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Zinc deficiency and tinnitus
Auris, Nasus, Larynx 30 (2003) S25 /S28 www.elsevier.com/locate/anl
Zinc deficiency and tinnitus Kentaro Ochi *, Hirotsugu Kinoshita, Mutsumi Kenmochi, Hirohito Nishino, Toru Ohashi Department of Otolaryngology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
Abstract Objective: To determine if there is a correlation between serum zinc levels and audiometric performance in tinnitus patients. Methods: Seventy-three patients participated in this study. Patient’s age was restricted to 20 /59 years. All patients were examined at the otolaryngology outpatient clinic of the St. Marianna University Toyoko Hospital. The control group consisted of 38 age- and sex-matched healthy volunteers. A blood sample was taken to measure serum zinc levels. Hypozincemia was set at a level of the mean minus one S.D. in the control group. An average hearing sensitivity was calculated as the mean value of hearing thresholds at five frequencies: 250, 500, 1000, 2000, and 4000 Hz. Normal hearing was indicated when the hearing threshold at each of these frequencies was within 20 dB of normal thresholds. Results: There was no significant difference in serum zinc levels between patients with tinnitus and controls. However, patients with tinnitus who had normal hearing had significantly lower serum zinc levels compared to controls. In contrast, no significant difference in serum zinc levels was found between patients with tinnitus who had hearing loss, and controls. A significant correlation between average hearing sensitivity and serum zinc level was observed. Conclusions: These findings suggest that zinc is involved in the generation of tinnitus, especially in patients whose hearing is relatively normal. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Zinc; Tinnitus; Hypozincemia
1. Introduction Zinc is one of the essential trace elements known to play an important role in human living cells, and it was first recognized as essential electrolyte mineral for humans in 1961 [1]. Zinc ions are distributed unevenly in the central nervous system, and can be released from nerve terminals. Zinc-containing neurons sequester zinc ions in their presynaptic vesicles and release it in a calcium- and impulse-dependent manner. The zinccontaining neurons are a subclass of the glutaminergic neurons [2]. It has also been reported that Hypozincemia activates the NMDA (N -methyl-D-aspartate) receptor */one of the glutamate family of receptors */
Part of this study was presented at the 6th International Tinnitus Seminar at Cambridge in 1999. * Corresponding author. Present address: Department of Otolaryngology, St. Marianna University Toyoko Hospital, 3-435, Kosugi-cho, Nakahara-ku, Kawasaki 211-0063, Japan. Tel.: /81-44722-2121; fax: /81-44-711-3316 E-mail address: [email protected] (K. Ochi).
which may play an important role in the induction of epileptic discharge [2,3]. Zinc has therefore been proposed as a likely modulator of tinnitus. The soft tissues of the guinea pig inner ear have the highest zinc content in the body [4]. Zinc deficiency may therefore result in some functional inner ear disorders such as sensorineural hearing loss, imbalance, and tinnitus [4]. It has been reported that when supplemented with zinc 25% of the patients exhibited reduction in tinnitus, and at least 20% of the patients showed a significant improvement in pure-tone hearing sensitivity [4]. In addition, zinc deficiency increases over the age of 60 years, and may be an etiologic factor in some cases of presbyacusis, tinnitus, and imbalance [5]. Gersdorff et al. [6] examined 115 patients suffering from tinnitus, of which 79 (68.7%) were found to have hypozincemia. However, using double-blind, randomized, placebocontrolled trials, Paaske et al. [7] reported that there was no significant difference in the improvement of tinnitus between zinc and placebo groups. The clinical correlation between zinc and tinnitus remains obscure.
0385-8146/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 8 5 - 8 1 4 6 ( 0 2 ) 0 0 1 4 5 - 1
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K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
The purpose of this study was to examine the correlation between serum zinc levels and audiometric performance, by measuring serum zinc levels in patients suffering from tinnitus.
2. Subjects and methods
2.5. Data analysis Statistical analyses were based on the Mann/Whitney U -test, the chi-square test, and linear regression analysis. Differences or changes at P B/0.05 level were considered significant. All tests were performed using the StatView 5.0J package for Microsoft Windows (SAS Institute, Cary, NC).
