Indian Journal of Otology

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 28  |  Issue : 3  |  Page : 189--193

Alterations in brain single-photon emission computed tomography perfusion pattern pre- and post-transcranial magnetic stimulation in tinnitus participants


Sepideh Hekmat1, Raheleh Hedayati2, Saeid Mahmoudian3, Fatemeh Teimourinejad2, Hadi Malek4, Nahid Yaghoobi4, Fereydoun Rastgoo4, Hassan Firuzabadi4, Forough Kalantari2,  
1 Department of Nuclear Medicine, Iran University of Medical Sciences, School of Medicine, Hasheminezhad Hospital, Tehran, Iran
2 Department of Nuclear Medicine, Iran University of Medical Sciences, School of Medicine, Hazrate Rasool Akram Hospital, Tehran, Iran
3 Department of ENT, Head and Neck Research Center, The Five Sense Institute, Iran University of Medical Sciences, School of Medicine, Hazrate Rasool Akram Hospital, Tehran, Iran
4 Department of Nuclear Medicine, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, School of Medicine, Tehran, Iran

Correspondence Address:
Prof. Raheleh Hedayati
Department of Nuclear Medicine, Faculty of Medicine, Iran University of Medical Sciences, Tehran
Iran

Abstract

Background and Aim: It have been shown that changes in organization of high stimulation related to tinnitus in special areas in brain can be eliminated using protocols based on transcranial magnetic stimulation (TMS). The current study aims to assess the pattern of brain perfusion and effects of TMS on brain activity in tinnitus participants as measured by single-photon emission computed tomography (SPECT) as well as evaluate the efficacy of TMS on severity of tinnitus. Methods: This was a cross-sectional randomized clinical trial, which was performed in 15 patients that referred to tinnitus clinic of Rasoul Akram Hospital during March 2017 to April 2018. These participant were randomly divided into two groups of active treatment with TMS and placebo. In each studied group, the variables of the brain perfusion, tinnitus handicap index (THI), pitch-matching test, loudness match of tinnitus, minimum masking level, and residual inhibition were investigated for all included tinnitus participants before and after TMS. Results: In all tinnitus participants, we had increased uptake in temporal lobes (unilateral or bilateral). In active treatment group, SPECT variables in hotspots were significantly decreased in comparison with placebo group (P < 0.05). Visual analog scale of tinnitus was significantly decreased in active group rather than placebo group (P = 0.023). Conclusion: Our findings showed that tinnitus patients have abnormal brain perfusion increased uptake in temporal lobes that decreased with treatment with TMS and therefore this modality could be an appropriate therapeutic option for the improvement of tinnitus in these patients and efficacy of therapy could assessed by brain perfusion scan as well.



How to cite this article:
Hekmat S, Hedayati R, Mahmoudian S, Teimourinejad F, Malek H, Yaghoobi N, Rastgoo F, Firuzabadi H, Kalantari F. Alterations in brain single-photon emission computed tomography perfusion pattern pre- and post-transcranial magnetic stimulation in tinnitus participants.Indian J Otol 2022;28:189-193


How to cite this URL:
Hekmat S, Hedayati R, Mahmoudian S, Teimourinejad F, Malek H, Yaghoobi N, Rastgoo F, Firuzabadi H, Kalantari F. Alterations in brain single-photon emission computed tomography perfusion pattern pre- and post-transcranial magnetic stimulation in tinnitus participants. Indian J Otol [serial online] 2022 [cited 2022 Dec 6 ];28:189-193
Available from: https://www.indianjotol.org/text.asp?2022/28/3/189/361639


Full Text



 Introduction



Tinnitus is a common physiological condition that can have a negative impact on the affected individual in multiple domains of everyday life.[1] It is well known that there is no objective diagnostic measurement for tinnitus, and consequently, patient assessment relies on self-report. Perhaps less well known is how wide-ranging self-reported symptomatology can be from one individual to another.[2] Up to 15%–20% of people experience of suffering from tinnitus permanent or long term in their lifetime that is sufficiently loud to be clinically significant heard in real-world environments.[3] Tinnitus can cause problems such as insomnia, difficulty concentrating, and poor psychological well-being, ultimately decreasing symptom-specific health-related quality of life.[4] The impact of tinnitus on a person can range from mildly problematic to completely debilitating with significant social and economic consequences.[5]

