Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%–80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.</jats:p><jats:p>Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).</jats:p></jats:sec>

Tinnitus Update

“…A recent phase I trial of caudate DBS for treatment-resistant tinnitus produced very encouraging results, and so this approach warrants further investigation. 85 …”

Deep Brain Stimulation for Refractory Tinnitus: Pilot Study Protocol for a Randomized Double-Blinded Crossover Trial

“…As this is a pilot study, no formal sample size calculation was performed. Based on previous rst-in-human DBS studies (43,56,57), we expect to adequately address the safety and the proof of concept purpose of the study by including six patients. Furthermore, this number of patients will enable collection of preliminary results that will provide meaningful information about differences between the intervention and sham stimulation.…”

Neuroanatomic Volume Differences in Tinnitus and Hearing Loss

“…4 There are three major neurophysiological theories of chronic tinnitus that have inspired translational development of brain-based (cortical and subcortical) neuromodulation treatments. [5][6][7][8][9][10][11][12][13] The first theory posits mismatch between what the brain predicts it should be hearing and what sounds are actually delivered to the brain. 14,15 Expectation mismatch triggers auditory attention by subcortical neuromodulatory systems, manifesting clinically as tinnitus awareness.…”

“…[18][19][20][21] Central to this theory is the critical role of the caudate nucleus of the striatum in phantom percept gate control. 6,20 Inconsistent replication of reported neuroanatomical alterations in chronic tinnitus across a multitude of studies has precluded the emergence of generally accepted features. In 2006, Mühlau et al 22 published one of the first tinnitus neuroanatomical studies and found decreased volume in the ventromedial prefrontal cortex of the limbic network.…”

“…Neither of these larger cohort studies identified neurovolumetric alterations in the nucleus accumbens nor was ROI analysis centered at the caudate nucleus, essential structures in neurophysiological theories of chronic tinnitus. 6,16,17,20 Given the clinical importance of chronic tinnitus and the need to advance understanding of structurefunction relationships for the development of innovative treatments, we performed a neurovolumetric MRI study in tinnitus cohorts with moderate severity and moderate hearing loss profile. ROI analyses were corrected for brain size, age, and sex to minimize variations and covariations that degrade power to detect significant differences.…”