Tinnitus and brain activation: insights from transcranial magnetic stimulation.Abstract
The mechanisms underlying tinnitus Tinnitus Definition
Tinnitus is hearing ringing, buzzing, or other sounds without an external cause. Patients may experience tinnitus in one or both ears or in the head. are still not completely elucidated, but advances in neuroimaging and brain stimulation have provided us with new insights. Evidence suggests that tinnitus might actually be generated by central rather than peripheral structures. To illustrate the importance of brain activity changes in the pathology of tinnitus, we report the cases of 2 patients who experienced a recurrence/worsening of their tinnitus after they had undergone treatment for major depression with repetitive transcranial magnetic stimulation Transcranial magnetic stimulation
A procedure used to treat patients with depression.
Mentioned in: Magnetic Field Therapy
transcranial magnetic stimulation,
n . We suggest that the tinnitus in these 2 patients was induced by changes in brain activity resulting from transcranial magnetic stimulation of the prefrontal cortex. We also review the pathophysiology pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function.
1. and other aspects of tinnitus, focusing on associated brain reorganization.
Tinnitus has been reported to occur in approximately 10 to 15% of adults, including as many as 33% of the elderly population. (l,2) In the United States, tinnitus affects some 30 to 40 million people; approximately 2 to 3 million are severely affected. (l,2) Tinnitus can negatively affect quality of life, sleep, memory, concentration, and mood; these sequelae sequelae Clinical medicine The consequences of a particular condition or therapeutic intervention are debilitating de·bil·i·tat·ing
Causing a loss of strength or energy.
Weakening, or reducing the strength of.
Mentioned in: Stress Reduction in up to 10% of patients. (3)
Despite the many therapeutic options that are available, a great number of patients continue to experience chronic tinnitus for years. One reason for our inability to cure tinnitus is that its underlying mechanisms have not been completely elucidated. Some authors have proposed that tinnitus is associated with a central rather than peripheral brain dysfunction. (4,5) According to this putative mechanism, peripheral alterations in the cochlear cochlear
pertaining to or emanating from the cochlea.
the coiled portion of the membranous labyrinth located inside the cochlea; contains endolymph.
see Table 14. structures still play an important role in triggering tinnitus, but tinnitus does not necessarily represent only end-organ damage; it may also be a consequence of dysfunctional brain activity. For example, Kaltenbach and Afman showed that brain changes in patients with noise-induced tinnitus are still present after the noise is terminated. (6) Therefore, a cortical reorganization in the auditory areas of the brain might sustain chronic tinnitus.
The study of brain alterations in patients with tinnitus might shed light on the pathophysiology of this symptom. Several neuroimaging studies have shown that patterns of brain activation in patients with tinnitus are different from those in healthy controls. (7-10) Although the results of these studies are mixed, they show that patients with tinnitus have increased activity in the temporal cortex. Given that tinnitus might be caused by brain dysfunction, newer techniques of noninvasive brain stimulation--such as transcranial magnetic stimulation (TMS TMS Transcranial Magnetic Stimulation (alternative medicine for depression)
TMS Test Match Special (sports - cricket)
TMS Texas Motor Speedway
TMS Transportation Management System
TMS Toyota Motor Sales )--might improve our understanding of and perhaps our treatment of this pathology. (11-14)
In this article, we briefly describe 2 cases of tinnitus that were induced by repetitive TMS (rTMS) administered for the treatment of major depression. Thereafter, we discuss the implications of these 2 cases and the possible mechanisms that might explain the development of tinnitus in these patients. We also review the literature on the central mechanisms of tinnitus.
Two patients with a history of tinnitus and medication-refractory depression had been participating in a study to evaluate the antidepressant antidepressant, any of a wide range of drugs used to treat psychic depression. They are given to elevate mood, counter suicidal thoughts, and increase the effectiveness of psychotherapy. efficacy of rTMS delivered to the dorsolateral prefrontal cortex The dorsolateral prefrontal cortex (DL-PFC or DLPFC) is the last area (45th) to develop (myelinate) in the human cerebrum. A more restricted definition of this area describes it as roughly equivalent to Brodmann's areas 9 and 46, . Both had been administered rTMS to the left side of the cortex for 10 consecutive days. At each daily session, 1,600 stimuli of 10 Hz rTMS at 90% of motor threshold intensity were delivered in 20 trains of 8 seconds each; there was a 52-second interval between trains.