2.1. Subjects Initially 103 patients participated in this study. All suffered from tinnitus but were free of other diseases and not on medication. Patient’s age was restricted to 20 /59 years because of the potential effects of aging [5]. This reduced the number of investigated subjects to 73, consisting of 50 females (68.5%) and 23 males (31.5%). The mean age was 42.7 years (S.D., 11.0 years). All patients were examined at the otolaryngology outpatient clinic of the St. Marianna University Toyoko Hospital. The control group consisted of 38 age- and sex-matched healthy volunteers (26 females and 12 males). The mean age of the control group was 42.4 years (S.D., 9.7 years). This study was performed in accordance with the principles of the Declaration of Helsinki.
3. Results 3.1. Serum zinc level The serum zinc level in patients with tinnitus was 88.19/12.4 mg/dl (mean9/S.D., n/73) and that in the control group was 92.59/10.6 mg/dl (n/38) (Fig. 1). This difference was close to the level of statistical significance (Mann/Whitney U -test, P /0.06). Based on the serum zinc levels for the control group, a level of less than 81.9 mg/dl (i.e. mean minus one S.D.) was assessed as hypozincemia and 24 patients (32.9%) had this condition. 3.2. Correlation between serum zinc level and hearing sensitivity
2.2. Measurement and evaluation of serum zinc level A blood sample was taken to measure serum zinc levels. Hypozincemia was set at a level of the mean minus one S.D. in the control group. 2.3. Audiometric testing The thresholds of air- and bone-conducted hearing were measured in decibels (dB) at normal hearing level. An average hearing sensitivity was calculated as the mean value of hearing thresholds at five frequencies: 250, 500, 1000, 2000, and 4000 Hz. Normal hearing was indicated when the hearing threshold at each of these frequencies was within 20 dB of normal thresholds. The frequency and loudness of tinnitus were measured using a tinnitus audiometer (Danac 100, Dana Japan Corp., Tokyo, Japan). The loudness of tinnitus was expressed as decibel sensation level (SL). Thirty-eight patients underwent pitch and loudness matching procedures.
Fig. 2 illustrates the relationship between a patient’s serum zinc levels and the average hearing sensitivity. There is a significant correlation between these two values (linear regression analysis, r2 /0.15, P B/0.001). We divided patients into two groups on the basis of the audiometric test described above: 45 patients (61.6%) had hearing loss. The serum zinc levels in patients with normal hearing and in patients with hearing loss were 82.89/10.3 mg/dl (n/28) and 91.49/12.6 mg/dl (n /45), respectively (Fig. 1). The difference in serum zinc levels
2.4. Characteristics of tinnitus Several characteristics of tinnitus, including the ear side, continuity, and duration, were assessed. Patients who were not able to decide the side of the tinnitus were assessed as having bilateral tinnitus. In bilateral tinnitus, continuity, duration, frequency, and loudness of tinnitus were evaluated in the subjectively worse ear.
Fig. 1. The serum zinc levels in controls and tinnitus patients are shown in the left part of this figure. Patients are divided into two groups: tinnitus without hearing loss (without HL) and tinnitus with hearing loss (with HL). The right part of this figure shows the serum zinc levels for these two divided groups. Each box plot represents five horizontal lines that display the 10th, 25th, 50th, 75th, and 90th percentile, respectively.
K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
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(Mann/Whitney U -test, P B/0.05). The loudness in patients with hypozincemia was significantly higher than in patients with normal serum zinc levels.
