**4. Evaluation of the experimental data in the context of previous observations of the action of thyroid hormone on mental speed**

Taken together, this short survey of measurable changes in sensory perception and reaction after a period of a few weeks of severe hypothyroidism indicates that the first effects of hypothyroidism to become significantly evident concern changes in the speed of speech and visual perception.

#### *Speed of speech*

Although slowing of speech and thinking had already been noticed in the first description of myxedema (2) and by the Committee of the Clinical Society in 1888 (4) to be one of the most prominent symptoms of hypothyroidism we are aware of only one published attempt to quantify changes in speech due to different thyroid states. This study reported a negative correlation between the basal frequency of speech and the duration of the achilles tendon reflex (50). These authors performed investigations before and after treatment of hypo- and hyperthyroidism with reported time intervals from 7 days to 17 weeks, but did not further comment on the severity of thyroid dysfunction and the time course of development of recovery of the changes in pitch. A further study observed a decrease of the fundamental frequency of speaking 4 days after thyroid ablation (51). Although the cause for the slowing of speech is difficult to interpret, increased intervals between the different words (see Fig. 1A) suggest, that in addition to a possible slowing of muscle contraction and a potential decrease in tension of the vocal cords a central slowing of neuronal information processing is likely to occur.

#### *Speed of processing of visual signals*

96 Thyroid Hormone

(49).

visual perception.

is likely to occur.

*Speed of speech* 

hormone resubstitution in this test person.

speed, a 0 for an unchanged performance and a –1 for a slowing of performance at retesting during hormone resubstitution. If a person showed no overall change in speed of performance, a score scattering around 0 should result, if the subject slowed considerably the score should be in the negative range and if a subject speeded in all tasks, the maximal score would reach 8. As depicted in Fig. 4D out of the 6 persons tested with all 8 identical tests 5 showed a considerable speeding which corresponded to an increased performance in at least 6 out of 8 tests. Only one of the test persons, aged 57, showed an increased performance in only 4 tests and a decreased performance in 4 tests. This person was the only one who showed no increase in the speed of speech with thyroid hormone substitution. Nevertheless Fourier- analysis revealed an increase in pitch by 11% after prolonged

Our findings, that younger persons are more impaired than older subjects after thyroid hormone withdrawal is in accordance with recent findings by Heinzel et al., who reported a stronger subjective impairment in younger patients after thyroid hormone withdrawal than in older patients (46). This is in accordance with observations of age-dependent effects on heart action potential parameters observed to parallel age-related thyroid states (47, 48). This observation might relate to a down-regulation of thyroid hormone receptors with aging

Taken together, this short survey of measurable changes in sensory perception and reaction after a period of a few weeks of severe hypothyroidism indicates that the first effects of hypothyroidism to become significantly evident concern changes in the speed of speech and

Although slowing of speech and thinking had already been noticed in the first description of myxedema (2) and by the Committee of the Clinical Society in 1888 (4) to be one of the most prominent symptoms of hypothyroidism we are aware of only one published attempt to quantify changes in speech due to different thyroid states. This study reported a negative correlation between the basal frequency of speech and the duration of the achilles tendon reflex (50). These authors performed investigations before and after treatment of hypo- and hyperthyroidism with reported time intervals from 7 days to 17 weeks, but did not further comment on the severity of thyroid dysfunction and the time course of development of recovery of the changes in pitch. A further study observed a decrease of the fundamental frequency of speaking 4 days after thyroid ablation (51). Although the cause for the slowing of speech is difficult to interpret, increased intervals between the different words (see Fig. 1A) suggest, that in addition to a possible slowing of muscle contraction and a potential decrease in tension of the vocal cords a central slowing of neuronal information processing

**4. Evaluation of the experimental data in the context of previous observations of the action of thyroid hormone on mental speed** 

The second most prominent effect of hypothyroidism revealed by our tests is a slowing of the speed of perception of visual information. These results confirm several previous studies, one of which reported critical flicker fusion frequencies (CFF) up to 41 - 48 Hz in 23 hyperthyroid patients and a decrease in flicker fusion frequency to the normal value of 37 Hz within one month after treatment of the hyperthyroidism (52). Decreased values of the critical flicker fusion frequency as well as of the maximal speed of finger movements were shown in hypothyroid patients (53). A third study revealed an increase in CFF in hypothyroid subjects with a delay of 2-3 weeks after an increase in dose of thyroid hormone substitution (54). We could find no previous reports on influences of thyroid hormone on the critical colour-fusion frequency (CCFF) which tests the speed of processing of chromatic pathways in addition to the CFF, which tests the speed of luminance processing. CCFF occurs at a lower frequency as CFF (55). The lower frequency of colour processing compared to luminance flicker already starts to arise at the level of the retina (56).

