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

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OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

ABBREVIATIONS AC-PC = anterior commissure–posterior commissure; AE = adverse event; DBS = deep brain stimulation; EF = executive function; FrSBe = Frontal Systems Behavior Scale; GIC = Global Impression of Change; IDE = investigational device exemption; IPG = internal pulse generator; MoCA = Montreal Cognitive Assessment; NRS = numeric rating scale; PD = Parkinson disease; TFI = Tinnitus Functional Index; THI = Tinnitus Handicap Inventory; UCSF = University of California, San Francisco; WRS = word recognition score.

OBJECTIVE

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

ABBREVIATIONS AC-PC = anterior commissure–posterior commissure; AE = adverse event; DBS = deep brain stimulation; EF = executive function; FrSBe = Frontal Systems Behavior Scale; GIC = Global Impression of Change; IDE = investigational device exemption; IPG = internal pulse generator; MoCA = Montreal Cognitive Assessment; NRS = numeric rating scale; PD = Parkinson disease; TFI = Tinnitus Functional Index; THI = Tinnitus Handicap Inventory; UCSF = University of California, San Francisco; WRS = word recognition score.

In Brief

This study investigated the efficacy and safety outcomes of experimental caudate nucleus deep brain stimulation to treat tinnitus (ringing of the ears) that had been unresponsive or inadequately responsive to standard therapies. The results from this early trial showed clinically significant improvement in 3 of 5 study participants and no safety concerns, providing new hope for tinnitus sufferers.

Tinnitus is a nonobservable, self-reported perceptual disorder in which elemental sounds that appear to be emanating from one ear, both ears, or inside the head are without corresponding physical sources. It is a common problem afflicting the general population, with an estimated prevalence of 10%–15%37 and incidence of 5.4%.23 Auditory phantoms are often described as ringing, hissing, buzzing, roaring, chirping, or clicking sounds. Occupational noise exposure is the major reason for the onset of constant, chronic tinnitus. Military personnel, veterans, and civilians in certain professions, such as firefighters and construction workers, are at increased risk for persistent auditory phantoms initiated by hearing loss. Whereas more than 80% of tinnitus patients adapt well to their auditory phantoms, still 13 million individuals in the United States and Europe seek medical attention.8

Conventional tinnitus treatment strategies aim to stabilize comorbid stress,3,5,40 depression and anxiety,16,17,38 and sleep disruption4,10 by using pharmacological or behavioral approaches,2,45 and to mitigate distress attributed to auditory phantoms by deploying acoustical, behavioral, or combined acoustical and behavioral therapies.14,22 Nonetheless, between 0.5% and 2% of the adult population or more than 1 million people in the United States are tinnitus sufferers,24,41 in whom auditory phantoms intrude on activities of daily living, exacerbate behavioral and emotional problems, and impair mental concentration. For those tinnitus sufferers with auditory phantoms that are unresponsive or inadequately responsive to conventional therapies, salvage treatment options remain rather limited. Some tinnitus sufferers with intractable symptoms may ultimately choose to participate in invasive, experimental approaches in the hopes of finding meaningful relief.11,12,34,39

Tinnitus is a distinctly auditory percept,26,29 but nonclassical auditory,27,42 limbic,20,35 and striatal18,36 interactive networks play important roles in its chronicity and severity, and the patient’s awareness of it. Targeting of the basal ganglia for direct electrical stimulation to effect tinnitus modulation was guided by case reports of impressive reduction in tinnitus loudness following caudate nucleus vascular infarction19,21 and by a resting-state functional MRI (fMRI) study that demonstrated increased corticostriatal connectivity in chronic tinnitus.15 In preliminary studies leading to this phase I clinical trial, caudate nucleus function was directly modulated during deep brain stimulation (DBS) electrode implantation surgery in awake and interactive human subjects with movement disorders (Parkinson disease [PD] or essential tremor) and comorbid constant, chronic tinnitus. In the first set of experiments, tinnitus loudness modulation was mediated by high-frequency striatal stimulation.7 Tinnitus loudness was suppressed to a nadir of level 2 or lower on a 0–10 rating scale in 5 subjects in whom the DBS lead traversed the dorsal striatum, but not in the subject in whom the DBS lead was positioned outside the caudate nucleus. Depending on the specific parameters of electrical stimulation, tinnitus loudness was temporarily increased in 2 subjects. In the second set of experiments on 6 subjects, also with movement disorders undergoing DBS surgery, 3 of them with and 3 without comorbid chronic tinnitus, auditory phantom sound quality modulation was mediated by both low- and high-frequency striatal stimulation.18 Caudate stimulation triggered phantom tones, clicks, and frequency-modulated sweeps in 5 subjects, and changed tinnitus baseline sound quality in 1 subject. All manifestations of auditory phantom modulation ceased shortly after stimulation was terminated, confirming the reversibility of DBS-related effects.

In this phase I trial of caudate DBS for treatment-resistant tinnitus, there were 3 main study goals: 1) develop a therapy that may have promise to meaningfully mitigate tinnitus severity in sufferers who have exhausted conventional therapies; 2) extend the short-term tinnitus loudness reduction benefit reported in preliminary studies to indefinite long-term relief; and 3) exercise critical evaluation of this nonauditory, basal ganglia–centric approach by selecting patients with chronic tinnitus who do not have movement disorders to remove the possible confounding factor of nigrostriatal degeneration. Here, we report on primary and secondary efficacy and safety outcomes in a cohort of 5 participants who underwent continuous caudate stimulation for 24 weeks at individualized stimulation parameters and who completed all required evaluations to deliver analyzable data sets.

Methods

This was a single-institution, open-label, phase I clinical trial to evaluate the efficacy and safety of bilateral caudate nucleus neuromodulation by DBS in adults with what they described as a “big” or “very big” chronic tinnitus problem25 that has been unresponsive or unsatisfactorily responsive to conventional therapy. The study protocol was approved by the University of California, San Francisco (UCSF) Human Research Committee and the San Francisco Veterans Affairs Research & Development Committee. This study was conducted in accordance with the Declaration of Helsinki and registered with ClinicalTrials.gov with the identifier NCT01988688 prior to study participant recruitment.

Study Participants

Eligible men and women participants had suffered subjective unilateral or bilateral constant tinnitus longer than 1 year; had disorder severity defined by a Tinnitus Functional Index (TFI) > 50 despite conventional treatment by acoustical or behavioral therapy; had a Montreal Cognitive Assessment30 (MoCA) score ≥ 26; and were between 22 and 75 years of age, inclusive. Exclusion criteria included hyperacusis, misophonia, and average air conduction of any 3 consecutive audiometric frequencies (0.5, 1, 2, 4, and 8 kHz) ≥ 56 dB in either ear, and any medical or psychiatric symptoms or conditions that could interfere with study activities or confound interpretation of study results. After completion of endpoint evaluations and prior to study separation, all participants with implants were provided ample opportunities to discuss the pros and cons of continuing with stimulation, stopping stimulation but leaving the DBS system in place, and stopping stimulation and removing either part or all of the DBS system. One participant elected complete DBS system removal, which was performed uneventfully, whereas all other participants chose to proceed with continuous caudate stimulation.