4. Discussion
Fig. 2. Scattergrams showing the correlation between serum zinc levels and average hearing sensitivities (on the basis of pure-tone audiograms). The horizontal line indicates the lower limit of normal serum zinc level.
between patients with normal hearing and controls was statistically significant (Mann /Whitney U -test, P B/ 0.01). There was also a significant difference in serum zinc levels between patients with normal hearing and patients with hearing loss (P B/0.01). However, the difference in serum zinc levels between patients with hearing loss and the controls was not significant (Mann /Whitney U -test, P /0.64). 3.3. Comparison of two tinnitus groups depending on their serum zinc level Patients were divided into two groups depending on their serum zinc levels: patients with hypozincemia (n / 24) and patients with normal serum zinc level (n /49). Table 1 demonstrates the statistical results comparing these two groups. There was no statistically significant difference between these two tinnitus groups (Mann / Whitney U -test for age, duration, pitch, and average hearing sensitivity; chi-square test for sex, laterality, and continuity) except for the loudness of the tinnitus Table 1 Summary of the statistical results comparing two tinnitus groups depending on their serum zinc levels: patients with hypozincemia and patients with normal zinc level
There was a significant correlation between serum zinc levels and average hearing sensitivities. In addition, a significantly lower serum zinc level was observed in patients with tinnitus who had normal hearing compared to controls. On the contrary, no significant difference was found in serum zinc levels between patients with tinnitus who had hearing loss, and controls. However, the average hearing sensitivities of patients with hypozincemia were not significantly different from those of patients with normal serum zinc levels (Table 1). These discrepancies suggest that not all patients with hypozincemia present normal hearing sensitivities (Figs. 1 and 2). The tinnitus loudness in patients with hypozincemia was significantly higher than that in patients without hypozincemia. The tinnitus loudness induced by cochlear disorders could be less than that induced by more central lesions, because of the recruitment phenomenon. These results suggest that the zinc deficiency is likely related to tinnitus originating more centrally rather than hearing loss due to a peripheral disorder. Zinc deficiency might relate to disorders in the non-lemniscal pathway rather than to disorders in the lemniscal pathway. Most neurons involved in the non-lemniscal pathway project to layers III/IV of secondary auditory cortex areas, and also diffusely to layer I of all cortical areas, while those in the lemniscal pathway are purely auditory and project in a strict topographic fashion to the primary auditory cortex and to the anterior auditory field [8,9]. The non-lemniscal pathway also receives input from the somatosensory system, and it has been found that some patients with severe tinnitus can be manipulated by activation of the somatosensory system [10]. In cat studies, the spontaneous firing rate of cells in the secondary auditory cortex increased after administration of both salicylate and quinine, while the firing rate of cells in the primary auditory cortex was little affected [11]. These animal data suggest that the non-lemniscal pathway is involved in tinnitus. In addition to animal data, the report of gaze-induced tinnitus [12 /14] and cutaneous-evoked tinnitus [15,16] support this hypothesis.
5. Conclusion The present data indicate that a significant correlation exists between serum zinc levels and the average hearing sensitivities in tinnitus patients. In addition, there is a
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K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
significantly lower serum zinc level in patients with tinnitus who have no hearing loss compared to controls. No significant difference was found in serum zinc levels between patients with tinnitus who had hearing loss, and controls. About one-third of the patients exhibited hypozincemia. These findings suggest that zinc is involved in the generation of tinnitus, especially in patients whose hearing is relatively normal. Zinc deficiency might relate to disorders in the non-lemniscal pathway rather than to disorders in the lemniscal pathway.
Acknowledgements This study was supported by the Grant-in-Aid for Scientific Research (C) (11671711) of the Japanese Ministry of Education, Science, Sports, and Culture.
References [1] Prasad AS, Halsted JA, Nadimi M. Syndrome of iron-deficiency, anaemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;31:532 /3. [2] Frederickson CJ, Moncrieff DW. Zinc-containing neurons. Biol Signals 1994;3:127 /39. [3] Izumi Y, Ishii K, Akiba K, Hayashi T. Hypozincemia during fever may trigger febrile convulsion. Med Hypotheses 1990;32:77 /80. [4] Shambaugh GE, Jr.. Zinc and presbyacusis. Am J Otol 1985;6:16 /117. [5] Shambaugh GE, Jr.. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J Otol 1986;7:476 /7.
