AC) and hippocampal regions. Sholl analysis and c-Fos counts were conducted for evidence of intersex differences. In addition, pro-BDNF serum levels were also measured. We found different patterns of c-Fos expression in hippocampus and AC. While in AC expression levels showed rapid and intense increases starting at 2 h, hippocampal areas showed slower rises that reached the highest levels at 21 days. Sholl analysis also evidenced regional differences in response to noise. Dendritic trees were reduced after 21 days in hippocampus but not in AC. Meanwhile, pro-BDNF levels augmented after EN exposure. In all analyzed variables, exposed males were the most affected. These findings suggest that noise may exert differential effects on male and female brains and that males could be more vulnerable to the chronic effects of noise.

Antioxidants reduce neurodegeneration and accumulation of pathologic Tau proteins in the auditory system after blast exposure.

Cochlear neurodegeneration commonly accompanies hair cell loss resulting from aging, ototoxicity, or exposures to intense noise or blast overpressures. However, the precise pathophysiological mechanisms that drive this degenerative response have not been fully elucidated. Our laboratory previously demonstrated that non-transgenic rats exposed to blast overpressures exhibited marked somatic accumulation of neurotoxic variants of the microtubule-associated protein, Tau, in the hippocampus. In the present study, we extended these analyses to examine neurodegeneration and pathologic Tau accumulation in the auditory system in response to blast exposure and evaluated the potential therapeutic efficacy of antioxidants on short-circuiting this pathological process. Blast injury induced ribbon synapse loss and retrograde neurodegeneration in the cochlea in untreated animals. An accompanying perikaryal accumulation of neurofilament light chain and pathologic Tau oligomers were observed in neurons from both the peripheral and central auditory system, spanning from the spiral ganglion to the auditory cortex. Due to its coincident accumulation pattern and well-documented neurotoxicity, our results suggest that the accumulation of pathologic Tau oligomers may actively contribute to blast-induced cochlear neurodegeneration. Therapeutic intervention with a combinatorial regimen of 2,4-disulfonyl α-phenyl tertiary butyl nitrone (HPN-07) and N-acetylcysteine (NAC) significantly reduced both pathologic Tau accumulation and indications of ongoing neurodegeneration in the cochlea and the auditory cortex. These results demonstrate that a combination of HPN-07 and NAC administrated shortly after a blast exposure can serve as a potential therapeutic strategy for preserving auditory function among military personnel or civilians with blast-induced traumatic brain injuries.

Monoaural musical hallucinations caused by a thalamocortical auditory radiation infarct: a case report.

INTRODUCTION: Musical hallucinations are complex auditory perceptions in the absence of an external acoustic stimulus and are often consistent with previous listening experience. Their causation can be classified as associated with either psychiatric disorders, such as schizophrenia, or organic disorders, such as epilepsy or sensorineural deafness. Non-epileptic musical hallucinosis due to lesions of the central auditory pathway, especially of the thalamocortical auditory radiation, is rare. CASE PRESENTATION: We describe the case of an 85-year old ethnic Chinese woman with a history of transient ischemic attacks and chronic bilateral hearing impairment, who experienced an acute onset of left unilateral musical hallucinations. Our patient did not experience any psychiatric symptoms and there was no other neurological deficit. Pure tone audiometry revealed bilateral hypacusis and magnetic resonance imaging revealed a right non-dominant hemisphere sublenticular lacunar infarct of the thalamocortical auditory radiation. Our patient was managed expectantly and after three months her symptoms subsided spontaneously. CONCLUSION: We propose that all patients with monoaural musical hallucinations have brain imaging to rule out a central organic cause, especially within the non-dominant hemisphere, regardless of the presence of a hearing impairment.

Impaired development and competitive refinement of the cortical frequency map in tumor necrosis factor-α-deficient mice.

Early experience shapes sensory representations in a critical period of heightened plasticity. This adaptive process is thought to involve both Hebbian and homeostatic synaptic plasticity. Although Hebbian plasticity has been investigated as a mechanism for cortical map reorganization, less is known about the contribution of homeostatic plasticity. We investigated the role of homeostatic synaptic plasticity in the development and refinement of frequency representations in the primary auditory cortex using the tumor necrosis factor-α (TNF-α) knockout (KO), a mutant mouse with impaired homeostatic but normal Hebbian plasticity. Our results indicate that these mice develop weaker tonal responses and incomplete frequency representations. Rearing in a single-frequency revealed a normal expansion of cortical representations in KO mice. However, TNF-α KOs lacked homeostatic adjustments of cortical responses following exposure to multiple frequencies. Specifically, while this sensory over-stimulation resulted in competitive refinement of frequency tuning in wild-type controls, it broadened frequency tuning in TNF-α KOs. Our results suggest that homeostatic plasticity plays an important role in gain control and competitive interaction in sensory cortical development.