Clinical management for the most part relies on counseling or cognitive therapy,[6] managing any associated hearing difficulties with hearing aid amplification,[7] or masking the tinnitus percept using sound devices such as hearing aids or sound generators.[8] Most tinnitus management options are poorly researched and might be considered experimental or even controversial.[9] No effective treatment of tinnitus that provides complete symptom relief has been found.[10] Therefore, finding new strategies for the treatment of tinnitus is going on.

Transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) are indirect and noninvasive ways used to induce excitability alters in the motor cortex through a wire coil making a magnetic field that moves through the scalp. Today, TMS has become a key method to find out brain functioning in humans. In addition, because rTMS can cause long-lasting after-effects in the brain, it could induce plasticity. This tool seems to be a potential therapy for neurological and psychiatric diseases. The physiological mechanisms underlying the effects induced by TMS and rTMS have not yet been clearly understood.

Opposite to single-pulse TMS, rTMS could change cortical activity beyond the stimulation period. Effect induced by rTMS depends on the stimulation frequency and duration of the stimulation period. Low-frequency stimulation (<1 Hz) has inhibitory effects, and high-frequency stimulation (>5 Hz) causes excitatory effects in the brain. The duration of the after-effects depends on the length of the stimulation. A longer stimulation causes a longer duration of after-effects.[11]

Recently, rTMS over the temporal or temporoparietal cortex has been investigated for the treatment of tinnitus, which appears to originate from maladaptive cortical reorganization. Tinnitus is associated with neural changes in both auditory and nonauditory brain areas.[12] Based on these findings, rTMS has been proposed as an innovative therapeutic strategy for tinnitus. Functional imaging studies have shown that individuals who experience tinnitus display increased activity in the auditory cortex.[13] Applying low-frequency TMS, about 1 Hz to the auditory or associated cortex may reduce patients' perceived severity or volume of tinnitus. Studies of the use of rTMS for chronic tinnitus showed that the severity of tinnitus was reduced by rTMS.[14] In several studies, using rTMS in complementary motor cortex and right and left prefrontal areas, leaded to increase response to therapy up to 25%–60%.[15] Extending the studies on tinnitus demonstrated that rTMS can affect activated auditory cortex by guiding magnetic resonance imaging (MRI) or single photon emission computed tomography (SPECT) and decrease the sensation of severity of sounds.[16] In this study, we evaluated the effects of TMS on subjective and objective symptoms of tinnitus and their relationship with objective data in brain cortex by imaging.

 Methods



Study participants

This study was a randomized double-blind cross-over clinical trial, which was performed in outpatient cases referred to tinnitus clinic of Rasoul-E-Akram Hospital, Tehran, during March 2017 to April 2018. The current study was conducted according to the Declarations of Helsinki with the approval of Editorial Review Board of Nuclear Medicine Department of Iran University of Medical Sciences and Ethical Committee of IUMS (Number: IR.IUMS.FMD.REC 1396.9411221001).

We obtained informed consent from each participants before enrollment in the study. Fifteen consecutive, fully informed, right-handed tinnitus participants were enrolled in the study after approval by the local ethics committee. Eight of them were male (53.5%). Inclusion criteria were age between 18 and 60 years old, presence subjective unilateral or bilateral nonpulsatile tinnitus from more than 6 months with normal hearing, presence tinnitus handicap index >38, Beck Depression Index ≤14, 60 of 100 points in tinnitus visual analog scale (VAS), and normal cranial magnetic resonance. Exclusion criteria were history of underlying disorders including psychiatric, cognitive, neurologic disorders, no consent for enroll in the study, consumption of drugs affected neurologic system during the past 6 months, sensory-neural hearing loss, congenital ear disorders, consumption of alcohol or any type of alkaloid addiction substance, underlying known ear, throat and nose disorders, and central nervous system disorder or any type of malignant disorders. Furthermore, MRI with and without gadolinium injection was performed to rule out any organic lesions in suspected patients.

