Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans

Marks, Kendra L.; Martel, David T.; Wu, Calvin; Basura, Gregory J.; Roberts, Larry E.; Schvartz-Leyzac, Kara C.; Shore, Susan E.

doi:10.1126/scitranslmed.aal3175

Cited by 129 publications

(195 citation statements)

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“…The method of noise exposure was previously described (Marks et al, ; Stefanescu et al, ; Wu et al, ). First, to investigate the effects of noise exposure on the hippocampus, guinea pigs were anesthetized with ketamine/xylazine (40 mg/kg ketamine; 10 mg/kg xylazine) and placed in a double‐walled soundproof booth.…”

Section: Methodsmentioning

confidence: 99%

“…Stress, sleep, hearing loss, gender and age are all associated with tinnitus (Kim et al, ; Park et al, ). Patients with tinnitus often report a history of acoustic overexposure (Schmuzigert, Fostiropoulos, & Probst, ), and noise exposure is widely used as a method of tinnitus induction in animal models (Berger et al, ; Marks et al, ; Wu, Martel, & Shore, ).…”

Section: Introductionmentioning

confidence: 99%

“…A large body of tinnitus‐related research has focused on auditory sensory pathways, including cochlear nucleus (Koehler & Shore, ; Stefanescu, Koehler, & Shore, ; Wu et al, ), inferior colliculus (Bauer, Turner, Caspary, Myers, & Brozoski, ; Smit et al, ; Wang et al, ), medial geniculate body (Kalappa, Brozoski, Turner, & Caspary, ; Sametsky, Turner, Larsen, Ling, & Caspary, ), and auditory cortex (Basura, Koehler, & Shore, ; Geven, de Kleine, Willemsen, & van Dijk, ; Llano, Turner, & Caspary, ). However, accumulating evidence suggests that non‐auditory systems (Landgrebe et al, ; Marks et al, ; Ouyang et al, ; Vanneste & De Ridder, ; Vanneste, Plazier, van der Loo, Van de Heyning, & De Ridder, ; Zhang, Luo, Pace, Li, & Liu, ) might also play a role in tinnitus. Upregulation of somatosensory inputs to cochlear nucleus in compensation for reduced auditory innervation after cochlear damage is related to altered neural plasticity in cochlear nucleus, which is thought to be an underlying mechanism of tinnitus (Koehler & Shore, ; Marks et al, ; Wu et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…However, accumulating evidence suggests that non‐auditory systems (Landgrebe et al, ; Marks et al, ; Ouyang et al, ; Vanneste & De Ridder, ; Vanneste, Plazier, van der Loo, Van de Heyning, & De Ridder, ; Zhang, Luo, Pace, Li, & Liu, ) might also play a role in tinnitus. Upregulation of somatosensory inputs to cochlear nucleus in compensation for reduced auditory innervation after cochlear damage is related to altered neural plasticity in cochlear nucleus, which is thought to be an underlying mechanism of tinnitus (Koehler & Shore, ; Marks et al, ; Wu et al, ). The hippocampus, a brain region implicated in learning and memory as well as mood (Mineur et al, ; Ramirez et al, ; Wang, Finnie, Hardt, & Nader, ), provides a dense input to auditory cortex (Cenquizca & Swanson, ) and receives auditory input from auditory association cortices directly or indirectly via the parahippocampal cortex, or via other forebrain pathways including medial frontal cortex, insula, or amygdala (Kraus & Canlon, ; Mohedano‐Moriano et al, ; Munoz‐Lopez, Mohedano‐Moriano, & Insausti, ).…”

Section: Introductionmentioning

confidence: 99%

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Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Zhang

Martel

et al. 2018

Hippocampus

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Here, we investigate remodeling of hippocampal cholinergic inputs after noise exposure and determine the relevance of these changes to tinnitus. To assess the effects of noise exposure on the hippocampus, guinea pigs were exposed to unilateral noise for 2 hr and 2 weeks later, immunohistochemistry was performed on hippocampal sections to examine vesicular acetylcholine transporter (VAChT) expression. To evaluate whether the changes in VAChT were relevant to tinnitus, another group of animals was exposed to the same noise band twice to induce tinnitus, which was assessed using gap‐prepulse Inhibition of the acoustic startle (GPIAS) 12 weeks after the first noise exposure, followed by immunohistochemistry. Acoustic Brainstem Response (ABR) thresholds were elevated immediately after noise exposure for all experimental animals but returned to baseline levels several days after noise exposure. ABR wave I amplitude‐intensity functions did not show any changes after 2 or 12 weeks of recovery compared to baseline levels. In animals assessed 2‐weeks following noise‐exposure, hippocampal VAChT puncta density decreased on both sides of the brain by 20–60% in exposed animals. By 12 weeks following the initial noise exposure, changes in VAChT puncta density largely recovered to baseline levels in exposed animals that did not develop tinnitus, but remained diminished in animals that developed tinnitus. These tinnitus‐specific changes were particularly prominent in hippocampal synapse‐rich layers of the dentate gyrus and areas CA3 and CA1, and VAChT density in these regions negatively correlated with tinnitus severity. The robust changes in VAChT labeling in the hippocampus 2 weeks after noise exposure suggest involvement of this circuitry in auditory processing. After chronic tinnitus induction, tinnitus‐specific changes occurred in synapse‐rich layers of the hippocampus, suggesting that synaptic processing in the hippocampus may play an important role in the pathophysiology of tinnitus.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Zhang