Outcome Assessments

Baseline assessments were performed prior to DBS surgery and endpoint assessments were performed after 24 weeks of continuous caudate nucleus stimulation. The primary objectives were to assess the efficacy of tinnitus mitigation by using the TFI25 and to monitor executive function (EF) safety by using a composite z-score (EF score) from select neuropsychological tests—Delis-Kaplan Executive Function System: Design Fluency, Color-Word Interference, Tower Test, Card Sort, and Letter Fluency; and Neuropsychological Assessment Battery: Digit Span Backward—that were administered by a licensed neuropsychologist. The secondary objectives were to assess the efficacy of tinnitus mitigation by using the Tinnitus Handicap Inventory (THI)31 for severity, a 0–10 numeric rating scale (NRS) (0, no tinnitus; 5, conversation level; 10, jet engine)13 for loudness, and a Global Impression of Change (GIC) for qualitative judgment of treatment-related change. Other secondary objectives were to assess neuropsychiatric safety by using the Frontal Systems Behavior Scale (FrSBe) to measure apathy, disinhibition, and executive dysfunction, and to assess hearing safety by measuring air conduction pure tone audiometric thresholds at 0.5, 1, 2, 3, 4, and 6 kHz and the word recognition score (WRS) by using the 25-item NU-6 word list for each ear.

Deep Brain Stimulation Surgery

Enrolled study participants underwent stereotactically guided functional neurosurgery to implant DBS leads (10.5-mm electrode array; model 3387, Medtronic) into both caudate nuclei with the aid of a Leksell Frame (Elekta) and Framelink software (Medtronic StealthStation). Participants were awake and interactive for intraoperative interrogation of striatal sites to determine the position of final lead placement. The caudate nucleus was targeted by selecting an entry point at or just anterior to the coronal suture. The preliminary target was set in the subthalamic region, 12 mm lateral, 3 mm posterior, and 4 mm below the midcommissural point. The entry point was modified to avoid sulci and visible blood vessels, and the trajectory was then shortened in the coronal plane and medialized to position the target at the base of the caudate. The entry point was further modified to place the trajectory along the long axis of the caudate in the coronal plane, avoiding the ventricle. The trajectory depth was adjusted to center the 10.5-mm-long electrode array of a model 3387 DBS electrode entirely within the caudate nucleus.

An initial microelectrode recording pass along the preplanned target trajectory in the first hemisphere captured recordings that marked physiological borders of the caudate nucleus (Alpha Omega). A DBS lead along the same tract was positioned at the center of the superior and inferior borders in the coronal plane. The electrode configuration was set with distal contact 0 as cathode and proximal contact 3 as anode for bipolar macrostimulation to assess tinnitus modulation relative to baseline, focusing on the following features: loudness (0–10 NRS) in each ear, spatial location (point source localized to one or both ears, sector of the acoustic panorama, inside or outside the head), and sound quality (modulation to a higher or lower pitch, addition of distinct sounds, change in intrusiveness, trigger of a new auditory phantom). Stimulation frequency, amplitude, and pulse width were varied only one at a time in a stepwise fashion to assess tinnitus modulation (Video 1).

VIDEO 1. Intraoperative DBS for tinnitus modulation. Published with permission. Click here to view.

A maximum of 3 microelectrode recording passes with macrostimulation (original target, 5 mm anterior and 5 mm posterior along the caudate anteroposterior axis) per hemisphere was carried out. The tract that modulated tinnitus features most strongly determined final positioning of the DBS lead on the first side. Macrostimulation results from the first side were used to inform initial tract exploration on the second side. In 9 of the 12 implanted hemispheres, one of the alternative tracts produced the most convincing tinnitus modulation. In one participant, stereotactic frame deviation discovered during surgery resulted in a lead being placed 2.5 mm posterior and medial to the intended target, but still within the caudate; macrostimulation resulted in striking tinnitus modulation at this location, so the lead was not moved.

Postoperative MRI was obtained in all participants and transferred to Framelink to document lead locations. The coronal and sagittal approach angles and lead entry and tip positions in anterior commissure–posterior commissure (AC-PC) coordinates are listed in Table 1, and 3D plots of the 4 contact locations on each lead in AC-PC space are shown in Fig. 1. Trajectories and lead locations were variable due to the intraoperative response to macrostimulation and caudate location in 3D space, which varied between participants according to the size of the lateral ventricles.

TABLE 1.

DBS entry and final lead tip positions

Approach Angle in Degrees; Coronal/SagittalEntry Position in AC-PC Coordinates [X, Y, Z]Lead Tip Position in AC-PC Coordinates [X, Y, Z]
Case No.LtRtLtRtLtRt
U01-028.3/61.59.1/56.2[−20.5, 36.8, 56.4][20.5, 39.9, 54.6][−14.3, 13.6, 13.6][14, 12.8, 14.1]
U01-0312.7/64.022.5/60.2[−21.6, 28.2, 64.0][30.8, 27.7, 57.9][−10.8, 4.9, 16.3][13.4, 3.8, 15.9]
U01-0428.4/47.510.8/61.4[−35.0, 33.9, 54.1][22.4, 30.7, 65.4][−14.9, −0.1, 17][13.3, 4.9, 17.9]
U01-1026.1/56.229.6/46.9[−29.2, 25.1, 50.2][25.3, 39.3, 49.3][−10.6, −0.24, 12.4][5.3, 6.4, 14.1]
U01-1220.1/64.848.0/37.4[−28.9, 25.8, 63.9][45.9, 36.5, 46.0][−12.1, 4.2, 17.9][10.8, −4.9, 14.3]
FIG. 1.
FIG. 1.

Three-dimensional plot of the 4 contact locations for each lead in AC-PC space with respect to the midcommissural point (MCP). Lead locations varied based on individual caudate anatomy and intraoperative response to macrostimulation. Marks on each axis are at 5-mm increments. Ant = anterior; Sup = superior.

Stimulation Optimization

After allowing a minimum of 5 weeks to ensure complete wound healing, participants with implants entered into a stimulation optimization period that was variable in duration and required logging of efficacy and safety events. At the conclusion of stimulation optimization, the most promising parameter group was chosen for continuous stimulation of the caudate nucleus for a fixed period of 24 weeks, allowing for only minor, defined adjustments to parameters to reach the endpoint.