[6] Gersdorff M, Robillard T, Stein F, Declaye X, Vanderbemden S. A clinical correlation between hypozincemia and tinnitus. Arch Otolaryngol 1987;244:190 /3. [7] Paaske PB, Pedersen CB, Kjems G, Sam ILK. Zinc in the management of tinnitus */placebo-controlled trial. Ann Otol Rhinol Laryngol 1991;100:647 /9. [8] Eggermont JJ, Komiya H. Auditory cortex reorganization after noise trauma: relation to tinnitus? In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. King’s Lynn (Norfolk, UK): Biddles Short Run Books Ltd., 1999. p. 146 /151. [9] Møller AR. Pathophysiology of severe tinnitus and chronic pain. In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. King’s Lynn (Norfolk, UK): Biddles Short Run Books Ltd., 1999. p. 26 /31. [10] Møller AR, Møller MB, Yokota M. Some forms of tinnitus may involve the extralemniscal pathway. Laryngoscope 1992;102:1165 /71. [11] Eggermont JJ, Kenmochi M. Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex. Hear Res 1998;117:149 /60. [12] Wall M, Rosenberg M, Richardson D. Gaze-evoked tinnitus. Neurology 1987;37:1034 /6. [13] Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS, Murphy BW. The functional neuroanatomy of tinnitus. Evidence for limbic system links and neural plasticity. Neurology 1998;50:114 /20. [14] Cacae AT, Lovely TJ, McFarland DJ, Parnes SM, Winter DF. Anomalous cross-modal plasticity following posterior fossa surgery: some speculations involving gaze-induced tinnitus. Hear Res 1994;81:22 /32. [15] Cacace AT, Cousins JP, Parness SM, Semenoff D, Holmes T, McFarland DJ, Davenport C, Stegbauer K, Lovely TJ. Cutaneous-evoked tinnitus. I. Phenomenology, psychophysics and functional imaging. Audiol Neurootol 1999;4:247 /57. [16] Cacace AT, Cousins JP, Parness SM, Semenoff D, Holmes T, McFarland DJ, Davenport C, Stegbauer K, Lovely TJ. Cutaneous-evoked tinnitus. II. Review of neuroanatomical, physiological and functional imaging studies. Audiol Neurootol 1999;4:258 /68.
Zinc deficiency and tinnitus Kentaro Ochi *, Hirotsugu Kinoshita, Mutsumi Kenmochi, Hirohito Nishino, Toru Ohashi Department of Otolaryngology, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-ku, Kawasaki 216-8511, Japan
Abstract Objective: To determine if there is a correlation between serum zinc levels and audiometric performance in tinnitus patients. Methods: Seventy-three patients participated in this study. Patient’s age was restricted to 20 /59 years. All patients were examined at the otolaryngology outpatient clinic of the St. Marianna University Toyoko Hospital. The control group consisted of 38 age- and sex-matched healthy volunteers. A blood sample was taken to measure serum zinc levels. Hypozincemia was set at a level of the mean minus one S.D. in the control group. An average hearing sensitivity was calculated as the mean value of hearing thresholds at five frequencies: 250, 500, 1000, 2000, and 4000 Hz. Normal hearing was indicated when the hearing threshold at each of these frequencies was within 20 dB of normal thresholds. Results: There was no significant difference in serum zinc levels between patients with tinnitus and controls. However, patients with tinnitus who had normal hearing had significantly lower serum zinc levels compared to controls. In contrast, no significant difference in serum zinc levels was found between patients with tinnitus who had hearing loss, and controls. A significant correlation between average hearing sensitivity and serum zinc level was observed. Conclusions: These findings suggest that zinc is involved in the generation of tinnitus, especially in patients whose hearing is relatively normal. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Zinc; Tinnitus; Hypozincemia
1. Introduction Zinc is one of the essential trace elements known to play an important role in human living cells, and it was first recognized as essential electrolyte mineral for humans in 1961 [1]. Zinc ions are distributed unevenly in the central nervous system, and can be released from nerve terminals. Zinc-containing neurons sequester zinc ions in their presynaptic vesicles and release it in a calcium- and impulse-dependent manner. The zinccontaining neurons are a subclass of the glutaminergic neurons [2]. It has also been reported that Hypozincemia activates the NMDA (N -methyl-D-aspartate) receptor */one of the glutamate family of receptors */
Part of this study was presented at the 6th International Tinnitus Seminar at Cambridge in 1999. * Corresponding author. Present address: Department of Otolaryngology, St. Marianna University Toyoko Hospital, 3-435, Kosugi-cho, Nakahara-ku, Kawasaki 211-0063, Japan. Tel.: /81-44722-2121; fax: /81-44-711-3316 E-mail address: [email protected] (K. Ochi).