The vestibulocochlear nerve (VIII).

The vestibulocochlear nerve (8th cranial nerve) is a sensory nerve. It is made up of two nerves, the cochlear, which transmits sound and the vestibular which controls balance. It is an intracranial nerve which runs from the sensory receptors in the internal ear to the brain stem nuclei and finally to the auditory areas: the post-central gyrus and superior temporal auditory cortex. The most common lesions responsible for damage to VIII are vestibular Schwannomas. This report reviews the anatomy and various investigations of the nerve.

Intracerebral neural stem cell transplantation improved the auditory of mice with presbycusis.

Stem cell-based regenerative therapy is a potential cellular therapeutic strategy for patients with incurable brain diseases. Embryonic neural stem cells (NSCs) represent an attractive cell source in regenerative medicine strategies in the treatment of diseased brains. Here, we assess the capability of intracerebral embryonic NSCs transplantation for C57BL/6J mice with presbycusis in vivo. Morphology analyses revealed that the neuronal rate of apoptosis was lower in the aged group (10 months of age) but not in the young group (2 months of age) after NSCs transplantation, while the electrophysiological data suggest that the Auditory Brain Stem Response (ABR) threshold was significantly decreased in the aged group at 2 weeks and 3 weeks after transplantation. By contrast, there was no difference in the aged group at 4 weeks post-transplantation or in the young group at any time post-transplantation. Furthermore, immunofluorescence experiments showed that NSCs differentiated into neurons that engrafted and migrated to the brain, even to sites of lesions. Together, our results demonstrate that NSCs transplantation improve the auditory of C57BL/6J mice with presbycusis.

Neuromagnetic indicators of tinnitus and tinnitus masking in patients with and without hearing loss.

Tinnitus is an auditory phenomenon characterised by the perception of a sound in the absence of an external auditory stimulus. Chronic subjective tinnitus is almost certainly maintained via central mechanisms, and this is consistent with observed measures of altered spontaneous brain activity. A number of putative central auditory mechanisms for tinnitus have been proposed. The influential thalamocortical dysrhythmia model suggests that tinnitus can be attributed to the disruption of coherent oscillatory activity between thalamus and cortex following hearing loss. However, the extent to which this disruption specifically contributes to tinnitus or is simply a consequence of the hearing loss is unclear because the necessary matched controls have not been tested. Here, we rigorously test several predictions made by this model in four groups of participants (tinnitus with hearing loss, tinnitus with clinically normal hearing, no tinnitus with hearing loss and no tinnitus with clinically normal hearing). Magnetoencephalography was used to measure oscillatory brain activity within different frequency bands in a 'resting' state and during presentation of a masking noise. Results revealed that low-frequency activity in the delta band (1-4 Hz) was significantly higher in the 'tinnitus with hearing loss' group compared to the 'no tinnitus with normal hearing' group. A planned comparison indicated that this effect was unlikely to be driven by the hearing loss alone, but could possibly be a consequence of tinnitus and hearing loss. A further interpretative linkage to tinnitus was given by the result that the delta activity tended to reduce when tinnitus was masked. High-frequency activity in the gamma band (25-80 Hz) was not correlated with tinnitus (or hearing loss). The findings partly support the thalamocortical dysrhythmia model and suggest that slow-wave (delta band) activity may be a more reliable correlate of tinnitus than high-frequency activity.

Auditory cortex lesions do not disrupt habituation of HPA axis responses to repeated noise stress.