At the initial programming session, each of the 4 contacts was activated in monopolar mode to perform a monopolar survey, with a single contact assigned to be the cathode and the internal pulse generator (IPG) as the anode. The pulse width and frequency were fixed at values typically used in movement disorders (pulse width 90 μsec, frequency 150 Hz), and the amplitude was increased by 1- to 2-V increments, from 0 to 10 V. At each amplitude, the participant was asked to rate his or her tinnitus in each ear independently on the 0–10 NRS loudness scale and to report any other modulation of phantom percept features, including spatial location and sound quality. An emphasis was placed on exploring the effects of parametric changes to settings that produced acute tinnitus modulation in the operating room, because these settings also produced modulation in most participants in the outpatient clinic. They tended to be bipolar settings (cathode and anode both located on the DBS electrode array) with stimulation distributed over several contacts.

At each programming session, the IPG was configured with 4 different parameter groups. One particular parameter of each group could be varied by participants using their home controllers within limits set by the study team. Initially, stimulation parameter variation focused on amplitude (from 0 to 10 V), but over time, it focused on frequency (from 10 to 250 Hz). The patient would cycle through each group as an outpatient, changing a particular parameter incrementally every 2–3 days in a systematic manner and logging tinnitus modulation and adverse events (AEs) in their diary. After the range of parameter variation in each of the 4 groups was exhausted, the patient would have an in-person visit with the study team for review of the diary to determine the next 4 stimulation groups for home evaluation.

Questioning about AEs was performed at all visits during stimulation optimization, as well as psychological, neurological, and audiological review of systems. Typically, the one best prior stimulation group was carried over to the next 4 groups to provide a reference for comparisons. Over time, groups that provided beneficial tinnitus modulation without side effects were explored in finer detail to identify the most promising stimulation parameters. This lengthy programming period ranged from 5 to 13 months.

Continuous Stimulation

Once the most promising set of stimulation parameters was agreed upon by the participant and study team, continuous stimulation was carried out for a fixed duration of 24 weeks. Minor adjustments to parameters were allowed for participant U01-04, who strongly believed that switching between defined parameter groups on demand when benefit was thought to be fluctuating or declining sustained the overall benefit at its highest level. Participants visited with the study team at the beginning, week 8, week 16, and the end of the continuous stimulation period (Video 2).

VIDEO 2. Summary of tinnitus modulation. Published with permission. Click here to view.

Efficacy and safety outcomes were monitored at intervening weeks 8 and 16 and comprised brief audiological (TFI and NRS) and neuropsychological (FrSBe and MoCA) assessments.

Sample Size Calculation

The main goal of data analysis from this phase I clinical trial on a limited number of study participants was to estimate treatment effect size and assess the safety of continuous caudate stimulation to inform the design and analysis of a phase II trial. The sample size of this phase I trial was set by the US FDA’s investigational device exemption (IDE; G120132) approval letter of 2012 that allowed a maximum of 10 adult (age ≥ 22) participants. Based on the assumption of 10 analyzable data sets, the ability to detect a difference in TFI score for a 1-tailed paired t-test with alpha = 0.05 and average effect size ≥ 15 TFI points yielded a power ≥ 0.86. However, this phase I trial closed with only 5 analyzable data sets, necessitating the application of nonparametric statistical analysis. We applied the Wilcoxon signed-rank test (1-tailed; alpha = 0.05), where H0 denotes the median difference = 0 and H1 denotes the median difference < 0.

Data Analyses

Primary and secondary outcomes were based on differences in assessments between baseline and after 24 weeks of continuous caudate stimulation. The primary outcome for efficacy was the difference in the TFI score, using a decline of ≥ 13 points as the cutoff for clinically significant improvement,25 and EF safety was the difference in the composite z-score (EF score). For both primary and secondary outcomes, the descriptive statistics convention of the mean (SE) was adopted.

The secondary outcomes for efficacy were the difference in the THI score, using a decline of ≥ 20 points as the cutoff for clinically significant improvement;31 the difference in NRS (averaged across both ears); and the qualitative GIC (very much better, much better, better, no change, worse, much worse, very much worse). The secondary outcome for neuropsychiatric safety was the difference in the FrSBe score, and for hearing safety it was the difference in air conduction pure tone average for both low-frequency (0.5, 1, and 2 kHz) and high-frequency (3, 4, and 6 kHz) bands, and WRS. The criterion for significant threshold shift (hearing loss) was a decrease of the low-frequency band ≥ 15 dB or the high-frequency band ≥ 20 dB, based on recommendations of the American Academy of Otolaryngology–Head and Neck Surgery.1 The criterion for significant WRS change was a decrease of ≥ 12%, based on the smallest 95% CI of the baseline WRS of the study cohort.6

Adverse Events

This was the first continuous caudate nucleus stimulation study conducted in humans. Before study enrollment, prospective participants were informed that they would be bearing unknown risks to executive, neuropsychiatric, and hearing functions; worsening of baseline tinnitus; and triggering of seizures and other phantom percepts. During the trial, participants with implants kept a log of stimulation-related AEs and were interviewed in detail during in-person visits with the study team. Participants with implants understood their unequivocal right to separate from the study at any time and the fact that the study team could terminate their participation for medical or safety reasons.

Results

One hundred ninety-five prospective participants were prescreened by reviewing suitability for enrollment based on inclusion and exclusion criteria. Undertreated tinnitus, anxiety and/or depression, misconceptions about invasive DBS surgery, and curiosity to seek information on interim results were some notable reasons for immediate disqualification.

Fourteen prospective participants advanced to screening and underwent comprehensive evaluations that established audiological and neuropsychological baseline data. Of the 9 prospective participants who met the criteria for enrollment, 3 declined further engagement. In the 6 enrolled participants, DBS leads were implanted in both caudate nuclei between August 2014 and February 2017. One participant with implants developed serious mood instability while stimulation was in the off mode and attempted suicide 2 months later, culminating in complete DBS system removal without incident. Although no analyzable primary outcomes data were captured, serious and other AEs reported by this participant were included in the safety analysis for inclusive reporting. Thus, 5 participants with implants who completed endpoint assessments following 24 weeks of continuous stimulation at their individualized, most promising parameter settings constituted primary and secondary outcomes data for this trial.

Study cohort demographics and stimulation parameters are shown in Table 2. There were 3 male and 2 female participants, and the mean age was 50.6 (4.8) years. The mean tinnitus duration was 14.8 (6.8) years. Tinnitus spatial location was bilateral in 4 of 5 participants and sound quality was tonal in 3 participants and modulated or multiple in 2. The mean stimulation optimization duration was 9.2 (1.0) months, accounting for the majority of time spent in the interval from initial baseline to endpoint evaluations, which had a mean duration of 18.6 (0.8) months (Table 3).

TABLE 2.