which may play an important role in the induction of epileptic discharge [2,3]. Zinc has therefore been proposed as a likely modulator of tinnitus. The soft tissues of the guinea pig inner ear have the highest zinc content in the body [4]. Zinc deficiency may therefore result in some functional inner ear disorders such as sensorineural hearing loss, imbalance, and tinnitus [4]. It has been reported that when supplemented with zinc 25% of the patients exhibited reduction in tinnitus, and at least 20% of the patients showed a significant improvement in pure-tone hearing sensitivity [4]. In addition, zinc deficiency increases over the age of 60 years, and may be an etiologic factor in some cases of presbyacusis, tinnitus, and imbalance [5]. Gersdorff et al. [6] examined 115 patients suffering from tinnitus, of which 79 (68.7%) were found to have hypozincemia. However, using double-blind, randomized, placebocontrolled trials, Paaske et al. [7] reported that there was no significant difference in the improvement of tinnitus between zinc and placebo groups. The clinical correlation between zinc and tinnitus remains obscure.
0385-8146/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 8 5 - 8 1 4 6 ( 0 2 ) 0 0 1 4 5 - 1
S26
K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
The purpose of this study was to examine the correlation between serum zinc levels and audiometric performance, by measuring serum zinc levels in patients suffering from tinnitus.
2. Subjects and methods
2.5. Data analysis Statistical analyses were based on the Mann/Whitney U -test, the chi-square test, and linear regression analysis. Differences or changes at P B/0.05 level were considered significant. All tests were performed using the StatView 5.0J package for Microsoft Windows (SAS Institute, Cary, NC).
2.1. Subjects Initially 103 patients participated in this study. All suffered from tinnitus but were free of other diseases and not on medication. Patient’s age was restricted to 20 /59 years because of the potential effects of aging [5]. This reduced the number of investigated subjects to 73, consisting of 50 females (68.5%) and 23 males (31.5%). The mean age was 42.7 years (S.D., 11.0 years). All patients were examined at the otolaryngology outpatient clinic of the St. Marianna University Toyoko Hospital. The control group consisted of 38 age- and sex-matched healthy volunteers (26 females and 12 males). The mean age of the control group was 42.4 years (S.D., 9.7 years). This study was performed in accordance with the principles of the Declaration of Helsinki.
3. Results 3.1. Serum zinc level The serum zinc level in patients with tinnitus was 88.19/12.4 mg/dl (mean9/S.D., n/73) and that in the control group was 92.59/10.6 mg/dl (n/38) (Fig. 1). This difference was close to the level of statistical significance (Mann/Whitney U -test, P /0.06). Based on the serum zinc levels for the control group, a level of less than 81.9 mg/dl (i.e. mean minus one S.D.) was assessed as hypozincemia and 24 patients (32.9%) had this condition. 3.2. Correlation between serum zinc level and hearing sensitivity
2.2. Measurement and evaluation of serum zinc level A blood sample was taken to measure serum zinc levels. Hypozincemia was set at a level of the mean minus one S.D. in the control group. 2.3. Audiometric testing The thresholds of air- and bone-conducted hearing were measured in decibels (dB) at normal hearing level. An average hearing sensitivity was calculated as the mean value of hearing thresholds at five frequencies: 250, 500, 1000, 2000, and 4000 Hz. Normal hearing was indicated when the hearing threshold at each of these frequencies was within 20 dB of normal thresholds. The frequency and loudness of tinnitus were measured using a tinnitus audiometer (Danac 100, Dana Japan Corp., Tokyo, Japan). The loudness of tinnitus was expressed as decibel sensation level (SL). Thirty-eight patients underwent pitch and loudness matching procedures.