Half of participants were first put into active TMS treatment and others in placebo group. After 2 weeks as washout time, the half of participants were changed into other group treatment options. We evaluated the parameters such as THI, pitch-matching test (PMT), loudness match of tinnitus (LMT), and minimum masking level (MML) before first intervention and after second intervention.

Tinnitus assessment

Pitch matching of tinnitus and loudness matching of tinnitus (PMT and LMT) were evaluated in tinnitus participants in the affected ear to an external tone presented to the contralateral ear. This task was accomplished using a tinnitus evaluation device (TinED®) which includes six channels to reconstruct the most troublesome tinnitus with a similar frequency and intensity. The accuracy of the calibrating equipment shall be sufficient to determine that the TinED® is within the tolerances permitted by American Standard Specification for Audiometers, S3.6-2004. The participants had to have LMT over six decibel sensation level (dB SL) to be included in this study. Using Persian version of tinnitus handicap inventory (THI), severity of tinnitus was evaluated, and participants with THI score of 44 or more were considered to have moderate-to-severe tinnitus.[17]

Transcranial magnetic stimulation procedures

Included participants with troublesome tinnitus underwent 2000 pulses of 1-Hz TMS. To determine whether a clinically significant change occurred, THI scores as well as PMT, LMT, and MML were examined immediately following the TMS and compared to baseline scores. Tinnitus participants in active TMS group received one session stimulation of frontotemporal for 20 min by TMS. This stimulation was inhibitory by 1 Hz and on the same cortex with power of 90% of motor threshold of patient. Motor threshold for each patient was obtained by the stimulation of vertex with severity that leaded to constriction of thumb finger. The placebo TMS coil used in the study which was the same in shape, weight, and acoustic features produced sounds and sensations similar to the active TMS coil. To better mimic the sounds and scalp sensations perceived by the tinnitus participants in the active TMS group, the placebo coil was set to a relatively high intensity, on average 61.2%. This stimulation intensity makes it possible that our placebo coil was not completely “inert.”

Single-photon emission computerized tomography imaging

No sedation was used and avoidance of caffeine, alcohol, and other drugs known to affect cerebral blood flow before arrival to nuclear medicine center considered for all patients.

A quiet, dimly lit room prepared for patient's to seat or reclining comfortably while instructed to keep eyes and ears open.

Intravenous access had been placed at least 10 min before radiotracer injection. Participants have to had no interaction before, during, and at least 5 min after injection.

20 mci of 99 mTc-bicisate (ethyl cystine dimer) which prepared by fresh eluted pertechnetate was intravenously injected.

They were asked to think about their tinnitus during the test.

Participants voided before start of acquisition to achieve maximal comfort during the study.

Forty five minutes after radiopharmacetical administration SPECT images was performed with a single head gamma camera with low energy, high-resolution collimators.

Camera parameter includes acquisition matrix of 128.128, 120 projection and 45 s/projection.

Nuclear medicine physician who was blinded to clinical information of participants interpreted the studies.

By visual assessment, image grades to two category: normal and hyperactivity.

Semi-quantitative analysis was also performed for the confirmation of visual analysis as comparing to contralateral and background region of interest. Lesion which shows region to background ratio >1 categorized as abnormal and otherwise classified as normal.[18]

Statistics

All data were entered in SPSS software version 22 (Chicago, Illinois, USA). Descriptive analysis did for presenting basic data. For evaluation of efficacy before and after therapeutic method, Paired t-test or Wilcoxon test were used. Regression analysis was used to assess the alterations of magnetic stimulation efficacy in treatment. P =0.05 was considered statistically significant.