Study cohort demographics and stimulation parameters

Case No.Age (yrs)SexTinnitus Duration (yrs)Prior TreatmentTinnitus Description by EarLead ContactsPulse Width (µsec)Amp (V)Freq (Hz)
U01-0238F2Hearing aid to lt ear w/ maskersLt, hiss w/ beeps[0−1−2+]150Off150
Rt, none[8−9−10+]1506.0150
U01-0358M2Hearing aids w/ maskersLt, high-pitched tone[C+2−3−]606.550
Rt, high-pitched tone[C+10−11−]606.050
U01-0458M40Notched noise maskers & TRTLt, high-pitched tone[0−1−2−3+]60 or 1803.0–5.0150 or 250
Rt, high-pitched tone[8−9−10−11+]60 or 1803.0–5.0150 or 250
U01-1037F25Hearing aids w/ maskersLt, lawn mower; table saw[C+1−2−]908.020
Rt, lawn mower; table saw[C+8−9−]908.020
U01-1262M5Hearing aids & support groupLt, medium-pitched tone[2+3−]906.010
Rt, medium-pitched tone[10+11−]906.010
Amp = amplitude; C = case of the IPG; Freq = frequency; TRT = tinnitus retraining therapy.Stimulation parameters for 24 weeks of continuous caudate stimulation to endpoint.
TABLE 3.

Primary efficacy and safety outcomes

Case No.Baseline to Endpoint Interval (mos)TFI at BaselineTFI at Endpoint∆ TFISignificant ImprovementEF Score at BaselineEF Score at Endpoint∆ EF Score*
U01-021876.873.2−3.6No−1.24−1.190.05
U01-031666.446−20.4Yes0.10−0.35−0.45
U01-042161.642−19.6Yes0.260.380.12
U01-101975.65.2−70.4Yes−0.060.190.25
U01-122089.286.8−2.4No−0.040.330.37
∆ = endpoint − baseline.Significant improvement denotes a ≥ 13-point decrease in TFI.

None of the differences were significant.

The stimulation parameters chosen for 24 weeks of continuous stimulation leading to endpoint evaluation were heterogeneous, reflecting case-by-case searches of parameter combinations that were most promising to mitigate tinnitus severity. Within individual participants, the stimulation geometry of lead contacts, pulse width, amplitude, and frequency were similar in both hemispheres, except in U01-02, in whom the lead in the left caudate was turned off; this particular participant preferred unilateral stimulation despite the fact that bilateral stimulation was well tolerated. Across all participants, the stimulation geometry of lead contacts varied widely, pulse width ranged from 60 to 180 μsec, amplitude ranged from 3.0 to 8.0 V, and frequency ranged from 10 to 250 Hz. It should be noted that in contrast to movement disorders, where the typical stimulation frequency is high, the best stimulation frequency in chronic tinnitus may be low or high.

Primary Outcomes

The primary outcomes for tinnitus efficacy and EF safety of continuous caudate DBS are shown in Table 3. All participants were categorized at the top 2 levels of tinnitus severity despite prior conventional treatment in which acoustical or combined acoustical and behavioral approaches were used. The mean baseline TFI score was 73.9 (4.3). The mean decrease in TFI score was 23.3 (12.4), ranged from 2.4 to 70.4, and qualified 60% of participants for clinically significant improvement. Application of the nonparametric Wilcoxon signed-rank test (1-tailed; alpha = 0.05) demonstrated that the change between TFI baseline and endpoint scores was statistically significant. The change in EF safety, measured by the composite EF score, was not significant in all participants. The patient in case U01-02 exhibited lower EF at baseline relative to the other participants, but there was no significant change between baseline and endpoint measurements, consistent with her known history of attention deficit hyperactivity disorder.

Secondary Outcomes

The secondary outcomes for tinnitus efficacy and neuropsychiatric safety of continuous caudate DBS are shown in Table 4. The mean decrease in THI score was 30.8 (10.4), ranged from 16 to 72, and qualified 80% of participants for clinically significant improvement. Application of the nonparametric Wilcoxon signed-rank test (1-tailed; alpha = 0.05) demonstrated that the change between THI baseline and endpoint scores was statistically significant. Of the 4 participants with clinically significant improvement according to the THI, 3 participants reported “much better” and 1 participant reported “no change” on GIC. The mean decrease in average NRS score for tinnitus loudness was 2.5 (1.4) and ranged from 0 to 7.8.

TABLE 4.

Secondary treatment efficacy and safety outcomes

Case No.THI at BaselineTHI at Endpoint∆ THINRS at BaselineNRS at EndpointAVG NRSGICFrSBe at BaselineFrSBe at Endpoint∆ FrSBe*
U01-027656−20Lt 860Much better67703
Rt 02
U01-035432−22Lt 63−2Much better5327−26
Rt 65
U01-043418−16Lt 75.5−1.8Minimally better405818
Rt 64
U01-10742−72Lt 92−7.8Much better4340−3
Rt 90.5
U01-128258−24Lt 98−1No change41454
Rt 98
∆ THI decrease by 20 points is the threshold for clinically significant improvement. ∆AVG NRS denotes the average NRS change across both ears. For FrSBe scores, T < 60 denotes normal range and T > 65 denotes clinically elevated.

None of the differences were significant.

There was no significant change in neuropsychiatric safety assessments in any of the participants as measured by the FrSBe score. Participant U01-02, who exhibited lower EF at baseline, also showed clinically elevated FrSBe scores, but there was no significant change between baseline and endpoint measurements. The Columbia-Suicide Severity Rating Scale (C-SSRS)33 was administered periodically throughout the trial and scores were all negative. Finally, there was no significant change in hearing safety (Table 5), assessed by difference in air conduction pure tone average for both low- and high-frequency bands and WRS, in any of the participants.

TABLE 5.

Hearing safety outcomes

Audio SPLAudio SPL
Case No.EarLow Freq (dB)High Freq (dB)WRS∆ Low Freq* (dB)∆ High Freq* (dB)∆ WRS*
U01-02Lt18.323.3Lt 96%1.78.3Lt 0%
Rt18.315.0Rt 96%3.38.3Rt 4%
U01-03Lt18.348.3Lt 96%3.3−1.7Lt 4%
Rt10.053.3Rt 92%1.7−3.3Rt 0%
U01-04Lt3.321.7Lt 100%1.73.3Lt 0%
Rt5.010.0Rt 100%0.05.0Rt 0%
U01-10Lt46.748.3Lt 84%−1.7−5.0Lt −4%
Rt48.345.0Rt 88%−1.7−3.3Rt 8%
U01-12Lt8.331.7Lt 100%1.78.3Lt 0%
Rt6.741.7Rt 96%0.08.3Rt 4%
Audio = audiogram; High Freq = air conduction average of 3, 4, and 6 kHz; Low Freq = air conduction average of 0.5, 1, and 2 kHz; SPL = sound pressure level; ∆ = endpoint – baseline.

None of the differences were significant.