Since thyroid hormone affects the renewal rate of the photoreceptor outer segments in the rat (57, 58) one locus of action of thyroid hormone could be the retina. This is confirmed by the finding of increased amplitudes of chiefly the b-waves of the electroretinogram in hyperthyroidism and a decrease in hypothyroidism (59, 60), suggesting that thyroid hormone influences retinal sensitivity to light. Since there is evidence that thyroid releasing hormone (TRH) in the circulation decreases the critical flicker fusion frequency (61) the effect could also be due to the enhanced TRH level in the investigated test persons. Since, however, no effects of hypothyroidism on peripheral circulating TRH values have been found (62) it seems presently more likely that the decrease in flicker fusion frequency is due to a direct effect of thyroid hormone.

Increased voltages of EEG records and a decreased duration of arousal responses to photic stimulation after administration of thyroid hormone (63) could be explained by an increased light-sensitivity of the retina, but additionally also by an increased transmission of sensory signals to the visual cortex. Substantial experimental evidence has been obtained to show that the upper frequency limit with which signals are transmitted in the visual pathways decreases with the number of synaptic stations traversed (for review see (64)). Hence a modulation of synaptic transmission at the thalamic level seems to be responsible for the increase of CFF by psychotropic stimulants and the decrease by sedatives (for reviews see (65, 66)). Furthermore, investigations of the relation between CFF and intelligence revealed only non-significant relations between different scores for intelligence and CFF (67, 68), however a decrease of 4 Hz of was found in mentally retarded persons (69) suggesting that a larger decline of cognitive function may be accompanied by decreases in CFF. In addition a correlation was found between the decline of CFF and the decline in performance on cognitive tests in old age (70).

Complementary to a reduction in CFF, flash evoked potentials showed increased latencies and reduced amplitudes in hypothyroid patients 6 weeks after thyroidectomy which were reversed after 8 weeks of treatment (16). Consistently, visual evoked potentials using

chequerboard reversal patterns showed reversible increases in latencies and reductions in amplitudes in hypothyroidism (17, 19–21, 23, 24, 71–73). However, this increase in latency is not consistently observed in all cases of hypothyroidism and thus it is still controversial after which duration and or severity of hypothyroidism significant increases in latency can be observed (74). Nevertheless, blink reflex prolongation could be consistently observed in hypothyroid patients confirming a slowing in visual pathways in adult onset hypothyroidism (75). From the available studies no definitive conclusion concerning the targets for thyroid hormone action in the visual pathways can be drawn. Thyroid hormone could already effect photoreceptor sensitivity as well as increase the speed of impulse propagation and synaptic transmission in any of the following relay stations.

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 99

one of a reaction time, an object memory and a figure identification test after a six month period of thyroxine supplementation (33). Likewise, in subclinically hypothyroid adults the Wechsler Memory Scale indicated a significant decrease in logical memory (91, 92) as well as verbal and visual memory (93) (for a recent review see (94)) and severe hypothyroidism for a short time decreased working memory (43). Using fMRI changes in hypothyroid subjects during working memory tasks could be visualized (95). Finally also changes in the estimation of time spans have been observed in hypothyroid subjects (96). All these experiments were performed after a longer period of hypothyroidism or latent thyroid dysfunction. To be able to complete our test battery in a reasonably short time we designed a short tests for calculation and visual-spatial performance. Our present results indicate that a severe hypothyroidism of a short duration already causes significantly slowed performance in a visuo-spatial orientation task. This is in line with findings of increased

Although perversions of taste and smell during myxoedema have already been noticed in the first descriptions of this disease (99, 100) there have only been a few investigations on this subject, which provided no clear answers concerning the prevalence of olfactory disorders during hypothyroidism. Reversible increases in the threshold of smell and taste have previously been found in hypothyroid subjects (30, 31, 101). In addition to the reduced threshold, hypothyroid persons rated bitter and salty tastes as more agreeable than euthyroid control persons in the latter study. Interestingly, a more general study concerned with smell and taste disorders reported a more than average complaint of patients taking levothyroxine about a loss of the sense of taste. The investigation of these patients revealed, in contrast to their subjective impressions, higher scores on a taste-identification test. Additionally, the patients taking thyroxine perceived a test concentration of coffeine as having a greater intensity as the other patients, without showing significantly different taste thresholds (102). The discrepancy between subjective impression and test results could have resulted from increases in thresholds of taste preceding hormone substitution resulting in an increased awareness of the sense of smell. A study of taste thresholds, measured in 11 hypothyroid subjects after total thyroid ablation, which had stopped taking replacement for 4-8 weeks prior to a 131I scan showed no increases in recognition thresholds to NaCl and urea (103). These patients showed, however, a decrease in intensity rating for the two tastants and less dislike to both substances at higher concentrations as compared to control subjects. Although the authors conclude that hypothyroidism probably has to persist for a longer time in order to develop more pronounced changes in taste, the preference and intensity rating tests could indicate the beginning of changes in taste after this period. Our present findings of an insignificant tendency towards a higher threshold of smell for both odours in the hypothyroid compared with the euthyroid subjects are in line with the assumption of a beginning loss of taste and smell after 4 weeks of hypothyroidism. In contrast, however, a study by Lewitt et al. (104) found no significant changes in the thresholds for taste and smell even in longer standing hypothyroidism. Since this study, in addition, reported no increase in the latencies of visual evoked potentials, in contrast to seven other available reports, it could