 Results



Totally, 15 participants were enrolled in the study. Eight of them were male (53.5%). The mean age of them was 47.43 ± 12.21 years old. Three of them had hypertension (20%). None of them received any treatment for their tinnitus before enrollment in the study. All of them had normal neurologic examinations, and general health questionnaire was normal in all of them. [Table 1] shows the demographic and basic tinnitus data of participants.{Table 1}

[Table 2] shows the basic parameters of tinnitus in placebo and active TMS groups. As it can be seen in [Table 2], there is no difference between two groups and no difference with basic amounts of every variable. [Table 3] demonstrates the findings of SPECT in participant in basic, after placebo, and after active treatment of TMS.{Table 2}{Table 3}

In comparison with basic results, placebo and active TMS had no significant difference (P > 0.05). However, active TMS in hotspot of tinnitus showed significantly higher amount in SPECT rather than placebo TMS in hotspot (P = 0.028).

The findings showed that there was no significant difference between placebo and basic amounts (P = 0.084). However, there was significantly difference in tinnitus VAS between active and placebo groups (P = 0.023).

In [Table 4] The results of Visual Analog Scale in basic, after placebo and after active treatment were compared.{Table 4}

 Discussion



This study was designed to evaluate the efficacy of TMS in treatment of tinnitus. Our findings showed that effects of TMS on hotspot of tinnitus could significantly lead to the improvement of SPECT perfusion. However, there was no efficacy about TMS on ipsilateral or occipital area in SPECT perfusion.

Zhang and Ma demonstrated that therapeutic rTMS is a solution for the improvement of sudden deafness. They showed in their study that participants who received rTMS beside medical therapy, there was a significant improvement in auditory threshold in comparison with control group who received only medical treatment.[19] They also indicated that adding rTMS to standard medical therapy including corticosteroid and hyperbaric oxygen can lead to a significant response in auditory function and tinnitus improvement compared with participants who received only medical therapy. They also revealed that SPECT perfusion can be improved by rTMS in participants with sudden sensory-neural hearing loss.[19] Wang et al. in another study showed that treatment by rTMS could lead to significant suppress of loudness of tinnitus.[20] Plewnia et al. expressed that all measured parameters including THI, tinnitus severity, and tinnitus stimulation had a significant improvement followed by rTMS therapy. They also showed that, in case group, grade of response in tinnitus questionnaire scale was correlated with the activation of anterior cingulate cortex. They showed that tinnitus could improve by increasing cortical activity, followed by low-frequency rTMS and activation of anterior cingulate cortex activation related to tinnitus could significantly predict response to treatment with rTMS.[21] Piccirillo et al. showed that daily active low frequency rTMS in left temporoparietal junction area for 4 weeks was not more effective rather than control group with tinnitus. It was probably due to failure of rTMS in stimulation of deeper areas of auditory cortex in Sylvian fissure and alterations of cortical network that could not lead to the localization of rTMS.[22] They also in another investigation reported similar results. However, the duration of treatment was 2 weeks.[23] It should be mentioned that May et al.[24] generated initial evidence that five sessions of rTMS applied to the superior temporal cortex might induce macroscopic changes in the auditory cortex. This finding may represent a neurophysiological substrate of persisting changes of cortical function. However, at present, the neuronal underpinnings are unclear. An alternative to prolonged rTMS for the treatment of chronic tinnitus has been suggested with long-term electrical stimulation of the primary or secondary through auditory cortex implantation.[25] Langguth et al. showed that chronic tinnitus is related to increase in metabolic unilateral activity of primary auditory intracortical area. Direction of this activity is dominantly in left side and independent from tinnitus lateralization or dominant hand. These unilateral activation patterns in tinnitus are completely in line with previous studies.[26] The results of our study and other investigations are in line with a hypothesis, in which alterations of tinnitus perception could significantly related to special area activity in electroencephalogram.[20]