Stimulation Safety

AEs considered probably or definitely related to surgery or caudate stimulation are summarized in Table 6. Surgery-related AEs such as incisional pain and headache were transient and expected. Stimulation-related AEs were also transient and associated with specific stimulation parameters above a certain stimulation amplitude; the effect was immediately reversible by reducing stimulation voltage or changing other stimulation parameters. The most common of these stimulation-induced AEs was transient worsening of tinnitus. This was observed at various times in all participants and was an expected outcome because acute caudate stimulation has been shown to both increase and decrease tinnitus loudness, depending on stimulation parameters, in patients with movement disorders and comorbid tinnitus undergoing awake DBS surgery.7,18 One participant experienced transient, stimulation-induced visual phantoms at specific stimulation parameters. Separately, this participant welcomed a feeling of increased energy or alertness while on stimulation parameters that provided the best tinnitus benefit.

TABLE 6.

Surgical and device AEs

AE DescriptionNo. of Participants
Postop incisional pain6
Transiently worsened tinnitus6
Postop headache4
Pulling sensation at IPG3
Facial/neck tingling2
Lightheadedness/dizziness2
Postop fatigue2
Sleep disturbance2
Worsened depression2
Increased energy1
Postop nausea1
Visual phantoms1
Suicidal ideation/attempt*1
AEs for all 6 participants who received implants. All AEs were transient with the exception of elevated electrode impedances in one participant.

Serious AE.

There were no surgery- or stimulation-related serious AEs. There was only one serious AE in the study, a suicide attempt in a participant that occurred while stimulation was off. This participant denied suicidality during screening, but later confided to the study team about a several-year history of passive suicidal ideation prior to enrollment and subsequent ongoing passive suicidal ideation approximately 5 months after surgery. Outpatient psychiatric care was urgently instituted. The stimulator was deactivated to remove any possible stimulation-related effect. During the 2 months of stimulation being off, leading to attempted suicide, tinnitus severity was unchanged. This participant was removed from the study due to expressed suicidality. Following stabilization of mood, the participant requested removal of the entire DBS system, which was performed without incident.

Discussion

This open-label, first-in-human phase I clinical trial to evaluate the efficacy and safety of long-term bilateral caudate nucleus neuromodulation by DBS for severe, treatment-resistant tinnitus in a cohort of 5 adults showed very encouraging results. Primary and secondary outcomes revealed a highly variable effect size and 60%–80% treatment response rate for clinically significant benefit, and a stable safety profile along the domains of EF, frontal behaviors, and audiometric thresholds.

A lengthy period of stimulation optimization in all participants to identify the individual-specific, most promising stimulation parameters for tinnitus mitigation was unanticipated, given the relative ease of DBS to effect a reduction in tinnitus loudness in the preliminary data cohort of patients with movement disorders and comorbid tinnitus.7 There are several nonexclusive explanations: 1) basal ganglia circuits in the phase I trial cohort are relatively more difficult to modulate compared to the preliminary data cohorts with known nigrostriatal degenerative disease; 2) functional connectivity networks in treatment-resistant tinnitus vary in location from individual to individual and are not easily modified should stimulation be delivered to a less than ideal treatment target position; and 3) neurological substrates of severe tinnitus refractory to conventional treatments in trial participants are different from those of comorbid chronic tinnitus in patients with movement disorders.

Variations in stimulation frequency among participants to modulate treatment-resistant tinnitus were a surprising finding. Optimal responses were identified at low (20 Hz), moderate (50 Hz), and high (> 150 Hz) frequencies. It is possible that different phantoms respond optimally to specific frequencies, although this conjecture cannot be assessed in this small cohort. It is noteworthy that all but one participant required 2 or 3 active cathodal contacts, and all but one preferred relatively high stimulation amplitudes (6- to 8-V range) to realize optimal benefit. Such settings reflect a relatively large volume of tissue activation. It is unclear if these stimulation parameters are necessary to achieve modulation of the underlying circuit most directly involved in tinnitus perception, or if the optimal locus of stimulation is farther away from the active contacts than desired. Four of the 5 participants who completed the study had bilateral tinnitus and all reported a preference for bilateral stimulation to achieve optimal tinnitus modulation. One participant had unilateral tinnitus localized to the left ear and reported a preference for right caudate stimulation only, even though bilateral stimulation was well tolerated. This participant was a nonresponder, so the significance of her preference for unilateral stimulation is unclear.

Surgical and device AEs were generally expected, always transient, and completely reversible. Notably, changing stimulation parameters dissipated stimulation-induced AEs, typically by reducing amplitude. One interesting AE was stimulation-dependent triggering of visual phantom percepts. This may represent striatal gating of visual phantoms, because connectivity between the caudate nucleus and extrastriate visual cortex has been demonstrated in rhesus monkeys.44 The best-known visual phantom variant is Charles Bonnet syndrome, which is associated with temporary or permanent visual impairment.9 DBS lead trajectories that penetrate the caudate have been associated with greater risk of cognitive decline in patients with PD, although these findings have been disputed by others.28,43 We observed no changes in cognition in our study cohort with direct caudate implantation and stimulation.

One concerning serious AE was a suicide attempt by a participant in whom stimulation had been off for 2 months; thus, the event was not stimulation related. This participant sequestered thoughts of passive suicidal ideation, which occurred as often as once a week for several years, prior to entering the study. This serious AE highlights the fragility of severe tinnitus sufferers, the need to treat comorbid mood and related disorders aggressively, and the fallibility of even the most rigorous screening procedure for study enrollment. There is not yet an objective diagnostic tool to measure self-reported subjective tinnitus severity and associated comorbidities.

There are two notable study limitations. First, tinnitus is a sensory phantom perceptual disorder and, despite our careful selection process for trial enrollment, efficacy outcomes are completely dependent on reliable participant reporting. Because this phase I trial was an open-label design, possible biased reporting could have contaminated results. We will consider implementation of randomized stimulation on and off trial blocks with crossovers in conjunction with blinding of study participants and study team members to capture efficacy and safety assessment data in future studies. Second, caudate nucleus target selection for tinnitus modulation was solely based on limited intraoperative macrostimulation interrogation. In contrast to PD, the most common disorder treated with DBS, tinnitus does not have the benefit of a robust animal model that can be used to explore and evaluate preclinical neuromodulation targets. Moreover, the basal ganglia targets implanted in PD are small and well characterized. The caudate is an anatomically large structure and the methodology for optimal target selection for implantation will require further refinements. Of note, our first report from this patient cohort demonstrated that acute reduction in tinnitus loudness was associated with more posterior lead locations in regions of the caudate with stronger functional connectivity to the auditory cortex on fMRI.32 We anticipate that an approach utilizing a participant-specific, personalized corticostriatal connectivity map15 will decrease the duration of stimulation optimization and increase the treatment effect size in a phase II trial of caudate DBS for treatment-resistant tinnitus.

Conclusions

Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus showed very encouraging results in this phase I trial. Primary and secondary outcomes revealed a highly variable treatment effect size and a 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 the uniformity of the treatment effect size.

Acknowledgments

This study was supported by the NIH-NIDCD (grant no. 5 U01DC013029 to S.W.C.); Department of Defense (grant nos. W81XWH-13-1-0494 and W81XWH1810741 to S.W.C.); and Coleman Memorial Fund (S.W.C.). It was performed under an IDE issued by the FDA (IDE no. G120132 to P.S.L.).

