Bilateral deep brain stimulation (DBS) of the caudate nucleus appears safe and effective for patients with severe refractory tinnitus, early research suggests.

Results of a small open-label study showed a 60% to 80% response rate for efficacy outcomes.

In addition, surgery-related and stimulation-related adverse events (AEs) were transient and expected.

Dr Steven Cheung

"For scientists, this is very exciting, and it represents a new biology," lead author Steven W. Cheung, MD, professor in the Department of Otolaryngology – Head and Neck Surgery, University of California, San Francisco, told Medscape Medical News.

"We hope that this opens up a treatment avenue for folks with good hearing but who have horrible tinnitus," Cheung added.

The findings were published online September 24 in the Journal of Neurosurgery.

Auditory Phantoms

Tinnitus is a sensory phantom perceptual disorder in which patients hear sounds that do not correspond with physical sources.

"Patients describe it as humming, buzzing, sometimes a piercing tone, sometimes a panoply of tones," which can change and be rhythmic, said Cheung.

A main cause of tinnitus is exposure to loud noises, but it is also associated with age-related hearing loss or occurs as an adverse reaction to medications.

About 15% of the population experience tinnitus. Although for most patients the condition improves, 1% to 2% will not recover.

For these patients, auditory phantoms affect their daily life, exacerbate behavioral and emotional problems, and impair concentration.

Conventional tinnitus treatments, including pharmacologic or behavioral approaches, may stabilize comorbid stress, depression, anxiety, and sleep disturbances. Hearing aids can be useful in drowning out or suppressing auditory sensations.

The caudate nucleus is one of the structures that make up the corpus striatum, a component of the basal ganglia. The caudate is important in the "gating" of sensory information and in "telling you what to pay attention to," Cheung said.

"We are bombarded with all sorts of senses ― visual, auditory, smell, and touch. If every sensation was just as important as any other sensation, you would be incredibly confused," he noted.

Caudate Nucleus Defective?

Cheung added that this "fits in with the narrative" that the caudate may be defective in patients with ongoing tinnitus.

A chance observation also fit in with the hypothesis that the caudate could be a target for tinnitus. After a patient underwent DBS for essential tremor in which the lead was placed at a location traversing the caudate nucleus, she recovered not only from the tremor but also from her tinnitus.

For the study, the researchers selected six patients who had experienced constant unilateral or bilateral tinnitus for longer than a year. To be included in the study, the participants could not have a movement disorder, because such disorders may have confounded results, Cheung noted.

Participants underwent stereotactically guided functional neurosurgery to implant DBS leads into both caudate nuclei. They were awake during this procedure in order that they could help guide the positioning of the leads.

The researchers obtained a postoperative MRI for all participants.

After allowing at least 5 weeks for complete wound healing, the investigators determined optimal stimulation parameters, including frequency, pulse width, and amplitude. This process took 5 to 13 months to complete.

"That was a clue to us that we needed new thoughts on how to refine the target, that we didn't have the road map yet," Cheung said.

He added that his team has since refined the targeting.

Individualized Approach

Cheung was surprised at the variation among the patients with regard to the stimulation frequency needed to modulate tinnitus. Unlike most patients with Parkinson disease, not all of the participants with tinnitus required high-frequency stimulation, he said.

Once the most promising set of stimulation parameters was determined by individual patients and the researchers, continuous stimulation was administered for 24 weeks.

DBS leads were implanted in both caudate nuclei in all six patients. One male participant developed serious mood instability while stimulation was in the off mode. He later attempted suicide. The DBS system was removed, and immediate outpatient psychiatric care was administered.

This event occurred despite a comprehensive evaluation that included assessment by a senior neuropsychologist, said Cheung. This patient did not disclose suicidal ideation until well into the trial.

The episode "points to how desperate these patients are" to find a successful tinnitus treatment, he noted.

The five remaining participants (three men and two women) ranged in age from 37 years to 62 years (mean age, 51 years). Their mean baseline Tinnitus Functional Index (TFI) score was 73.9, despite all having tried conventional treatments.