Many efforts were done to find out the neurophysiological mechanisms of tinnitus.[27] Consensus on tinnitus indicated that imaginary perception may be related to abnormal neurologic signals such as burst firing or neurologic synchronous.[18],[28] Imaging alterations, both positron emission tomography (PET) and functional MRI, are confirmatory components that change in neuronal activity can lead to local metabolism and brain perfusion.[18] The period of initiation time of therapeutic effect in neuropsychiatric disorders with TMS is indicator of this point that cortical plasticity in structural level might be involved by lasting clinical improvement.[29] Local alterations are indicator of neuroplasticity of brain structures in line with recent studies and showed that rTMS can influence on it by low frequency and leaded to strong and wide changes in synaptic activity in cortex and subcortical structures.[30] Significant in gray matter cortex in superior temporal area which is contralateral to stimulation site is expressive of the relationship between close function between both auditory cortexes.[31] Moreover, increase in gray matter of thalamus is expressive of mirror relationship between brain structures and temporal cortex. Either intracorpuscular electrical stimulation of cortex or low frequency rTMS in participants with depression showed that could lead to neurobiological effects on thalamus nucleus.[17]

Our study had some limitations

Because of high costs of doing rTMS, we chose lower sample size that was inevitable due to time limitations of the project. Another limitation was related to no long-term follow-up which was partly due to pandemic of corona. We did not performed PET scan or functional MRI for patients which warrants more founds. In our study, physicians were blinded to groups and interventions during crossover washout time that leaded to the least interobserver bias.