Previous research has suggested that sensory areas may play a role in adaptation to repeated stress. The auditory cortex was the target of the present studies because it is a major projection area of the auditory thalamus, where functional inactivation disrupts stress habituation to repeated loud noise. Large bilateral excitotoxic lesions of the auditory cortex were made in male rats 2 weeks prior to (Experiment 1) or a few days after (Experiment 2) a 5 day 30 min repeated 95 dBA noise or no noise regimen. Blood was collected immediately after exposure on days 1, 3, and 5. Two weeks after the 5th exposure, the rats were retested with 30 min noise or no noise to determine retention of the habituated responses. Animals were killed immediately after the retest and trunk blood and brains collected for lesion verification. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels were determined. In both experiments, significant between-subjects effects were found for noise (95 dBA or no noise) but not for surgery (lesion, sham, or no surgery control rats), with lesion groups exhibiting similar levels of ACTH and corticosterone across days as the sham and no surgery control groups. All noise exposed groups displayed similar habituation rates and retention levels. A third experiment indicated that similar auditory cortex lesions significantly disrupted background noise gap detection in an acoustic startle paradigm. Overall, these data suggest that the information mediating hypothalamic-pituitary-adrenal axis response habituation to repeated loud noise exposures is not derived from the auditory cortex.

Complications of pediatric auditory brain stem implantation via retrosigmoid approach.

OBJECTIVE: We aimed to present the complications of auditory brain stem implantations (ABI) in pediatric patients which were performed via retrosigmoid approach. METHODS: Between March 2007 and February 2010, five prelingually deaf children underwent ABI (Medel device) operation via retrosigmoid approach. All children had severe cochlear malformations. The ages ranged from 20 months to 5 years. The perioperative complications encountered in 2 patients were evaluated retrospectively. RESULTS: No intraoperative complication was observed in the patients. Cerebrospinal fluid (CSF) leakage was the most common postoperative complication that was seen in 2 patients. The CSF leak triggered a cascade of comorbidities, and elongated the hospitalization. CONCLUSION: Pediatric ABI surgery can lead to morbidity. The CSF leak is the most common complication encountered in retrosigmoid approach. The other complications usually result from long-term hospital stay during treatment period of the CSF leak. Therefore, every attempt must be made to prevent occurrence of CSF leaks in pediatric ABI operations.

Effects of damage to auditory cortex on the discrimination of speech sounds by rats.

The intensity of a noise-induced startle response can be reduced by the presentation of an otherwise neutral stimulus immediately before the noise ("prepulse inhibition" or PPI). We used a form of PPI to study the effects of damage to auditory cortex on the discrimination of speech sounds by rats. Subjects underwent control surgery or treatment of the auditory cortex with the vasoconstrictor endothelin-1. This treatment caused damage concentrated in primary auditory cortex (A1). Both before and after lesions, subjects were tested on 5 tasks, most presenting a pair of human speech sounds (consonant-vowel syllables) so that the capacity for discrimination would be evident in the extent of PPI. Group comparisons failed to reveal any consistent lesion effect. At the same time, the analysis of individual differences in performance by multiple regression suggests that some of the temporal processing required to discriminate speech sounds is concentrated anteroventrally in the right A1. These results also confirm that PPI can be adapted to studies of the brain mechanisms involved in the processing of speech and other complex sounds.

Altered language processing in autosomal dominant partial epilepsy with auditory features.

BACKGROUND: Autosomal dominant partial epilepsy with auditory features (ADPEAF) is an idiopathic focal epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 (LGI1) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG). METHODS: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included. RESULTS: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls. CONCLUSIONS: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant partial epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing.

Audition differently activates the visual system in neonatally enucleated mice compared with anophthalmic mutants.

The occipital cortex, normally visual, can be activated by auditory or somatosensory tasks in the blind. This cross-modal compensation appears after early or late onset of blindness with differences in activation between early and late blind. This could support the hypothesis of a reorganization of sensory pathways in the early blind that does not occur in later onset blindness. Using immunohistochemistry of the c-Fos protein following a white noise stimulus and injections of the anterograde tracer dextran-biotin in the inferior colliculus, we studied how the occurrence of blindness influences cross-modal compensation in the mutant anophthalmic mouse strain and in C57BL/6 mice enucleated at birth. We observed, in mutant mice, immunolabeled nuclei in the visual thalamus - the dorsal lateral geniculate nucleus - in the primary visual area (V1) and a few labeled nuclei in the secondary visual area (V2). In enucleated mice, we observed auditory activity mainly in V2 but also sparsely in V1. No labeled cells could be found in the visual thalamus. Tracing studies confirmed the difference between anophthalmic and birth-enucleated mice: whereas the first group showed inferior colliculus projections entering both the dorsal lateral geniculate and the latero-posterior nuclei, in the second, auditory fibers were found only within the latero-posterior thalamic nucleus. None was found in controls with intact eyes. We suggest that the prenatal period of spontaneous retinal activity shapes the differences of the sensory reorganization in mice.