Significant Improvement

A primary efficacy outcome was the difference in TFI score, using a decline of at least 13 points as the cutoff for clinically significant improvement. Because TFI is a relatively new test, the researchers also used an older severity measurement, the Tinnitus Handicap Inventory (THI). For THI, a decrease of 20 points was considered clinically significant.

Results showed that the mean decrease in TFI score was 23.3; clinically significant improvement was achieved for 60% of the participants (three of five patients). The investigators determined that the change between TFI baseline and endpoint scores was statistically significant.

The mean decrease in THI score was 30.8; 80% of the participants demonstrated clinically significant improvement. The change from baseline was also considered statistically significant.

One patient did not receive relief. Cheung said his "hunch" is that for this patient, the target was incorrect.

Cheung believes that the intervention works because "we are fundamentally modulating or changing the gate where these phantoms are accessed."

Another main outcome was executive function (EF), as measured by various neurocognitive tests. The results of these tests were used to determine a composite z-score (EF score). There were no significant changes in EF scores for any of the participants.

For neuropsychiatric safety, the outcome was the difference in the frontal Systems Behavior Scale score. Again, there was no significant change.

Continuous caudate DBS did not significantly alter hearing thresholds, indicating that hearing safety was preserved.

Adverse Events

Surgery-related AEs, such as incisional pain and headache, were transient and expected. Stimulation-related AEs, including worsening of tinnitus symptoms and, in one case, visual phantoms, were also transient and were associated with specific stimulation parameters. These AEs were addressed by changing parameters, typically by reducing amplitude.

The procedure was safe and had no impact on hearing, Cheung said.

A limitation of this early open-label study was that efficacy outcomes were completely dependent on reliable participant reporting. Possible biased reporting could therefore have contaminated results.

"We are encouraged by these new results and would like to move forward with a personalized targeting approach" in a phase 2 trial, Cheung said. "This would mean using brain imaging to pinpoint the area that would help us implant the lead and result in a shorter time to where the patient is experiencing benefit."

The results suggest that the caudate nucleus deserves further study, not only for its promise to treat tinnitus but also for its potential to mitigate other classes of sensory phantoms, Cheung added.

Following the study, four of the five patients opted to continue using the device.

Patient Acceptance?

In an accompanying editorial, Martin Jakobs, MD, and Andres M. Lozano, MD, PhD, Division of Neurosurgery, Toronto Western Hospital, University Health Network, Canada, note that the investigators "have successfully worked on the concept of caudate DBS for treatment resistant tinnitus."

After incidentally finding that tinnitus was suppressed after implantation of DBS in treating a caudate lesion in a patient with a movement disorder, the group was able to translate this concept "to the first ever prospective phase one trial of DBS in patients with tinnitus," Jakobs and Lozano add.

Although questions remain as to how to define the optimal target and stimulation settings, "this effort represents an important contribution in the field of surgical neuromodulation," they write.

But will patients with tinnitus opt for such an invasive treatment?

A recent study cited by Jakobs and Lozano showed that 20% of these patients would fully accept DBS if there was at least a 50% chance of curing the disorder, whereas 60% would not accept DBS.

"These rates were lower than for hearing aids (control group) but did not differ significantly from established treatments such as cochlear implants," they write.

The overall acceptance rate for invasive treatments was higher among patients for whom other treatments had failed.

"These findings demonstrate a certain place and demand for invasive neuromodulatory treatments for chronic tinnitus in a subset of patients," the editorialists write.

Cheung noted that patients' willingness to accept invasive therapy is related directly to tinnitus severity and the magnitude of treatment benefit.

The study was supported by grants from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health; the Department of Defense; and the Coleman Memorial Fund. Cheung has reported no relevant financial relationships. Lozano is a consultant for Medtronic, the company that manufactures the DBS device used for the study, and for St. Jude and Boston Scientific.

J Neurosurg. Published online September 24, 2019. Abstract, Editorial

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