Disclosures

Dr. Larson has received honoraria from and Ms. Heath has been an educator and consultant for DBS courses and course development for Medtronic, the company that manufactures the DBS device used for this study.

Author Contributions

Conception and design: Cheung, Molinaro, Larson. Acquisition of data: Cheung, Racine, Henderson-Sabes, Demopoulos, Heath, Bourne, Rietcheck, Wang, Larson. Analysis and interpretation of data: Cheung, Racine, Henderson-Sabes, Demopoulos, Nagarajan, Wang, Larson. Drafting the article: Cheung, Larson. Critically revising the article: Cheung, Racine, Henderson-Sabes, Demopoulos, Molinaro, Wang, Larson. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Cheung. Statistical analysis: Cheung, Racine, Henderson-Sabes. Administrative/technical/material support: Wang, Larson. Study supervision: Cheung, Wang, Larson.

Supplemental Information

References

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    American Academy of Otolaryngology–Head and Neck Surgery: Otologic Referral Criteria for Occupational Hearing Conservation Programs. Alexandria, VA: AAO-HNS1997

    • Search Google Scholar
    • Export Citation
  • 2

    Beebe Palumbo DJoos KDe Ridder DVanneste S: The management and outcomes of pharmacological treatments for tinnitus. Curr Neuropharmacol 13:6927002015

    • Search Google Scholar
    • Export Citation
  • 3

    Betz LTMühlberger ALangguth BSchecklmann M: Stress reactivity in chronic tinnitus. Sci Rep 7:415212017

  • 4

    Bhatt JMBhattacharyya NLin HW: Relationships between tinnitus and the prevalence of anxiety and depression. Laryngoscope 127:4664692017

    • Search Google Scholar
    • Export Citation
  • 5

    Canlon BTheorell THasson D: Associations between stress and hearing problems in humans. Hear Res 295:9152013

  • 6

    Carney ESchlauch RS: Critical difference table for word recognition testing derived using computer simulation. J Speech Lang Hear Res 50:120312092007

    • Search Google Scholar
    • Export Citation
  • 7

    Cheung SWLarson PS: Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience 169:176817782010

    • Search Google Scholar
    • Export Citation
  • 8

    Coles RR: Epidemiology of tinnitus: (1) prevalence. J Laryngol Otol Suppl 9:7151984

  • 9

    Coltheart M: Charles Bonnet syndrome: cortical hyperexcitability and visual hallucination. Curr Biol 28:R1253R12542018

  • 10

    Crönlein TLangguth BPregler MKreuzer PMWetter TCSchecklmann M: Insomnia in patients with chronic tinnitus: cognitive and emotional distress as moderator variables. J Psychosom Res 83:65682016

    • Search Google Scholar
    • Export Citation
  • 11

    De Ridder DJoos KVanneste S: Anterior cingulate implants for tinnitus: report of 2 cases. J Neurosurg 124:8939012016

  • 12

    De Ridder DVanneste SPlazier MMenovsky Tvan de Heyning PKovacs S: Dorsolateral prefrontal cortex transcranial magnetic stimulation and electrode implant for intractable tinnitus. World Neurosurg 77:7787842012

    • Search Google Scholar
    • Export Citation
  • 13

    Dewyer NAKiringoda RKram YAChang JLChang CYCheung SW: Stapedectomy effects on tinnitus: relationship of change in loudness to change in severity. Otolaryngol Head Neck Surg 153:101910232015

    • Search Google Scholar
    • Export Citation
  • 14

    Henry JASchechter MAZaugg TLGriest SJastreboff PJVernon JA: Outcomes of clinical trial: tinnitus masking versus tinnitus retraining therapy. J Am Acad Audiol 17:1041322006

    • Search Google Scholar
    • Export Citation
  • 15

    Hinkley LBMizuiri DHong ONagarajan SSCheung SW: Increased striatal functional connectivity with auditory cortex in tinnitus. Front Hum Neurosci 9:5682015

    • Search Google Scholar
    • Export Citation
  • 16

    Kehrle HMSampaio ALGranjeiro RCde Oliveira TSOliveira CA: Tinnitus annoyance in normal-hearing individuals: correlation with depression and anxiety. Ann Otol Rhinol Laryngol 125:1851942016

    • Search Google Scholar
    • Export Citation
  • 17

    Langguth BLandgrebe MKleinjung TSand GPHajak G: Tinnitus and depression. World J Biol Psychiatry 12:4895002011

  • 18

    Larson PSCheung SW: Deep brain stimulation in area LC controllably triggers auditory phantom percepts. Neurosurgery 70:3984062012

    • Search Google Scholar
    • Export Citation
  • 19

    Larson PSCheung SW: A stroke of silence: tinnitus suppression following placement of a deep brain stimulation electrode with infarction in area LC. J Neurosurg 118:1921942013

    • Search Google Scholar
    • Export Citation
  • 20

    Leaver AMRenier LChevillet MAMorgan SKim HJRauschecker JP: Dysregulation of limbic and auditory networks in tinnitus. Neuron 69:33432011

    • Search Google Scholar
    • Export Citation
  • 21

    Lowry LDEisenman LMSaunders JC: An absence of tinnitus. Otol Neurotol 25:4744782004

  • 22

    Martinez-Devesa PPerera RTheodoulou MWaddell A: Cognitive behavioural therapy for tinnitus. Cochrane Database Syst Rev (9):CD0052332010

    • Search Google Scholar
    • Export Citation
  • 23

    Martinez CWallenhorst CMcFerran DHall DA: Incidence rates of clinically significant tinnitus: 10-year trend from a cohort study in England. Ear Hear 36:e69e752015

    • Search Google Scholar
    • Export Citation
  • 24

    McFadden D: Tinnitus: Facts Theories and Treatments. Washington, DC: National Academy Press1982

  • 25

    Meikle MBHenry JAGriest SEStewart BJAbrams HBMcArdle R: The Tinnitus Functional Index: development of a new clinical measure for chronic, intrusive tinnitus. Ear Hear 33:1531762012

    • Search Google Scholar
    • Export Citation
  • 26

    Melcher JRSigalovsky ISGuinan JJ JrLevine RA: Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 83:105810722000

    • Search Google Scholar
    • Export Citation
  • 27

    Mirz FGjedde AIshizu KPedersen CB: Cortical networks subserving the perception of tinnitus—a PET study. Acta Otolaryngol Suppl 543:2412432000

    • Search Google Scholar
    • Export Citation
  • 28

    Morishita TOkun MSJones JDFoote KDBowers D: Cognitive declines after deep brain stimulation are likely to be attributable to more than caudate penetration and lead location. Brain 137:e2742014

    • Search Google Scholar
    • Export Citation
  • 29

    Mühlnickel WElbert TTaub EFlor H: Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A 95:10340103431998

