Effect of ketamine and brain stimulation on tinnitus loudness and distress

INTERVENTION: Brief Name: Ketamine and High Definition, Trancranial Infraslow Pink Noise Stimulation (HD‐tIPNS) The intervention arm will receive a low dose of subcutaneous ketamine (0.5mg/kg) as a bolus, from a clinician experienced in administration. This will be followed by HD‐tIPNS administered for a single session of 30 minutes duration, beginning 25 minutes after ketamine delivery, by a researcher experienced in administering neuromodulation techniques. A battery‐driven wireless 32 channel transcranial current stimulator (Starstim32 TCS®, Neuroelectrics, Spain, http://www.neuroelectrics.com) will be used to deliver stimulation while the participants are comfortably and quietly seated. Simulation is delivered by AgCl electrodes placed in the international 10‐20 arrangement, secured in a neoprene cap (see Neuroelectrics website for headset image). For the active treatment group, the stimulation will be delivered at a current strength of maximum of 2mA for 30min, with 60s ramp up and ramp down at the beginning and end of each stimulation session, with continuous stimulation in between. For sham stimulation, to create an identical skin sensation to the active stimulation, the current will be applied for a 60s ramp up (0‐2mA) and 60s ramp down (2‐0mA) at the beginning and the end of each stimulation session, without any current for the remainder of the stimulation period. This Intervention will be delivered twice, spaced 10 days apart. Intervention duration will be a total of 2 hours in length to allow for safety monitoring. After a 20 day washout, both groups will transition to the intervention, delivered twice again, 10 days apart. The delayed start occurs as follows: Participants can be allocated to start with Ketamine + Active Stimulation or Ketamine + Sham CONDITION: Ear ‐ Other ear disorders Tinnitus; ; Tinnitus SECONDARY OUTCOME: Changes in resting state brain activity, via resting‐state electroencephalography (EEG) and source localization, obtained in a quiet room while the participant is sitting upright in a comfortable chair by an independent researcher blinded to the treatment group. EEG data will be collected using the 32 channel neuroelectrics amplifier (Starstim32 TCS®, Neuroelectrics, Spain, http://www.neuroelectrics.com). [Baseline, 10,60, and 120 minutes after the Ketamine infusions in the first treatment period, Before the second treatment period, 10,60, and 120 minutes after Ketamine infusions of the second treatment period, and at One month follow‐up.] European Quality of Life–5 Dimensions 5 levels Questionnaire (EQ‐5D‐5L)[Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] The Depression, Anxiety, and Stress Scale (DASS)[Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] The Tinnitus Questionnaire (TQ) will be used to assess tinnitus‐related distress. The TQ is a 52‐item questionnaire, covering 5 subscales of Emotional Distress, Auditory Perceptual Difficulties, Intrusiveness, Sleep Disturbance, and Somatic Complaints. [Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] Tinnitus loudness and distress will be measured using an 11‐point Numeric Rating Scale (0=no tinnitus/not distressing, 10=very loud tinnitus/extreme levels of distress).[Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] INCLUSION CRITERIA: Adults aged between 18‐70 years with constant subjective tinnitus and a grade of 3 or above on the tinnitus questionnaire. PRIMARY OUTCOME: Feasibility outcomes: The following feasibility outcomes will be measured by the study’s research fellow using study records:; a) Recruitment rate, i.e., number of participants recruited per month, until the proposed sample size is reached. The recruitment rate will be recorded on a weekly basis, since the release of the advertisements, and the number of advertisements will also be recorded.; b) Proportion of participants recruited from the total number screened (with reasons for exclusion) and expressed as a percentage.; c) Adherence to intervention measured as number of treatment sessions attended by each participant and expressed as a percentage of the total number of sessions. Adherence rates will be calculated once the treatment phase is completed.; c) Drop‐out rates, measured as the number of participants who dropped‐out in each group, and expressed as a percentage of the total number of participants enrolled in the study. Drop‐outs rates will be calculated once the follow‐up phase is completed.; d) These feasibility measures will be assessed by ethnicity (Maori and non‐ Maori) to permit an understanding of how successful were measures to engage Maori participants and honour Te Tiriti.; e) Participant satisfaction levels and the acceptability of the treatment will also be recorded on an 11‐point numeric rating scale (0‐Not at all satisfied/acceptable to 10‐Very satisfied/acceptable).; [Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] Saftey Measures, including:; a) Vital Signs (Heart rate [pulse oximeter], blood pressure [digital sphygmomanometer], blood O2 saturation [pulse oximeter]) will be measured before ketamine administration and then at 30‐minute intervals until completion of the intervention sessions.; b) Any adverse effects that likely have a causal relationship with the intervention will be recorded by the study’s assistant research fellow at each session, before the intervention, during the intervention (at intervals of 10 min), and after completion of that day’s intervention session. This will help evaluate adverse events from both the previous session’s (delayed) effects and the same session’s (immediate) effects. The following variables will be recorded:; (i) Qualitative description of each symptom.; (ii) Intensity of each symptom measured using a Likert scale ranging from 0 (none) to 10 (extreme).; (iii) Relation of the symptom to the treatment, measured on a scale ranging from 1 (unrelated) to 5 (strongly related). ; (iv)Duration of each symptom and the time taken for resolution of each symptom, expressed in minutes. ; (v) Visual Analog Scales (VAS): The VAS will consist of a series of 19 horizontal 100‐mm lines, each labelled with an adjective: Alert, Anxious, Bad Medication Effect, Confusion, Down, Friendly, Good Medication Effect, High, Hungry, Irritable, Liking, Miserable, On Edge, Sedated, Self‐Conscience, Social, Stimulated, Talkative, and Tired. Participants will be instructed to place a mark on each line indicating how they feel now from ‘not at all’ to ‘extremely’.; (vi) Any drop‐outs due to adverse effects will also be recorded; [Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.] Tinnitus Functional Index (TFI). The TFI has eight subscales that address the intrusiveness of tinnitus, the sense of control the patient has, cognitive interference, sleep disturbance, auditory issues, relaxation issues, quality of life, and emotional distress. This provides an overall measure of how much of a problem tinnitus is for participants (severity).[Baseline, After the first treatment period, Before the second treatment period, After the second treatment period, and at One month follow‐up.]