Which tinnitus patients benefit from transcranial magnetic stimulation?

OBJECTIVES: Chronic tinnitus is associated with hyperactivity of the central auditory system. Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been proposed as a treatment for chronic tinnitus. This study determined the factors that predict a beneficial outcome with rTMS treatment. STUDY DESIGN: Forty-five patients with chronic tinnitus underwent 10 sessions of low-frequency rTMS to their left auditory cortex. The treatment outcome was assessed with a tinnitus questionnaire. Therapeutic success was related to the patients' clinical characteristics. RESULTS: A significant reduction in tinnitus complaints occurred after rTMS. In the questionnaire, 40% of the patients improved by five points or more. Treatment responders were characterized by shorter duration of tinnitus complaints and no hearing impairment. CONCLUSION: Tinnitus-related neuroplastic changes might be less pronounced in patients with normal hearing and a short history of complaints. This could explain why those patients benefitted more from rTMS treatment.

Detection of sinusoidal amplitude modulated sounds: deficits after bilateral lesions of auditory cortex in the rat.

The ability of rats to detect the presence of sinusoidal amplitude modulation (AM) of a broadband noise carrier was determined before and after bilateral ablation of auditory cortex. The rats were trained to withdraw from a drinking spout to avoid a shock when they detected a modulation of the sound. Sensitivity was evaluated by testing the rats at progressively smaller depths of modulation. Psychophysical curves were produced to describe the limits of detection at modulation rates of 10, 100 and 1000Hz. Performance scores were based on the probability of withdrawal from the spout during AM (warning periods) relative to withdrawal during the un-modulated noise (safe periods). A threshold was defined as the depth of modulation that produced a score halfway between perfect avoidance and no avoidance (performance score=0.5). Bilateral auditory cortical lesions resulted in significant elevations in threshold for detection of AM at rates of 100 and 1000Hz. No significant shift was found at a modulation rate of 10Hz. The magnitude of the deficit for AM rates of 100 and 1000Hz was positively correlated with the size of the cortical lesion. Substantial deficits were found only in animals with lesions that included secondary as well as primary auditory cortical areas. The results show that the rat's auditory cortex is important for processing sinusoidal AM and that its contribution is most apparent at high modulation rates. The data suggest that the auditory cortex is a crucial structure for maintaining normal sensitivity to temporal modulation of an auditory stimulus.

Functional magnetic resonance imaging of hearing-impaired children under sedation before cochlear implantation.

OBJECTIVE: To investigate functional magnetic resonance imaging (fMRI) in pediatric cochlear implantation candidates with residual hearing who are under sedation for evaluation of auditory function. DESIGN: During fMRI, subjects heard a random sequence of tones (250-4000 Hz) presented 10 dB above hearing thresholds. Tones were interleaved with silence in a block-periodic fMRI design with 30-second on-off intervals. Twenty-four axial sections (5 mm thick) covering most of the brain were obtained every 3 seconds for a total acquisition time of 5.5 minutes. SETTING: Single tertiary academic medical institution. PATIENTS: Severely to profoundly hearing-impaired children (n=10; mean age, 49.1 months). During fMRI, subjects were awake (n=2) or sedated with pentobarbital sodium if their weight was 10 kg or greater (n=4) or chloral hydrate if their weight was less than 10 kg (n=4). MAIN OUTCOME MEASURES: Detection of brain activation by fMRI in the primary auditory cortex (A1) in hearing-impaired patients under sedation, and correlation of A1 activation with hearing levels measured after cochlear implantation. RESULTS: In most subjects, fMRI detected significant levels of activation in the A1 region before cochlear implantation. The improvement in hearing threshold after cochlear implantation correlated strongly (linear regression coefficient, R=0.88) with the amount of activation in the A1 region detected by fMRI before cochlear implantation. CONCLUSIONS: Functional MRI can be considered a means of assessing residual function in the A1 region in sedated hearing-impaired toddlers. With improvements in acquisition, processing, and sedation methods, fMRI may be translated into a prognostic indicator for outcome after cochlear implantation in infants.