Patient 1. A 50-year-old left-handed woman had been first evaluated for tinnitus 12 years earlier; she had been symptom-free for 3 years prior to rTMS. Her audiograms and tympanograms had been normal on two previous occasions 15 and 9 years earlier. Her tinnitus began after her second rTMS session, and it continued well after rTMS had been completed. The character of the new tinnitus was similar to that of her previous tinnitus. She likened the sound to that of "an ambulance in the middle of my head." The tinnitus was audible under all levels of background noise, and it frequently woke her during the night. It interfered with her ability to concentrate and to fall asleep.
Patient 2. A 57-year-old right-handed man had a history of tinnitus for 5 years prior to rTMS. The tinnitus had become markedly more intense during his first rTMS session, and it remained so for several months following the completion of rTMS. According to the patient's subjective assessment, the loudness "more than doubled." He described the tinnitus as a high-pitched "screaming" that he generally heard inside his head toward his left ear. Unlike the intensity, the characteristic tone, pitch, and location of the tinnitus did not change during rTMS. An audiogram au·di·o·gram
A graphic record of hearing ability for various sound frequencies.
A chart or graph of the results of a hearing test conducted with audiographic equipment. obtained 3 years earlier revealed a mild sensorineural hearing loss Sensorineural hearing loss
Hearing loss caused by damage to the nerves or parts of the inner ear governing the sense of hearing.
Mentioned in: Tinnitus
sensorineural hearing loss , and no change in that was seen on post-rTMS follow-up.
In both cases, these patients had experienced new or intensified tinnitus during rTMS despite their use of earplugs. Their tinnitus diminished somewhat after treatment with clonazepam clonazepam /clo·naz·e·pam/ (klo-naz´e-pam) a benzodiazepine used as an anticonvulsant and as an antipanic agent.
n. at 1 mg twice daily, but it did not resolve. The 2 patients' respective Hamilton Depression Rating Scale The Hamilton Depression Rating Scale (HAM-D) is a 21-question multiple choice questionnaire which doctors may use to rate the severity of a patient's depression. It was originally published in 1960 by Max Hamilton, and is presently one of the most commonly used scales for rating scores were 31 and 34 at baseline and 17 and 35 at the end of their rTMS course, indicating that rTMS was helpful in only 1 of the 2 patients.
Pathophysiology of tinnitus. Several mechanisms have been proposed to explain the development of tinnitus on the basis of peripheral disturbances, such as (1) dysfunction of the hair cells Hair cells
Sensory receptors in the inner ear that transform sound vibrations into messages that travel to the brain.
Mentioned in: Cochlear Implants of the cochlea cochlea (kŏk`lēə): see ear. , (2) changes in intracochlear calcium concentration, (3) dysfunction of VIIIth cranial nerve cranial nerve
Any of 12 pairs of nerves that emerge from or enter the brain, comprising the olfactory (I), optic (II), oculomotor (III), trochlear (IV), trigeminal (V), abducent (VI), facial (VII), vestibulocochlear (VIII), glossopharyngeal (IX), fibers, and (4) other alterations of the auditory pathways. However, peripheral alterations might represent only the first step in the development of tinnitus; it is possible that brain changes induced by peripheral changes might sustain and perhaps intensify tinnitus. (15)
The brain has a great capacity to adapt to changes in the environment. For instance, it has been shown that in people who become blind early in life (e.g., those with congenital blindness), the original visual areas of the brain are activated when the patient performs sensorimotor sensorimotor /sen·so·ri·mo·tor/ (sen?sor-e-mo´ter) both sensory and motor.
Of, relating to, or combining the functions of the sensory and motor activities. tasks. (16) A system capable of such flexible reorganization is also susceptible to unwanted change. For example, focal hand dystonia dystonia /dys·to·nia/ (-to´ne-ah) dyskinetic movements due to disordered tonicity of muscle.dyston´ic
dystonia musculo´rum defor´mans in musicians is one of the pathologic consequences of plasticity. (17) Likewise, a peripheral alteration in the cochlea may cause a nonadaptive reorganization in the brain that manifests as a perception of tinnitus.