  • 30

    Nasreddine ZSPhillips NABédirian VCharbonneau SWhitehead VCollin I: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:6956992005

    • Search Google Scholar
    • Export Citation
  • 31

    Newman CWSandridge SAJacobson GP: Psychometric adequacy of the Tinnitus Handicap Inventory (THI) for evaluating treatment outcome. J Am Acad Audiol 9:1531601998

    • Search Google Scholar
    • Export Citation
  • 32

    Perez PLWang SSHeath SHenderson-Sabes JMizuiri DHinkley LB: Human caudate nucleus subdivisions in tinnitus modulation. J Neurosurg [epub ahead of print February 8 2019. DOI: 10.3171/2018.10.JNS181659]

    • Search Google Scholar
    • Export Citation
  • 33

    Posner KBrown GKStanley BBrent DAYershova KVOquendo MA: The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168:126612772011

    • Search Google Scholar
    • Export Citation
  • 34

    Rammo RAli RPabaney ASeidman MSchwalb J: Surgical neuromodulation of tinnitus: a review of current therapies and future applications. Neuromodulation 22:3803872019

    • Search Google Scholar
    • Export Citation
  • 35

    Rauschecker JPLeaver AMMühlau M: Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66:8198262010

  • 36

    Rauschecker JPMay ESMaudoux APloner M: Frontostriatal gating of tinnitus and chronic pain. Trends Cogn Sci 19:5675782015

  • 37

    Shargorodsky JCurhan GCFarwell WR: Prevalence and characteristics of tinnitus among US adults. Am J Med 123:7117182010

  • 38

    Trevis KJMcLachlan NMWilson SJ: Psychological mediators of chronic tinnitus: the critical role of depression. J Affect Disord 204:2342402016

    • Search Google Scholar
    • Export Citation
  • 39

    Tyler RCacace AStocking CTarver BEngineer NMartin J: Vagus nerve stimulation paired with tones for the treatment of tinnitus: a prospective randomized double-blind controlled pilot study in humans. Sci Rep 7:119602017

    • Search Google Scholar
    • Export Citation
  • 40

    Vanneste SPlazier Mder Loo Evde Heyning PVCongedo MDe Ridder D: The neural correlates of tinnitus-related distress. Neuroimage 52:4704802010

    • Search Google Scholar
    • Export Citation
  • 41

    Vio MMHolme RH: Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov Today 10:126312652005

    • Search Google Scholar
    • Export Citation
  • 42

    Weisz NMoratti SMeinzer MDohrmann KElbert T: Tinnitus perception and distress is related to abnormal spontaneous brain activity as measured by magnetoencephalography. PLoS Med 2:e1532005

    • Search Google Scholar
    • Export Citation
  • 43

    Witt KGranert ODaniels CVolkmann JFalk Dvan Eimeren T: Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson’s disease: results from a randomized trial. Brain 136:210921192013

    • Search Google Scholar
    • Export Citation
  • 44

    Yeterian EHPandya DN: Corticostriatal connections of extrastriate visual areas in rhesus monkeys. J Comp Neurol 352:4364571995

  • 45

    Zenner HPDelb WKröner-Herwig BJäger BPeroz IHesse G: A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus. Eur Arch Otorhinolaryngol 274:207920912017

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Contributor Notes

Correspondence Steven W. Cheung: University of California, San Francisco, CA. steven.cheung@ucsf.edu.ACCOMPANYING EDITORIAL DOI: 10.3171/2019.4.JNS191023.INCLUDE WHEN CITING Published online September 24, 2019; DOI: 10.3171/2019.4.JNS19347.Disclosures Dr. Larson has received honoraria from and Ms. Heath has been an educator and consultant for DBS courses and course development for Medtronic, the company that manufactures the DBS device used for this study.

© AANS, except where prohibited by US copyright law.

Headings
Figures
  • View in gallery

    Three-dimensional plot of the 4 contact locations for each lead in AC-PC space with respect to the midcommissural point (MCP). Lead locations varied based on individual caudate anatomy and intraoperative response to macrostimulation. Marks on each axis are at 5-mm increments. Ant = anterior; Sup = superior.

References
  • 1

    American Academy of Otolaryngology–Head and Neck Surgery: Otologic Referral Criteria for Occupational Hearing Conservation Programs. Alexandria, VA: AAO-HNS1997

    • Search Google Scholar
    • Export Citation
  • 2

    Beebe Palumbo DJoos KDe Ridder DVanneste S: The management and outcomes of pharmacological treatments for tinnitus. Curr Neuropharmacol 13:6927002015

    • Search Google Scholar
    • Export Citation
  • 3

    Betz LTMühlberger ALangguth BSchecklmann M: Stress reactivity in chronic tinnitus. Sci Rep 7:415212017

  • 4

    Bhatt JMBhattacharyya NLin HW: Relationships between tinnitus and the prevalence of anxiety and depression. Laryngoscope 127:4664692017

    • Search Google Scholar
    • Export Citation
  • 5

    Canlon BTheorell THasson D: Associations between stress and hearing problems in humans. Hear Res 295:9152013

  • 6

    Carney ESchlauch RS: Critical difference table for word recognition testing derived using computer simulation. J Speech Lang Hear Res 50:120312092007

    • Search Google Scholar
    • Export Citation
  • 7

    Cheung SWLarson PS: Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience 169:176817782010

    • Search Google Scholar
    • Export Citation
  • 8

    Coles RR: Epidemiology of tinnitus: (1) prevalence. J Laryngol Otol Suppl 9:7151984

  • 9

    Coltheart M: Charles Bonnet syndrome: cortical hyperexcitability and visual hallucination. Curr Biol 28:R1253R12542018

  • 10

    Crönlein TLangguth BPregler MKreuzer PMWetter TCSchecklmann M: Insomnia in patients with chronic tinnitus: cognitive and emotional distress as moderator variables. J Psychosom Res 83:65682016

    • Search Google Scholar
    • Export Citation
  • 11

    De Ridder DJoos KVanneste S: Anterior cingulate implants for tinnitus: report of 2 cases. J Neurosurg 124:8939012016

  • 12

    De Ridder DVanneste SPlazier MMenovsky Tvan de Heyning PKovacs S: Dorsolateral prefrontal cortex transcranial magnetic stimulation and electrode implant for intractable tinnitus. World Neurosurg 77:7787842012

    • Search Google Scholar
    • Export Citation
  • 13

    Dewyer NAKiringoda RKram YAChang JLChang CYCheung SW: Stapedectomy effects on tinnitus: relationship of change in loudness to change in severity. Otolaryngol Head Neck Surg 153:101910232015

    • Search Google Scholar
    • Export Citation
  • 14

    Henry JASchechter MAZaugg TLGriest SJastreboff PJVernon JA: Outcomes of clinical trial: tinnitus masking versus tinnitus retraining therapy. J Am Acad Audiol 17:1041322006

