Draft:Bimodal Stimulation for Tinnitus

Bimodal stimulation is an innovative therapeutic approach that involves the simultaneous or sequential activation of two different sensory modalities to modulate neural activity. This technique is gaining attention for its potential to treat various neurological conditions, including tinnitus. Bimodal stimulation for tinnitus typically involves the concurrent use of auditory (sound) stimuli and somatosensory (tactile or electrical) stimuli. Bimodal stimulation represents a novel and promising approach for tinnitus treatment, leveraging the plasticity and interconnectedness of sensory systems. By simultaneously engaging the auditory and somatosensory pathways, bimodal stimulation aims to modulate neural circuits involved in tinnitus perception. While current evidence supports its efficacy, further research is needed to optimize treatment protocols, understand underlying mechanisms, and establish long-term benefits. As the field progresses, bimodal stimulation could become a cornerstone of personalized tinnitus therapy, offering hope to millions of individuals affected by this challenging condition.

Principles of Bimodal Stimulation
The primary principle behind bimodal stimulation is to leverage the brain's plasticity by engaging multiple sensory pathways simultaneously. By doing so, bimodal stimulation aims to promote adaptive changes in neural circuits through synergistic sensory inputs and reduce abnormal neural hyperactivity associated with conditions like tinnitus.

Mechanisms of Bimodal Stimulation
Bimodal stimulation operates through several neurophysiological mechanisms. The underlying hypothesis is that concurrent stimulation of the auditory and somatosensory systems can modulate neural circuits involved in tinnitus, thereby reducing its volume and frequency. Research so far has demonstrated two primary mechanisms for this. First, bimodal stimulation may promote synaptic plasticity, leading to reorganization of neural pathways in the auditory cortex and other related areas. Studies have shown that paired auditory and somatosensory stimuli can induce long-term potentiation or depression, which might help recalibrate abnormal neural activity associated with tinnitus. Second, the auditory and somatosensory systems are interconnected at multiple levels of the central nervous system. Bimodal stimulation can enhance these cross-modal interactions, potentially normalizing hyperactivity in the auditory cortex.

Clinical Studies on Bimodal Stimulation
Marks et al. (2018) applied long term depression (LTD) inducing bimodal stimulation to 20 human subjects with tinnitus as part of a double-blinded, sham-controlled, crossover study design. Twenty-eight days of LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. Bimodal stimulation consisted of sounds and transcutaneous electrical stimulation of the neck. The sound stimuli were derived from each individual's tinnitus spectrum and audiogram delivered through calibrated insert earphones. The electrical (somatosensory) stimuli were administered using Ag-AgCl cups placed on the skin of the cervical spine or the cheek. Participants used the devices for 30 min once a day for 4-weeks. Weekly progress was monitored through loudness matching and the tinnitus functional index (TFI). At the conclusion of the four-week treatment, tinnitus loudness decreased an average of 8.035 ± 1.33 dB from a baseline of 54.42 ± 13.3 and TFI scores decreased from baseline of 29.2 ± 2.6 to 22.9 ± 1.8. The authors concluded that bimodal auditory-somatosensory stimulation induces LTD in the dorsal cochlear nucleus.

Conlon et al. (2020) conducted a parallel-arm, double-blind, randomized exploratory study investigating the efficacy of three different stimulation settings. The study included a large sample size of 326 participants, each fitted with a bimodal neuromodulation device. The device consisted of bimodal auditory and tongue stimulation. The auditory stimulus included sequences of tone bursts with a continuous structured wideband noise in the background presented through a headset. Audiometric thresholds were used to configure the intensity of the auditory stimuli to ~10 dB in SL (dB SL) above their hearing thresholds at each tone frequency. The tongue was stimulated electrically by a 32-electrode transmucosal array placed on the anterior dorsal surface of the tongue. The participants were asked to use the device for two 30-minute treatment sessions daily for a twelve-week period. Progress was assessed by comparing baseline and final tinnitus handicap inventory (THI) assessments and tinnitus functional index (TFI) assessments. Additionally, after participants stopped treatment, long term follow-up assessments were done at week 18 (6-week follow-up), week 38 (6-month follow-up), and week 64 (12-month follow-up) to assess the long-term efficacy of the treatment.

Three different treatment parameters were compared. Conlon et al. (2020) found that in the highest performing group (the group with synchronized tones and tongue stimulation), the average THI score dropped 14.6 points after 12 weeks of treatment and the average TFI score dropped 13.9 points. These benefits were also sustained when reassessed 12 weeks after treatment had stopped. Conlon et al. (2020) also observed during the second 6 weeks of stimulation, the improvement in tinnitus symptoms was less than that which occurred during the first 6 weeks of treatment. They concluded there may be habituation effects where the brain becomes less sensitive in response to repetitive stimuli over time.

In a follow-up to their first study, Conlon et al. (2022) explored if background wideband noise was necessary for efficacy during bimodal neuromodulation and if adjusting the parameter settings six weeks into treatment could overcome treatment habituation and progression plateaus. The stimulation device, prescribed frequency and duration of treatment, and outcome measures were the same as those described in Conlon et al. (2020). In this study Conlon et al. (2022) discovered that background wideband noise stimulation was not necessary for bimodal neuromodulation efficacy. Additionally, they discovered that adjusting the treatment parameters at six weeks (halfway through the 12-week treatment period) prevented a progression plateau at six weeks, with the participants showing a significant reduction in THI and TFI scores from week six to week twelve. The overall score improvements for the THI and the TFI when the treatment was adjusted at six weeks were 18.5 points and 15.3 point respectively.