Support for the idea that tinnitus is a nonadaptive change in the neural network has been provided by research showing that tinnitus is frequently observed in patients with hearing loss. (18) Because active cochlear cells have a specific cortical representation, restricted lesions in some areas of the cochlea can cause a missing frequency representation in the auditory cortex auditory cortex
The region of the cerebral cortex that receives auditory data from the medial geniculate body. Also called auditory area. . (19,20) Therefore, a decrease in the peripheral input to the auditory cortex leaves it open to receiving input from other areas of the brain, such as the neighboring cortical areas. The new input can generate an abnormal signal that is perceived as tinnitus. Such an abnormal signal changes the connectivity of the auditory cortex, resulting in the development of new neural circuits that are responsible for sustaining tinnitus. This process is an example of nonadaptive brain plasticity.
As mentioned, some clinical studies support the idea of a central rather than a peripheral dysfunction as an underlying cause of tinnitus. (4,5) For instance, patients who undergo VIIIth cranial nerve section, which blocks peripheral input, continue to experience tinnitus and gaze-evoked tinnitus months after surgery. (4) Furthermore, a magnetic resonance imaging magnetic resonance imaging (MRI), noninvasive diagnostic technique that uses nuclear magnetic resonance to produce cross-sectional images of organs and other internal body structures. (MRI 1. (application) MRI - Magnetic Resonance Imaging.
2. MRI - Measurement Requirements and Interface. ) study demonstrated that the organization of the auditory cortex in patients with tinnitus is significantly different from that seen in healthy subjects. (5) This was particularly observed in brain areas associated with the perception of tinnitus, such as the temporal cortex. This MRI study also demonstrated that tinnitus is accompanied by a change in the tonotopic map of the auditory cortex.
Tinnitus can be compared with another type of nonadaptive brain plasticity: phantom limb pain phantom limb pain
Pain or discomfort felt by an amputee in the area of the missing limb.
phantom limb pain,
n . Both are associated with cortical plastic changes (auditory and motor, respectively) following the deafferentation deafferentation /de·af·fer·en·ta·tion/ (de-af?er-en-ta´shun) the elimination or interruption of sensory nerve fibers.
n. of peripheral input. Just as changes in cortical brain topography occur following the amputation amputation (ăm'pyətā`shən), removal of all or part of a limb or other body part. Although amputation has been practiced for centuries, the development of sophisticated techniques for treatment and prevention of infection has greatly of a limb, brain changes might occur after the deafferentation of auditory input.
Neuroimaging. Neuroimaging can aid in improving our understanding of the pathophysiology of tinnitus. Although several neuroimaging studies (7-10,20) have shown that tinnitus is associated with asymmetry in auditory cortex activity, there is controversy over whether it is the left or the right hemisphere that is associated with dysfunctional activity in tinnitus. While some authors (7,20) postulate that the left hemisphere is more active in patients with tinnitus, others (8-10) contend that the preferential activation occurs toward the right or even toward both hemispheres. Alternately, the asymmetric cortical overactivation that is observed in tinnitus might be correlated with the side of the tinnitus--that is, left-sided tinnitus might be associated with a right hemisphere overactivation and vice versa VICE VERSA. On the contrary; on opposite sides. . (21,22) Furthermore, tinnitus may be correlated with changes in brain activity in areas other than the auditory cortex--for example, the parietal parietal /pa·ri·e·tal/ (pah-ri´e-t'l)
1. of or pertaining to the walls of a cavity.
2. pertaining to or located near the parietal bone.
1. and frontal cortex frontal cortex
The cortex of the frontal lobe of the cerebral hemisphere. Also called frontal area, prefrontal area.
Frontal cortex and areas of the limbic system limbic system
A group of deep brain structures, common to all mammals and including the hippocampus, amygdala, gyrus fornicatus, and connecting structures, associated with olfaction, emotion, motivation, behavior, and various autonomic functions. .