    • Search Google Scholar
    • Export Citation
  • 15

    Hinkley LBMizuiri DHong ONagarajan SSCheung SW: Increased striatal functional connectivity with auditory cortex in tinnitus. Front Hum Neurosci 9:5682015

    • Search Google Scholar
    • Export Citation
  • 16

    Kehrle HMSampaio ALGranjeiro RCde Oliveira TSOliveira CA: Tinnitus annoyance in normal-hearing individuals: correlation with depression and anxiety. Ann Otol Rhinol Laryngol 125:1851942016

    • Search Google Scholar
    • Export Citation
  • 17

    Langguth BLandgrebe MKleinjung TSand GPHajak G: Tinnitus and depression. World J Biol Psychiatry 12:4895002011

  • 18

    Larson PSCheung SW: Deep brain stimulation in area LC controllably triggers auditory phantom percepts. Neurosurgery 70:3984062012

    • Search Google Scholar
    • Export Citation
  • 19

    Larson PSCheung SW: A stroke of silence: tinnitus suppression following placement of a deep brain stimulation electrode with infarction in area LC. J Neurosurg 118:1921942013

    • Search Google Scholar
    • Export Citation
  • 20

    Leaver AMRenier LChevillet MAMorgan SKim HJRauschecker JP: Dysregulation of limbic and auditory networks in tinnitus. Neuron 69:33432011

    • Search Google Scholar
    • Export Citation
  • 21

    Lowry LDEisenman LMSaunders JC: An absence of tinnitus. Otol Neurotol 25:4744782004

  • 22

    Martinez-Devesa PPerera RTheodoulou MWaddell A: Cognitive behavioural therapy for tinnitus. Cochrane Database Syst Rev (9):CD0052332010

    • Search Google Scholar
    • Export Citation
  • 23

    Martinez CWallenhorst CMcFerran DHall DA: Incidence rates of clinically significant tinnitus: 10-year trend from a cohort study in England. Ear Hear 36:e69e752015

    • Search Google Scholar
    • Export Citation
  • 24

    McFadden D: Tinnitus: Facts Theories and Treatments. Washington, DC: National Academy Press1982

  • 25

    Meikle MBHenry JAGriest SEStewart BJAbrams HBMcArdle R: The Tinnitus Functional Index: development of a new clinical measure for chronic, intrusive tinnitus. Ear Hear 33:1531762012

    • Search Google Scholar
    • Export Citation
  • 26

    Melcher JRSigalovsky ISGuinan JJ JrLevine RA: Lateralized tinnitus studied with functional magnetic resonance imaging: abnormal inferior colliculus activation. J Neurophysiol 83:105810722000

    • Search Google Scholar
    • Export Citation
  • 27

    Mirz FGjedde AIshizu KPedersen CB: Cortical networks subserving the perception of tinnitus—a PET study. Acta Otolaryngol Suppl 543:2412432000

    • Search Google Scholar
    • Export Citation
  • 28

    Morishita TOkun MSJones JDFoote KDBowers D: Cognitive declines after deep brain stimulation are likely to be attributable to more than caudate penetration and lead location. Brain 137:e2742014

    • Search Google Scholar
    • Export Citation
  • 29

    Mühlnickel WElbert TTaub EFlor H: Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A 95:10340103431998

  • 30

    Nasreddine ZSPhillips NABédirian VCharbonneau SWhitehead VCollin I: The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:6956992005

    • Search Google Scholar
    • Export Citation
  • 31

    Newman CWSandridge SAJacobson GP: Psychometric adequacy of the Tinnitus Handicap Inventory (THI) for evaluating treatment outcome. J Am Acad Audiol 9:1531601998

    • Search Google Scholar
    • Export Citation
  • 32

    Perez PLWang SSHeath SHenderson-Sabes JMizuiri DHinkley LB: Human caudate nucleus subdivisions in tinnitus modulation. J Neurosurg [epub ahead of print February 8 2019. DOI: 10.3171/2018.10.JNS181659]

    • Search Google Scholar
    • Export Citation
  • 33

    Posner KBrown GKStanley BBrent DAYershova KVOquendo MA: The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry 168:126612772011

    • Search Google Scholar
    • Export Citation
  • 34

    Rammo RAli RPabaney ASeidman MSchwalb J: Surgical neuromodulation of tinnitus: a review of current therapies and future applications. Neuromodulation 22:3803872019

    • Search Google Scholar
    • Export Citation
  • 35

    Rauschecker JPLeaver AMMühlau M: Tuning out the noise: limbic-auditory interactions in tinnitus. Neuron 66:8198262010

  • 36

    Rauschecker JPMay ESMaudoux APloner M: Frontostriatal gating of tinnitus and chronic pain. Trends Cogn Sci 19:5675782015

  • 37

    Shargorodsky JCurhan GCFarwell WR: Prevalence and characteristics of tinnitus among US adults. Am J Med 123:7117182010

  • 38

    Trevis KJMcLachlan NMWilson SJ: Psychological mediators of chronic tinnitus: the critical role of depression. J Affect Disord 204:2342402016

    • Search Google Scholar
    • Export Citation
  • 39

    Tyler RCacace AStocking CTarver BEngineer NMartin J: Vagus nerve stimulation paired with tones for the treatment of tinnitus: a prospective randomized double-blind controlled pilot study in humans. Sci Rep 7:119602017

    • Search Google Scholar
    • Export Citation
  • 40

    Vanneste SPlazier Mder Loo Evde Heyning PVCongedo MDe Ridder D: The neural correlates of tinnitus-related distress. Neuroimage 52:4704802010

    • Search Google Scholar
    • Export Citation
  • 41

    Vio MMHolme RH: Hearing loss and tinnitus: 250 million people and a US$10 billion potential market. Drug Discov Today 10:126312652005

    • Search Google Scholar
    • Export Citation
  • 42

    Weisz NMoratti SMeinzer MDohrmann KElbert T: Tinnitus perception and distress is related to abnormal spontaneous brain activity as measured by magnetoencephalography. PLoS Med 2:e1532005

    • Search Google Scholar
    • Export Citation
  • 43

    Witt KGranert ODaniels CVolkmann JFalk Dvan Eimeren T: Relation of lead trajectory and electrode position to neuropsychological outcomes of subthalamic neurostimulation in Parkinson’s disease: results from a randomized trial. Brain 136:210921192013

    • Search Google Scholar
    • Export Citation
  • 44

    Yeterian EHPandya DN: Corticostriatal connections of extrastriate visual areas in rhesus monkeys. J Comp Neurol 352:4364571995

  • 45

    Zenner HPDelb WKröner-Herwig BJäger BPeroz IHesse G: A multidisciplinary systematic review of the treatment for chronic idiopathic tinnitus. Eur Arch Otorhinolaryngol 274:207920912017

    • Search Google Scholar
    • Export Citation
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