Spencer et al. (2022) investigated the efficacy of bimodal stimulation for decreasing the severity of tinnitus in individuals with chronic subjective tinnitus. Twenty-nine participants were enrolled and received six 30-minute sessions of bimodal auditory and electrical stimulation over a period of 3 weeks. The auditory stimulation was in the form of tone bursts delivered through headphones and matched to the participant's tinnitus frequency. The electrical stimulation was delivered using a TENS device with electrodes located either bilaterally next to the spinal process of C2 or with one electrode positioned unilaterally on the temporomandibular joint and the second electrode placed ipsilaterally next to the spinal process of C2. During treatment each auditory stimulus was followed by an electrical stimulus with a delay of 5ms. Progress was measured using the tinnitus functional index administered pre and post treatment and 9-12 weeks following the final treatment session. Their results showed that only 2 out of 26 patients reported improvement immediately after the treatment and 6 out of 24 patients at follow up. While Spencer et al. (2022) was able to report a statistically significant TFI improvement, only small proportion of those patients could actually perceive the improvement in their tinnitus (TFI score improvement by 13 or more points). The possible explanation for the conflicting results in this study when compared to Conlon et al. (2020) or Marks et al. (2018) is the lower total duration of treatment and the single tone auditory stimulus with standardized timing between tones. The overall takeaway from this study was the need for further research on individualized parameter sets.

Perrotta et al. (2022) investigated the efficacy of bimodal stimulation using auditory tones plus haptic vibrations on the wrist. Instead of electrical stimulation, they set out to understand if tactile vibration was enough to elicit a similar modulation of the neural circuits responsible for tinnitus. A total of 45 participants were randomly assigned to an experimental condition that received bimodal stimulation with tones plus haptic vibrations, or a control condition that received tones only. Each participant completed ten minutes of daily treatment over the course of eight weeks. The auditory stimulus was delivered through a phone app in a random order and with random timing. The range of tone frequencies was set to be specific to the participant's main tinnitus frequency and spread logarithmically between an octave above and below each participant's tinnitus frequency. The haptic vibrations were delivered by a wristband with four vibrating motors embedded in the strap. The tones and vibrations were played simultaneously with the location of the vibration determined as a function of the frequency of each individual tone, such that the frequency map was spread across the skin. The results showed that participants who received tones paired with simultaneous vibrations of the wristband showed a clinically significant average improvement in TFI scores of 17.9 while the audio-only group only showed an average TFI score improvement of 7.5. Additionally, participants who started with study with a baseline TFI score of 50 or above, indicated more severe tinnitus, ended the study with an average TFI score improvement of 21.8. The contribution of these results is that they suggest convergence of neural signals at the dorsal cochlear nucleus is not the primary mechanism through which bimodal stimulation mitigates tinnitus. Equivalent or greater improvements in TFI score can be achieved using a tactile stimulus on the wrist in sequence with auditory tones for 10 minutes a day.

Challenges and Future Research
The results of bimodal stimulation studies are promising, however further research is still needed to fully take advantage of its capabilities. Tinnitus is a heterogeneous condition with diverse etiologies and manifestations. This variability can affect the outcomes of bimodal stimulation, highlighting the need for personalized treatment approaches. The efficacy of bimodal stimulation depends on various parameters, including the type, timing, and intensity of stimuli. Further research is needed to optimize these parameters for different tinnitus subtypes. Although some studies have shown sustained benefits, the long-term efficacy of bimodal stimulation remains uncertain. Longitudinal studies with extended follow-up periods are necessary to evaluate the durability of treatment effects. Finally, Despite progress, the precise mechanisms underlying bimodal stimulation are not fully understood. Advances in neuroimaging and neurophysiology could provide deeper insights into how bimodal stimulation influences neural circuits involved in tinnitus.

Future research on bimodal stimulation for tinnitus should focus on several key areas:

 * 1. Large-Scale Clinical Trials: Conducting large-scale, multicenter trials with diverse patient populations will help validate the clinical efficacy and generalizability of bimodal stimulation.
 * 2. Personalized Treatment Protocols: Developing algorithms and tools to personalize stimulation parameters based on individual patient characteristics and tinnitus profiles could enhance treatment outcomes.
 * 3. Mechanistic Studies: Employing advanced neuroimaging techniques and animal models to elucidate the neural mechanisms of bimodal stimulation will inform the development of more effective protocols.
 * 4. Combination Therapies: Exploring the potential of combining bimodal stimulation with other interventions, such as cognitive-behavioral therapy or pharmacotherapy, could provide synergistic benefits.

Currently Available Devices
The Lenire system by Neuromod includes a handheld controller, headphones for delivering auditory stimuli, and a tongue stimulator for somatosensory input. The device delivers simultaneous tones and mild electrical pulses to the tongue. These stimuli are designed to promote neuroplasticity in the brain, for the reduction of tinnitus symptoms. Patients typically use the device for 60 minutes per day over a period of twelve weeks.

The Duo system by Neosensory includes a haptic wristband with four vibrating motors and a phone app. The Phone app delivers auditory tones calibrated to the user's tinnitus frequency in synchrony with vibrations to the wrist. This system is also designed to promote neuroplasticity in the brain for the reduction of tinnitus symptoms. Patients use the device for 10 minutes a day over a period of eight weeks.