Two studies have shown a predominance of left-hemisphere activity in patients with tinnitus. (7,20) Arnold et al observed that patients with tinnitus who had undergone fluorodeoxyglucose positron-emission tomography (PET) had a higher level of metabolic activity in the left auditory cortex (BA41/42) than did normal controls. (7) In an interesting study of PET in 4 patients with tinnitus, Lockwood et al found that the loudness of tinnitus could be modulated by orofacial movements, and that these modulations are associated with brain metabolic changes. (20) Two of these 4 patients were able to increase the loudness of their tinnitus with orofacial movements, and they demonstrated an increase in cerebral blood flow Cerebral blood flow, or CBF, is the blood supply to the brain in a given time. In an adult, CBF is 750 mls/min or 15% of the cardiac output. On a weight basis, this is 50 to 54 milllitres/100grams/minute. in the left primary auditory cortex The primary auditory cortex is the region of the brain that is responsible for processing of auditory (sound) information. Function of the Primary Auditory Cortex and in the medial geniculate nuclei. In contrast, the other 2 patients were able to decrease the loudness of their tinnitus with orofacial movements, and they demonstrated a decrease in cerebral blood flow in the left temporal gyms. Lockwood et al suggested that the areas of the brain that are associated with tinnitus might be the left primary and secondary auditory cortices cor·ti·ces
A plural of cortex. .
Only a few reports have suggested that the right hemisphere might be the side that is associated with the perception of tinnitus. (8,9) In these reports, investigators compared brain cortical activation before and after suppression of tinnitus with either lidocaine lidocaine /li·do·caine/ (li´do-kan) an anesthetic with sedative, analgesic, and cardiac depressant properties, applied topically in the form of the base or hydrochloride salt as a local anesthetic; also used in the latter form as a infusion or masking sound. Using single-photon-emission computed tomography Computed tomography (CT scan)
X rays are aimed at slices of the body (by rotating equipment) and results are assembled with a computer to give a three-dimensional picture of a structure. (SPECT SPECT single-photon emission computed tomography.
single photon emission computed tomography
n See single photon emission computer tomography. ), Staffen et al found that prior to lidocaine infusion, 1 patient demonstrated an increase in cerebral blood flow in both temporal lobes that was higher in the right hemisphere; following lidocaine infusion, however, as the tinnitus loudness decreased, the authors observed a reduction in global perfusion with no left-right predominance. (8) Similarly, Reyes et al observed that following lidocaine infusion, activity in the right auditory cortex decreased as the loudness of the tinnitus decreased and vice versa. (9) These findings were confirmed by Mirz et al. (10) These authors hypothesized that the sensation of tinnitus is associated with activity in areas of the brain that are linked to attention, emotion, and memory.
In light of all this evidence, we can confidently hypothesize hy·poth·e·size
v. hy·poth·e·sized, hy·poth·e·siz·ing, hy·poth·e·siz·es
To assert as a hypothesis.
To form a hypothesis. that tinnitus is indeed associated with changes in brain activity that are characterized by asymmetries between the right and left cortical areas related to auditory processing. However, the direction of this asymmetry is not yet clear, perhaps merely because of differences in study methodology. Whereas greater activity in the left hemisphere was associated with tinnitus following peripheral deafferentation, (5,15,20,23,24) a predominance of activity in the right hemisphere was seen in studies that compared tinnitus loudness in patients before and after tinnitus suppression with lidocaine infusion or masking sound. (8,9)
Tinnitus and prefrontal prefrontal /pre·fron·tal/ (-fron´t'l) situated in the anterior part of the frontal lobe or region.
1. activity. The brain dysfunction associated with tinnitus is not restricted to the auditory processing areas; it includes other cortical areas, such as the prefrontal cortex. In 1989, Knight et al showed that unilateral prefrontal lesions increase the amplitude of middle-latency auditory evoked potentials, suggesting that the prefrontal cortex exerts an early inhibitory modulation of input to the primary auditory cortex in humans. (25) More recently, Norena et al (26) and Weisz et al (27) compared auditory evoked potentials in patients with tinnitus and in healthy controls, and they suggested that tinnitus might occur as the result of a dysfunction in the top-down inhibitory processes that originate in the prefrontal lobe.
