Tinnitus is the perception of sound when no actual external sound is present, and is therefore regarded as a phantom sensation comparable with phantom limb pain. It is a common disorder in industrialized countries, especially when levels of exposure to noise in professional or private life are high.
Peripheral hearing loss with reduced cochlear function is often present when tinnitus develops. Reduced input from the cochlear system is thought to cause central auditory system deafferentation, hyperactivity, and hyperexcitability.2,4 Lack of input in thalamic neurons causes hyperpolarization, burst firing, and pathological gamma band oscillations, and overall thalamocortical dysrhythmia.5,12 It has been observed that the primary auditory cortex also shows maladaptive neuroplasticity with reorganized frequency maps (tonotopy), focal hyperactivity, neuronal synchrony, burst firing, and gamma-theta phase–amplitude coupling.5,6,13 These features resemble alterations found in other circuitopathies like movement disorders or chronic pain—both of which are amenable to surgical neuromodulation.
One structure that may act as a bridging point between the auditory and the limbic system and therefore between the sensorineural perception of sounds and the awareness and emotional charge of said percepts is the dorsal striatum including the locus of caudate neurons (area LC).
The current article “Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus” by Cheung et al.3 represents the first phase I trial of continuous bilateral deep brain stimulation (DBS) in area LC for treatment-resistant tinnitus.
Area LC represents the transition zone between the head and body of the caudate and it came to the group’s attention after a patient with Parkinson disease (PD) and coexisting chronic bilateral tinnitus underwent left-sided subthalamic nucleus DBS lead placement and reported markedly reduced phantom percepts in both ears the day after surgery; this occurred without any stimulation.7 Postoperative imaging showed a stroke-like vascular injury medial to the DBS lead in the head and anterior portion of the body of the caudate. The patient remained tinnitus free in the ipsilateral ear and with substantially reduced phantom percepts in the contralateral ear for the follow-up duration of 18 months.
This and a published case of elimination of a preexisting bilateral tinnitus due to a left-sided ischemic lacunar stroke in the body of the caudate and the bordering white matter tracts without changes in overall hearing10 spawned interest in assessing the possibility of neuromodulation of the caudate to treat tinnitus. Targeting the caudate with DBS was thought to be easily achievable because typical trajectories of DBS leads for common movement disorder targets such as the subthalamic nucleus run close to the caudate or even traverse it.
The current article investigates whether bilateral continuous caudate DBS has meaningful beneficial effects in a population of patients that suffers severely from tinnitus and objectively investigates hearing safety before and after the procedure.3 Five of 6 patients were able to successfully complete the study protocol with a 60%–80% response rate regarding the Tinnitus Functional Index and Tinnitus Handicap Inventory after 24 weeks of DBS on the most effective stimulation settings.
Consistent with previous findings, continuous caudate DBS did not significantly alter hearing thresholds, thereby preserving hearing safety. No surgical complications or permanent stimulation-related side effects were observed.
To further refine targeting, the authors applied microelectrode recording and macrostimulation in up to 3 tracts spanning an area of up to 10 mm along the anterior-posterior axis of the caudate to define the optimal position for the implant. In a recent publication that includes the 6 patients from this phase I study, a more posterior position of implanted leads was associated more often with acute tinnitus loudness reduction during acute stimulation.11 This area located more in the body of the caudate comprises the section of −8 to −15 mm in MNI (Montreal Neurological Institute) space. These caudate body subdivisions also showed a stronger functional connectivity to the auditory cortex compared to the caudate head.
Given the size of the nucleus, further refinement of the most effective target within the caudate is warranted and a preoperative functional connectivity analysis may be a feasible option to do so.
The study protocol allowed the group to find the optimal stimulation parameters before entering the 24-week stimulation period. This led to two distinct findings: 1) stimulation parameters (including frequency, pulse width, and amplitude) varied greatly between patients; and 2) the process of finding the optimal stimulation parameters was a lengthy one (5–13 months).3 The authors speculate that phantoms of different qualities may respond to different stimulation frequencies. This can only be proven within a bigger study population in which the tonal qualities of the phantoms are defined and compared to effective stimulation parameters or to the area of strongest functional connectivity within the caudate.
It seems tempting to record local field potentials from the DBS electrodes to find a neurophysiological biomarker (such as a decrease in the power spectrum of gamma oscillations) that coincides with phantom loudness reduction and to then apply closed-loop DBS to adjust stimulation settings accordingly, as has been investigated in PD patients.8,9 Furthermore, studies of transcranial and cortical stimulation found differential effects on tinnitus loudness when applying either tonic, burst, or noise stimulation.4,15 However, current commercially available DBS systems only allow for open-loop tonic stimulation and therefore have technical limitations that need to be overcome in the future.
The question whether a certain level of emotional distress or presence of psychiatric comorbidities would favor neuromodulation of the ventral striatum/limbic system rather than the dorsal striatum cannot currently be answered.
Overall, a recent study has evaluated the willingness of patients suffering from tinnitus to undergo invasive treatments. Approximately 20% of patients would fully accept DBS as an invasive treatment if it was able to cure tinnitus with an at least 50% chance, whereas 60% would not accept DBS.14 These rates were lower than for hearing aids (control group) but did not differ significantly from established treatments such as cochlear implants. Patients with previously failed treatment attempts showed an overall higher acceptance rate for invasive treatments. These findings demonstrate a certain place and demand for invasive neuromodulatory treatments for chronic tinnitus in a subset of patients.
It remains unclear how high acceptance rates for incision- and implant-free lesional neuromodulation techniques such as focused ultrasound (FUS) might be. Given that the interest in the caudate for treatment of tinnitus was sparked by unilateral stroke lesions and their sustained bilateral effect on auditory phantoms, FUS may represent a potential future treatment option to be explored, because functional and structural neuroimaging has been shown to help refine targeting.1
The group around Cheung and Larson have successfully worked on the concept of caudate DBS for treatment-resistant tinnitus. Starting with the incidental finding of a caudate lesion after DBS implantation for movement disorders suppressing tinnitus, the group was able to translate this concept with pilot trials in patients with movement disorders to the first ever prospective phase I trial of DBS in patients with tinnitus. Although questions on how to define the optimal target and stimulation settings remain and may only be answered in a bigger phase II trial, this effort represents an important contribution in the field of surgical neuromodulation.
Disclosures
Dr. Lozano is a consultant for Medtronic, St. Jude, and Boston Scientific.
References
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