latencies of event-related evoked potentials in hypothyroidism (97, 98).

*Perception of smells* 

#### *Cognitive performance*

Several reports have described mental changes in hypothyroidism, ranging from difficulties to perform simple calculations to memory impairments and finally to hallucinations (76–79). Although these impairments are probably the most troublesome symptoms for the patients, it has been difficult to quantify cognitive problems in adult-onset hypothyroidism. Daytime sleepiness as well as mental and physical fatigue are complaints in 70 - 80% of the hypothyroids (80, 81). Disturbances of sleep during thyroid dysfunction might account for some of the problems delineated above, as the different sleep stages are necessary for memory consolidation (82, 83). Sleep fragmentation in hypothyroids is not necessarily caused by nocturnal breathing disorders (sleep apnea) (84, 85).

The trail making test, which tests skills including vigilance, concentration, visual scanning and visuomotor tracking speed was shown by Reitan (44, 86) to respond to different types of organic brain damage. Later on slowed performance on the trail making test (part B) was shown in hypothyroid patients (78, 87). Subsequently Osterweil et al. (24) observed that the performance for Trail A was significantly slowed in old and very old hypothyroid patients as compared to age-matched controls and Wahlin et al. (88) reported that TSH was predictive for Trail-B in very old persons. Our finding of a non-significant slowing in the trail making tests confirms the observation of Osterweil et al., that carcinoma patients off thyroid hormone replacement show no statistically significant differences in test performance compared to euthyroid controls. However, 5 of the six persons tested showed an increase in performance when retested after hormone replacement, which escaped statistical significance because of the large scatter between the different individuals. This suggests that thyroid hormone withdrawal of longer duration is necessary before changes in this test become statistically significant.

Apart from this relatively simple test effects of thyroid hormone on more complex cognitive tasks have been investigated. The first measurement of an increase in the intelligence level by a mean of 20 I. Q. points of three adult myxedematous patients after three months of treatment with thyroid hormone has been reported by Crown (32). Especially in older hypothyroid persons, reversible decreases in the Folstein mini mental state score were found (24, 89, 90). In a double-blind study on adult persons with subclinical hypothyroidism out of 17 patients 4 showed improved performance on at least two and 7 test persons improved in one of a reaction time, an object memory and a figure identification test after a six month period of thyroxine supplementation (33). Likewise, in subclinically hypothyroid adults the Wechsler Memory Scale indicated a significant decrease in logical memory (91, 92) as well as verbal and visual memory (93) (for a recent review see (94)) and severe hypothyroidism for a short time decreased working memory (43). Using fMRI changes in hypothyroid subjects during working memory tasks could be visualized (95). Finally also changes in the estimation of time spans have been observed in hypothyroid subjects (96). All these experiments were performed after a longer period of hypothyroidism or latent thyroid dysfunction. To be able to complete our test battery in a reasonably short time we designed a short tests for calculation and visual-spatial performance. Our present results indicate that a severe hypothyroidism of a short duration already causes significantly slowed performance in a visuo-spatial orientation task. This is in line with findings of increased latencies of event-related evoked potentials in hypothyroidism (97, 98).

#### *Perception of smells*

98 Thyroid Hormone

*Cognitive performance* 

chequerboard reversal patterns showed reversible increases in latencies and reductions in amplitudes in hypothyroidism (17, 19–21, 23, 24, 71–73). However, this increase in latency is not consistently observed in all cases of hypothyroidism and thus it is still controversial after which duration and or severity of hypothyroidism significant increases in latency can be observed (74). Nevertheless, blink reflex prolongation could be consistently observed in hypothyroid patients confirming a slowing in visual pathways in adult onset hypothyroidism (75). From the available studies no definitive conclusion concerning the targets for thyroid hormone action in the visual pathways can be drawn. Thyroid hormone could already effect photoreceptor sensitivity as well as increase the speed of impulse