Given that the prefrontal cortex might modulate auditory processing activity, one would expect that stimulation of this area--with TMS, for example--might indeed interfere with auditory sensation, and presumably pre·sum·a·ble
That can be presumed or taken for granted; reasonable as a supposition: presumable causes of the disaster. tinnitus. Therefore, a reactivation reactivation
to become active after a period of quiescence or, as in bacterial and viral infections, latency.
cross reactivation of tinnitus following dorsolateral prefrontal cortex rTMS, which occurred in the 2 cases we described, could be the result of (1) a disruption of the temporal-prefrontal neocortical ne·o·cor·tex
n. pl. ne·o·cor·ti·ces or ne·o·cor·tex·es
The dorsal region of the cerebral cortex, especially large in higher mammals and the most recently evolved part of the brain. Also called neopallium. network, which is considered to be critical for the transient storage of auditory stimuli auditory stimuli,
n.pl in dentistry, the irregularities or deposits on the surface of a tooth that may be detected by ear of both patient and clinician during examination and probing. (28,29) and which also could modulate tinnitus storage, and (2) inhibition of the prefrontal activity that would result in a decrease in frontal inhibition of the tinnitus generated in the auditory cortex.
Repetitive TMS for tinnitus treatment. Repetitive TMS can be used therapeutically in tinnitus to control the dysfunctional area of brain activity. In fact, it can modulate cortical brain excitability excitability
readiness to respond to a stimulus; irritability. in humans. Indeed, several studies have shown that rTMS--a focal, painless type of brain stimulation--can be effective in treating tinnitus. (11-13)
Given that tinnitus is associated with an overactivation in the temporal lobe and that this area is relevant to auditory function, focal modulation of the overactivated area might relieve tinnitus. Indeed, rTMS can reduce cortical excitability in a focal cortical area, (30-31) and therefore it has been investigated for tinnitus treatment. Some investigators have applied low- and high-frequency rTMS to different brain areas in tinnitus patients, and their results have been encouraging. (11-14) In 2003, Plewnia et al became the first to demonstrate that rTMS exerted a significant effect in tinnitus reduction. (14) They applied 10 Hz rTMS to different positions on the scalp in 14 patients and found that stimulation of the left temporoparietal cortex significantly reduced the patients' tinnitus. Other studies likewise showed that brain stimulation with rTMS using other parameters of stimulation can alleviate tinnitus. (11-13) All of these investigators reported that the specific location of rTMS application was correlated with the therapeutic effect. This finding prompted some researchers to wonder if stimulation of a different area of the brain would induce or increase tinnitus. Indeed, that is precisely what we observed in the 2 cases described in this article after rTMS was delivered to the prefrontal cortex in an effort to treat major depression.
Tinnitus and depression. Studies have shown an association between tinnitus and psychiatric disorders such as depression and anxiety. (3,32) For instance, the prevalence of tinnitus in patients with a history of depressive disorder depressive disorder Psychiatry Any of a number of conditions characterized by one or more depressive episodes–major DD, depressed mood–dysthymic disorder and adjustment disorder with depressed mood, and those that do not fit the criteria of other might be 62% higher than the rate in the normal population. (32,33) The association between tinnitus and depression raises two questions: (1) Do they share a common etiology ? and (2) Does depression arise as a result of the psychological distress psychological distress The end result of factors–eg, psychogenic pain, internal conflicts, and external stress that prevent a person from self-actualization and connecting with 'significant others'. See Humanistic psychology. caused by the tinnitus?
