Abstract
Tinnitus, a phantom auditory perception that can seriously affect quality of life, is generally triggered by cochlear trauma and associated with aberrant activity throughout the auditory pathways, often referred to as hyperactivity. Studies suggest that non-auditory structures, such as prefrontal cortex (PFC), may be involved in tinnitus generation, by affecting sensory gating in auditory thalamus, allowing hyperactivity to reach the cortex and lead to perception. Indeed, human studies have shown that repetitive transcranial magnetic stimulation (rTMS) of PFC can alleviate tinnitus. The current study investigated whether this therapeutic effect is achieved through inhibition of thalamic hyperactivity, comparing effects of two common clinical rTMS protocols with sham treatment, in a guinea pig tinnitus model. Animals underwent acoustic trauma and once tinnitus developed were treated with either intermittent theta burst stimulation (iTBS), 20 Hz rTMS, or sham rTMS (10 days, 10 min/day; weekdays only). Tinnitus was reassessed and extracellular recordings of spontaneous tonic and burst firing rates in auditory thalamus made. To verify effects in PFC, densities of neurons positive for calcium-binding proteins, calbindin and parvalbumin, were investigated using immunohistochemistry. Both rTMS protocols significantly reduced tinnitus compared to sham. However, spontaneous tonic firing decreased following 20 Hz stimulation and increased following iTBS in auditory thalamus. Burst rate was significantly different between 20 Hz and iTBS stimulation, and burst duration was increased only after 20 Hz treatment. Density of calbindin, but not parvalbumin positive neurons, was significantly increased in the most dorsal region of PFC indicating that rTMS directly affected PFC. Our results support the involvement of PFC in tinnitus modulation, and the therapeutic benefit of rTMS on PFC in treating tinnitus, but indicate this is not achieved solely by suppression of thalamic hyperactivity.
Highlights
Tinnitus is a phantom auditory percept, often described as a ringing or buzzing in the ear, which affects 10–15% of the population (Baguley et al, 2013)
Baseline behavioral tinnitus testing was performed to establish that the neural circuitry underlying startle response and prepulse inhibition (PPI) was normal and to ensure there was no evidence of pre-existing tinnitus
Once animals presented with behavioral signs of tinnitus, active repetitive transcranial magnetic stimulation (rTMS) or sham rTMS was administered over the prefrontal cortex (PFC) of the awake animal for 10 min, weekdays only, over a period of 2 weeks
Summary
Tinnitus is a phantom auditory percept, often described as a ringing or buzzing in the ear, which affects 10–15% of the population (Baguley et al, 2013). Clinical studies in tinnitus patients have shown that noninvasive stimulation of PFC, using techniques such as repetitive transcranial stimulation (rTMS) and direct current stimulation, can alleviate tinnitus loudness and distress (Kleinjung et al, 2008; Vanneste et al, 2011; De Ridder et al, 2013; Lehner et al, 2013; Langguth et al, 2014) This was recently replicated in a randomised placebo-controlled, single-blinded clinical trial using high frequency rTMS over the dorsomedial PFC, which showed a statistically significant reduction in tinnitus severity (Ciminelli et al, 2020). We investigated the effects of rTMS on PFC, through quantitative immunohistochemical analysis of calcium binding proteins, as studies have shown changes in these proteins following rTMS treatment (Benali et al, 2011; Hoppenrath and Funke, 2013; Volz et al, 2013; Labedi et al, 2014; Mix et al, 2014; Mulders et al, 2019)
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