Fig. 2 illustrates the relationship between a patient’s serum zinc levels and the average hearing sensitivity. There is a significant correlation between these two values (linear regression analysis, r2 /0.15, P B/0.001). We divided patients into two groups on the basis of the audiometric test described above: 45 patients (61.6%) had hearing loss. The serum zinc levels in patients with normal hearing and in patients with hearing loss were 82.89/10.3 mg/dl (n/28) and 91.49/12.6 mg/dl (n /45), respectively (Fig. 1). The difference in serum zinc levels
2.4. Characteristics of tinnitus Several characteristics of tinnitus, including the ear side, continuity, and duration, were assessed. Patients who were not able to decide the side of the tinnitus were assessed as having bilateral tinnitus. In bilateral tinnitus, continuity, duration, frequency, and loudness of tinnitus were evaluated in the subjectively worse ear.
Fig. 1. The serum zinc levels in controls and tinnitus patients are shown in the left part of this figure. Patients are divided into two groups: tinnitus without hearing loss (without HL) and tinnitus with hearing loss (with HL). The right part of this figure shows the serum zinc levels for these two divided groups. Each box plot represents five horizontal lines that display the 10th, 25th, 50th, 75th, and 90th percentile, respectively.
K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
S27
(Mann/Whitney U -test, P B/0.05). The loudness in patients with hypozincemia was significantly higher than in patients with normal serum zinc levels.
4. Discussion
Fig. 2. Scattergrams showing the correlation between serum zinc levels and average hearing sensitivities (on the basis of pure-tone audiograms). The horizontal line indicates the lower limit of normal serum zinc level.
between patients with normal hearing and controls was statistically significant (Mann /Whitney U -test, P B/ 0.01). There was also a significant difference in serum zinc levels between patients with normal hearing and patients with hearing loss (P B/0.01). However, the difference in serum zinc levels between patients with hearing loss and the controls was not significant (Mann /Whitney U -test, P /0.64). 3.3. Comparison of two tinnitus groups depending on their serum zinc level Patients were divided into two groups depending on their serum zinc levels: patients with hypozincemia (n / 24) and patients with normal serum zinc level (n /49). Table 1 demonstrates the statistical results comparing these two groups. There was no statistically significant difference between these two tinnitus groups (Mann / Whitney U -test for age, duration, pitch, and average hearing sensitivity; chi-square test for sex, laterality, and continuity) except for the loudness of the tinnitus Table 1 Summary of the statistical results comparing two tinnitus groups depending on their serum zinc levels: patients with hypozincemia and patients with normal zinc level
There was a significant correlation between serum zinc levels and average hearing sensitivities. In addition, a significantly lower serum zinc level was observed in patients with tinnitus who had normal hearing compared to controls. On the contrary, no significant difference was found in serum zinc levels between patients with tinnitus who had hearing loss, and controls. However, the average hearing sensitivities of patients with hypozincemia were not significantly different from those of patients with normal serum zinc levels (Table 1). These discrepancies suggest that not all patients with hypozincemia present normal hearing sensitivities (Figs. 1 and 2). The tinnitus loudness in patients with hypozincemia was significantly higher than that in patients without hypozincemia. The tinnitus loudness induced by cochlear disorders could be less than that induced by more central lesions, because of the recruitment phenomenon. These results suggest that the zinc deficiency is likely related to tinnitus originating more centrally rather than hearing loss due to a peripheral disorder. Zinc deficiency might relate to disorders in the non-lemniscal pathway rather than to disorders in the lemniscal pathway. Most neurons involved in the non-lemniscal pathway project to layers III/IV of secondary auditory cortex areas, and also diffusely to layer I of all cortical areas, while those in the lemniscal pathway are purely auditory and project in a strict topographic fashion to the primary auditory cortex and to the anterior auditory field [8,9]. The non-lemniscal pathway also receives input from the somatosensory system, and it has been found that some patients with severe tinnitus can be manipulated by activation of the somatosensory system [10]. In cat studies, the spontaneous firing rate of cells in the secondary auditory cortex increased after administration of both salicylate and quinine, while the firing rate of cells in the primary auditory cortex was little affected [11]. These animal data suggest that the non-lemniscal pathway is involved in tinnitus. In addition to animal data, the report of gaze-induced tinnitus [12 /14] and cutaneous-evoked tinnitus [15,16] support this hypothesis.