It is intuitive to assume that one causes the other--that is, patients with tinnitus develop depressive symptoms because of the discomfort associated with tinnitus, and the depression in turn increases their perception of tinnitus. In fact, some studies have shown that pharmacologic treatment of depression can reduce the distress caused by tinnitus. (3,33) On the other hand, some evidence supports the hypothesis that the two disorders have a similar underlying cause rather than a cause-and-effect relationship. (3,33-35) The existence of a common mechanism is supported by the fact that (1) psychological symptoms would precede or coincide with the onset of persistent tinnitus, (3,33) and (2) neuroimaging studies have demonstrated that left and right brain activity is asymmetric in both conditions. (7,8,34,35) Patients with depression have a higher degree of activity in the right prefrontal cortex, and most patients with tinnitus have an asymmetric cortical activation related to their perception of tinnitus. Therefore, it seems that the two conditions may be characterized by similar abnormalities of prefrontal cortical activation and that an antidepressant treatment that focuses on the prefrontal cortex, such as rTMS, might cause undesirable side effects Side effects
Effects of a proposed project on other parts of the firm. such as tinnitus.
In conclusion, patients with depression and a history of tinnitus might not be good candidates for rTMS treatment of their depression. In our 2 patients, the mechanism underlying the enhancement of their tinnitus was not evident. We speculate that the high-frequency rTMS induced an increase in left dorsolateral prefrontal cortex activity and a decrease in this activity on the right (through transcallosal connections). The decrease in activity on the right might have caused the tinnitus relapse in both patients. This proposed mechanism is consistent with the findings of a study by Gardner et al, who found reduced activity in the fight prefrontal area in patients with tinnitus. (36) Furthermore, the modulation of the prefrontal activity by rTMS in our 2 patients might have inhibited the top-down inhibitory processes from the prefrontal cortex to the auditory cortex. Moreover, we do not believe that the tinnitus in our 2 patients was induced by rTMS noise for two reasons. First, both patients wore earplugs throughout the stimulation period. Second, rTMS has been used for many years (thousands of rTMS experiments have been carried out), and there are no reports that it has ever induced tinnitus. Eliminating these two possibilities further supports the explanation that the tinnitus recurred as the result of brain activity modulation induced by rTMS.
Although several efforts have been made to elucidate specific brain dysfunctions following tinnitus, our understanding of these brain changes remains unclear. The results of neuroimaging studies have been inconsistent with respect to identifying which areas of the brain are associated with tinnitus. Although some of these inconsistencies might be attributable to differences in study methodology, the primary reason might be the weak causal relationship that is suggested by neuroimaging studies--that is, changes in brain activity seen in some areas of neuroimaging studies in patients with tinnitus may be just an epiphenomenon epiphenomenon /epi·phe·nom·e·non/ (ep?i-fe-nom´e-non) an accessory, exceptional, or accidental occurrence in the course of any disease.
n. . As a result, the study of brain function in patients with tinnitus may benefit from other types of research tools, such as TMS. TMS may be important not only for tinnitus treatment, but also for the investigation of the mechanisms underlying this pathology. Because many aspects of tinnitus still need to be investigated, further studies conducted with new techniques of brain investigation should be pursued.
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Renata Marcondes, MD; Felipe Fregni, MD, PhD; Alvaro Pascual-Leone, MD, PhD
From the Department of Otolaryngology, Clinics Hospital, University of Silo silo, watertight and airtight structure for making and storing silage. Silos vary in form from a covered pit, such as was used by the early Romans, to the modern storage tower, dating from the 19th cent. Paulo, Brazil (Dr. Marcondes), and the Harvard Center for Non-Invasive Brain Stimulation, Beth Israel Deaconess Medical Center Both an international and regional referral center, Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts is a major teaching hospital of Harvard Medical School. It was formed out of the 1996 merger of Beth Israel Hospital (founded in 1916) and , Harvard Medical School Harvard Medical School (HMS) is one of the graduate schools of Harvard University. It is a prestigious American medical school located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts. , Boston (Dr. Fregni and Dr. Pascual-Leone).
Reprint requests: Felipe Fregni, MD, Harvard Center for Non-Invasive Brain Stimulation, Harvard Medical School, 330 Brookline Ave., KS 452, Boston, MA 02215. Phone: (617) 667-5272; fax: (617) 975-5322; e-mail: firstname.lastname@example.org
Dr. Fregni is supported by a grant from the Harvard Medical School Scholars in Clinical Sciences Program (NIH "Not invented here." See digispeak.
NIH - The United States National Institutes of Health. K30 HL04095), and Dr. Pascual-Leone is supported by a grant from the National Institutes of Health (NIH K24 RR018875).