Martel

et al. 2018

Hippocampus

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“…The guinea pig is an excellent experimental model for many aspects of human physiology and pathophysiology -including maternal and fetal adaptations to pregnancy [14][15][16][17] cardiac excitation-contraction coupling [18], asthma and airway drug responsiveness [19][20], auditory somatosensory processes [21], type 2 diabetes [22] and vitamin C deficiency [23] yet there is limited experimental information regarding the proteome available for this species. In an effort to overcome this obstacle, we sought to generate, via numerous LC-MS/MS measurements, a spectral library of the guinea pig proteome.…”

Section: Introductionmentioning

confidence: 99%

The generation of a comprehensive spectral library for the analysis of the guinea pig proteome by SWATH-MS

Palmowski

Watson

Europe‐Finner

et al. 2019

Preprint

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Advances in liquid chromatography-mass spectrometry have facilitated the incorporation of proteomic studies to many biology experimental workflows. Data-independent acquisition platforms, such as sequential window acquisition of all theoretical mass spectra (SWATH-MS), offer several advantages for label-free quantitative assessment of complex proteomes over data-dependent acquisition (DDA) approaches. However, SWATH data interpretation requires spectral libraries as a detailed reference resource. The guinea pig (Cavia porcellus) is an excellent experimental model for translation to many aspects of human physiology and disease, yet there is limited experimental information regarding its proteome. To overcome this knowledge gap, a comprehensive spectral library of the guinea pig proteome is generated. Homogenates and tryptic digests are prepared from 16 tissues and subjected to >200 DDA runs. Analysis of >250 000 peptide-spectrum matches resulted in a library of 73 594 peptides from 7666 proteins. Library validation is provided by i) analyzing externally derived SWATH files (https:// doi.org/10.1016/j.jprot.2018.03.023) and comparing peptide intensity quantifications; ii) merging of externally derived data to the base library. This furnishes the research community with a comprehensive proteomic resource that will facilitate future molecular-phenotypic studies using (re-engaging) the guinea pig as an experimental model of relevance to human biology. The spectral library and raw data are freely accessible in the MassIVE repository (MSV000083199).

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Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

et al. 2023

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ImportanceAnimal models have shown altered dorsal cochlear nucleus circuitry in animals that develop tinnitus; however, precise treatment using bisensory (auditory and somatosensory) stimuli can reverse altered neural patterns and lessen tinnitus.ObjectiveTo confirm and extend the findings of a pilot study, which suggested an increased efficacy of bisensory stimulation, to a clinical trial with a greater duration and greater number of participants.Design, Setting, and ParticipantsThis double-blind, crossover, single-center randomized clinical trial was conducted from March 2019, with a 3-month follow-up per participant ending in July 2022. Eligible adults were recruited from the University of Michigan Health System in Ann Arbor, Michigan. Eligibility criteria included bothersome tinnitus (Tinnitus Functional Index [TFI] score, ≥17 points), somatic tinnitus, normal to moderate hearing loss, and no other tinnitus treatments in the 6 months prior to the trial. Included participants were randomized to either treatment group 1, which received active (bisensory) treatment, or group 2, which received the control (auditory-only) treatment. Results were analyzed using intent-to-treat (ITT) and per protocol (PP) populations.InterventionPrecisely timed bisensory (combined auditory and somatosensory) treatment was delivered through a portable, custom, take-home device that was provided to each participant for daily, at-home treatments. Group 1 participants received 30 minutes per day of the bisensory treatment for 6 weeks, followed by a 6-week washout phase, and then 30 minutes per day of the auditory-only treatment followed by a second 6-week washout phase. Group 2 participants received the auditory-only treatment first, followed by a washout phase, and then the bisensory treatment followed by a second washout phase.Main Outcomes and MeasuresPrimary end points were changes in TFI score and tinnitus loudness level from baseline through week 6 and week 12.ResultsOf 337 screened individuals, 99 (mean [SD] age, 47 [12.7] years; 59 males [60%]; 85 with non-Hispanic White [86%] race and ethnicity) were enrolled into the study and randomized to treatment group 1 (n = 49) or group 2 (n = 50). The active but not the control treatment resulted in clinically significant decreases in TFI scores at week 6 of phase 1 (ITT population: –12.0 [95% CI, –16.9 to –7.9] points; P &lt; .001; PP population: –13.2 [95% CI, –16.0 to –10.5] points; P &lt; .001). Decreases in tinnitus loudness level were greater than 6 dB sensation level (SL; &gt;half as loud) at week 6 for the bisensory treatment group, with little effect for the auditory-only treatment control group at week 6 of phase 1 (ITT population: –5.8 [95% CI, –9.5 to –2.2] dB; P = .08; PP population: –7.2 [95% CI, –11.4 to –3.1] dB; P = .03), and up to 11 dB SL at week 12 of phase 2 (ITT population: –10.9 [95% CI, –15.2 to –6.5] dB; P = .001; PP population: –14.1 [95% CI, –18.4 to –9.8] dB; P &lt; .001). Decreased tinnitus loudness level and TFI scores extended into the washout phase, indicating a prolonged treatment effect.Conclusions and RelevanceThis trial found that precisely timed bisensory treatment using stimuli and timing developed in a validated animal model was effective for adults with somatic tinnitus. Prolonged reduction in tinnitus symptoms can result from using an extended treatment duration.Trial RegistrationClinicalTrials.gov Identifier: NCT03621735

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Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans

Cited by 129 publications

References 72 publications

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

Remodeling of cholinergic input to the hippocampus after noise exposure and tinnitus induction in Guinea pigs

The generation of a comprehensive spectral library for the analysis of the guinea pig proteome by SWATH-MS

Reversing Synchronized Brain Circuits Using Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts

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