 Conclusion



Our findings showed that TMS could be a suitable option as a therapeutic modality for patient's suffering tinnitus in its hotspot evaluated by brain SPECT perfusion scan. We use TMS as a regular therapeutic option for tinnitus patients in our hospital, and we can use brain perfusion scan (SPECT) for the evaluation of effectiveness of TMS. However, we could not perform long-term patient's follow-up due to the COVID-19 pandemic. We can collect more sample sizes and use long-term follow-up after ending of the coronavirus pandemic.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Watts EJ, Fackrell K, Smith S, Sheldrake J, Haider H, Hoare DJ. Why is tinnitus a problem? A qualitative analysis of problems reported by tinnitus patients. Trends in hearing. 2018;22:2331216518812250.
2Hall DA, Fackrell K, Li AB, Thavayogan R, Smith S, Kennedy V, et al. A narrative synthesis of research evidence for tinnitus-related complaints as reported by patients and their significant others. Health Qual Life Outcomes 2018;16:61.
3Shargorodsky J, Curhan GC, Farwell WR. Prevalence and characteristics of tinnitus among US adults. Am J Med 2010;123:711-8.
4Nondahl DM, Cruickshanks KJ, Huang GH, Klein BE, Klein R, Nieto FJ, et al. Tinnitus and its risk factors in the Beaver Dam offspring study. Int J Audiol 2011;50:313-20.
5Stockdale D, McFerran D, Brazier P, Pritchard C, Kay T, Dowrick C, et al. An economic evaluation of the healthcare cost of tinnitus management in the UK. BMC Health Serv Res 2017;17:577.
6Henry JA, Loovis C, Montero M, Kaelin C, Anselmi KA, Coombs R, et al. Randomized clinical trial: Group counseling based on tinnitus retraining therapy. J Rehabil Res Dev 2007;44:21-32.
7Hoare DJ, Edmondson-Jones M, Sereda M, Akeroyd MA, Hall D. Amplification with hearing aids for patients with tinnitus and co-existing hearing loss. Cochrane Database Syst Rev 2014;31(1):CD010151.
8Hobson J, Chisholm E, El Refaie A. Sound therapy (masking) in the management of tinnitus in adults. Cochrane Database Syst Rev 2010;8(12):Cd006371.
9Folmer RL, Theodoroff SM, Martin WH, Shi Y. Experimental, controversial, and futuristic treatments for chronic tinnitus. J Am Acad Audiol 2014;25:106-25.
10Skog C, Fjellner J, Ekberg E, Häggman-Henrikson B. Tinnitus as a comorbidity to temporomandibular disorders – A systematic review. J Oral Rehabil 2019;46:87-99.
11Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil Med 2015;58:208-13.
12Adjamian P, Sereda M, Hall DA. The mechanisms of tinnitus: Perspectives from human functional neuroimaging. Hear Res 2009;253:15-31.
13Folmer RL. Lateralization of neural activity associated with tinnitus. Neuroradiology 2007;49:689-91.
14Marcondes RA, Sanchez TG, Kii MA, Ono CR, Buchpiguel CA, Langguth B, et al. Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: A double-blind controlled, clinical and neuroimaging outcome study. Eur J Neurol 2010;17:38-44.
15Ruffini C, Locatelli M, Lucca A, Benedetti F, Insacco C, Smeraldi E. Augmentation effect of repetitive transcranial magnetic stimulation over the orbitofrontal cortex in drug-resistant obsessive-compulsive disorder patients: A controlled investigation. Prim Care Companion J Clin Psychiatry 2009;11:226-30.
16Eichhammer P, Langguth B, Marienhagen J, Kleinjung T, Hajak G. Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: A short case series. Biol Psychiatry 2003;54:862-5.
17Li X, Nahas Z, Kozel FA, Anderson B, Bohning DE, George MS. Acute left prefrontal transcranial magnetic stimulation in depressed patients is associated with immediately increased activity in prefrontal cortical as well as subcortical regions. Biol Psychiatry 2004;55:882-90.
18Melcher JR, Sigalovsky IS, Guinan JJ Jr., Levine RA. Lateralized tinnitus studied with functional magnetic resonance imaging: Abnormal inferior colliculus activation. J Neurophysiol 2000;83:1058-72.
19Zhang, D, Ma Y. Repetitive transcranial magnetic stimulation improves both hearing function and tinnitus perception in sudden sensorineural hearing loss patients. Scientific Reports, 2015;5:1-10.
20Wang H, Li B, Feng Y, Cui B, Wu H, Shi H, et al. A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus. PLoS One 2015;10:e0139622.
21Plewnia C, Reimold M, Najib A, Reischl G, Plontke SK, Gerloff C. Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: A randomised, controlled pilot study. J Neurol Neurosurg Psychiatry 2007;78:152-6.
22Piccirillo JF, Kallogjeri D, Nicklaus J, Wineland A, Spitznagel EL Jr, Vlassenko AG, et al. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: Four-week stimulation trial. JAMA Otolaryngol Head Neck Surg 2013;139:388-95.
23Piccirillo JF, Kallogjeri D, Nicklaus J, Wineland A, Spitznagel EL, Vlassenko AG, et al. Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial. JAMA otolaryngology–head & neck surgery. 2013;139:388-95.
24May A, Hajak G, Gänssbauer S, Steffens T, Langguth B, Kleinjung T, et al. Structural brain alterations following 5 days of intervention: Dynamic aspects of neuroplasticity. Cereb Cortex 2007;17:205-10.
25De Ridder D, De Mulder G, Verstraeten E, Van der Kelen K, Sunaert S, Smits M, et al. Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J Otorhinolaryngol Relat Spec 2006;68:48-54.
26Langguth B, Eichhammer P, Wiegand R, Marienhegen J, Maenner P, Jacob P, et al. Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment. Neuroreport. 2003;14:997-80.
27Henry JA, Roberts LE, Caspary DM, Theodoroff SM, Salvi RJ. Underlying mechanisms of tinnitus: Review and clinical implications. J Am Acad Audiol 2014;25:5-22.
28Seki S, Eggermont JJ. Changes in spontaneous firing rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss. Hear Res 2003;180:28-38.
29Tergau F, Naumann U, Paulus W, Steinhoff BJ. Low-frequency repetitive transcranial magnetic stimulation improves intractable epilepsy. Lancet 1999;353:2209.
30Bäumer T, Lange R, Liepert J, Weiller C, Siebner HR, Rothwell JC, et al. Repeated premotor rTMS leads to cumulative plastic changes of motor cortex excitability in humans. Neuroimage 2003;20:550-60.
31Read HL, Winer JA, Schreiner CE. Functional architecture of auditory cortex. Curr Opin Neurobiol 2002;12:433-40.