5. Conclusion The present data indicate that a significant correlation exists between serum zinc levels and the average hearing sensitivities in tinnitus patients. In addition, there is a
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K. Ochi et al. / Auris, Nasus, Larynx 30 (2003) S25 /S28
significantly lower serum zinc level in patients with tinnitus who have no hearing loss compared to controls. No significant difference was found in serum zinc levels between patients with tinnitus who had hearing loss, and controls. About one-third of the patients exhibited hypozincemia. These findings suggest that zinc is involved in the generation of tinnitus, especially in patients whose hearing is relatively normal. Zinc deficiency might relate to disorders in the non-lemniscal pathway rather than to disorders in the lemniscal pathway.
Acknowledgements This study was supported by the Grant-in-Aid for Scientific Research (C) (11671711) of the Japanese Ministry of Education, Science, Sports, and Culture.
References [1] Prasad AS, Halsted JA, Nadimi M. Syndrome of iron-deficiency, anaemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 1961;31:532 /3. [2] Frederickson CJ, Moncrieff DW. Zinc-containing neurons. Biol Signals 1994;3:127 /39. [3] Izumi Y, Ishii K, Akiba K, Hayashi T. Hypozincemia during fever may trigger febrile convulsion. Med Hypotheses 1990;32:77 /80. [4] Shambaugh GE, Jr.. Zinc and presbyacusis. Am J Otol 1985;6:16 /117. [5] Shambaugh GE, Jr.. Zinc for tinnitus, imbalance, and hearing loss in the elderly. Am J Otol 1986;7:476 /7.
[6] Gersdorff M, Robillard T, Stein F, Declaye X, Vanderbemden S. A clinical correlation between hypozincemia and tinnitus. Arch Otolaryngol 1987;244:190 /3. [7] Paaske PB, Pedersen CB, Kjems G, Sam ILK. Zinc in the management of tinnitus */placebo-controlled trial. Ann Otol Rhinol Laryngol 1991;100:647 /9. [8] Eggermont JJ, Komiya H. Auditory cortex reorganization after noise trauma: relation to tinnitus? In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. King’s Lynn (Norfolk, UK): Biddles Short Run Books Ltd., 1999. p. 146 /151. [9] Møller AR. Pathophysiology of severe tinnitus and chronic pain. In: Hazell J, editor. Proceedings of the Sixth International Tinnitus Seminar. King’s Lynn (Norfolk, UK): Biddles Short Run Books Ltd., 1999. p. 26 /31. [10] Møller AR, Møller MB, Yokota M. Some forms of tinnitus may involve the extralemniscal pathway. Laryngoscope 1992;102:1165 /71. [11] Eggermont JJ, Kenmochi M. Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex. Hear Res 1998;117:149 /60. [12] Wall M, Rosenberg M, Richardson D. Gaze-evoked tinnitus. Neurology 1987;37:1034 /6. [13] Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS, Murphy BW. The functional neuroanatomy of tinnitus. Evidence for limbic system links and neural plasticity. Neurology 1998;50:114 /20. [14] Cacae AT, Lovely TJ, McFarland DJ, Parnes SM, Winter DF. Anomalous cross-modal plasticity following posterior fossa surgery: some speculations involving gaze-induced tinnitus. Hear Res 1994;81:22 /32. [15] Cacace AT, Cousins JP, Parness SM, Semenoff D, Holmes T, McFarland DJ, Davenport C, Stegbauer K, Lovely TJ. Cutaneous-evoked tinnitus. I. Phenomenology, psychophysics and functional imaging. Audiol Neurootol 1999;4:247 /57. [16] Cacace AT, Cousins JP, Parness SM, Semenoff D, Holmes T, McFarland DJ, Davenport C, Stegbauer K, Lovely TJ. Cutaneous-evoked tinnitus. II. Review of neuroanatomical, physiological and functional imaging studies. Audiol Neurootol 1999;4:258 /68.