Several reports have described mental changes in hypothyroidism, ranging from difficulties to perform simple calculations to memory impairments and finally to hallucinations (76–79). Although these impairments are probably the most troublesome symptoms for the patients, it has been difficult to quantify cognitive problems in adult-onset hypothyroidism. Daytime sleepiness as well as mental and physical fatigue are complaints in 70 - 80% of the hypothyroids (80, 81). Disturbances of sleep during thyroid dysfunction might account for some of the problems delineated above, as the different sleep stages are necessary for memory consolidation (82, 83). Sleep fragmentation in hypothyroids is not necessarily

The trail making test, which tests skills including vigilance, concentration, visual scanning and visuomotor tracking speed was shown by Reitan (44, 86) to respond to different types of organic brain damage. Later on slowed performance on the trail making test (part B) was shown in hypothyroid patients (78, 87). Subsequently Osterweil et al. (24) observed that the performance for Trail A was significantly slowed in old and very old hypothyroid patients as compared to age-matched controls and Wahlin et al. (88) reported that TSH was predictive for Trail-B in very old persons. Our finding of a non-significant slowing in the trail making tests confirms the observation of Osterweil et al., that carcinoma patients off thyroid hormone replacement show no statistically significant differences in test performance compared to euthyroid controls. However, 5 of the six persons tested showed an increase in performance when retested after hormone replacement, which escaped statistical significance because of the large scatter between the different individuals. This suggests that thyroid hormone withdrawal of longer duration is necessary before changes in

Apart from this relatively simple test effects of thyroid hormone on more complex cognitive tasks have been investigated. The first measurement of an increase in the intelligence level by a mean of 20 I. Q. points of three adult myxedematous patients after three months of treatment with thyroid hormone has been reported by Crown (32). Especially in older hypothyroid persons, reversible decreases in the Folstein mini mental state score were found (24, 89, 90). In a double-blind study on adult persons with subclinical hypothyroidism out of 17 patients 4 showed improved performance on at least two and 7 test persons improved in

propagation and synaptic transmission in any of the following relay stations.

caused by nocturnal breathing disorders (sleep apnea) (84, 85).

this test become statistically significant.

Although perversions of taste and smell during myxoedema have already been noticed in the first descriptions of this disease (99, 100) there have only been a few investigations on this subject, which provided no clear answers concerning the prevalence of olfactory disorders during hypothyroidism. Reversible increases in the threshold of smell and taste have previously been found in hypothyroid subjects (30, 31, 101). In addition to the reduced threshold, hypothyroid persons rated bitter and salty tastes as more agreeable than euthyroid control persons in the latter study. Interestingly, a more general study concerned with smell and taste disorders reported a more than average complaint of patients taking levothyroxine about a loss of the sense of taste. The investigation of these patients revealed, in contrast to their subjective impressions, higher scores on a taste-identification test. Additionally, the patients taking thyroxine perceived a test concentration of coffeine as having a greater intensity as the other patients, without showing significantly different taste thresholds (102). The discrepancy between subjective impression and test results could have resulted from increases in thresholds of taste preceding hormone substitution resulting in an increased awareness of the sense of smell. A study of taste thresholds, measured in 11 hypothyroid subjects after total thyroid ablation, which had stopped taking replacement for 4-8 weeks prior to a 131I scan showed no increases in recognition thresholds to NaCl and urea (103). These patients showed, however, a decrease in intensity rating for the two tastants and less dislike to both substances at higher concentrations as compared to control subjects. Although the authors conclude that hypothyroidism probably has to persist for a longer time in order to develop more pronounced changes in taste, the preference and intensity rating tests could indicate the beginning of changes in taste after this period. Our present findings of an insignificant tendency towards a higher threshold of smell for both odours in the hypothyroid compared with the euthyroid subjects are in line with the assumption of a beginning loss of taste and smell after 4 weeks of hypothyroidism. In contrast, however, a study by Lewitt et al. (104) found no significant changes in the thresholds for taste and smell even in longer standing hypothyroidism. Since this study, in addition, reported no increase in the latencies of visual evoked potentials, in contrast to seven other available reports, it could be possible, that the discordant findings of this report were due to the high median age of the investigated subjects (61 ± 16 years) which could already have displayed age-dependent declines in sensory function. In addition, the possibility exists, that only a fraction of the hypothyroid subjects shows changes in taste thresholds (105).

Thyroid Hormone Effects on Sensory Perception, Mental Speed, Neuronal Excitability and Ion Channel Regulation 101

could be necessary for the proper development of cochlear sensory transduction. Furthermore, hypothyroidism causes delays in the development of synaptic inhibition in the auditory brainstem (130). In line with a larger susceptibility of the immature auditory system to thyroid hormone deficiency Heinemann (131) reported no case of hearing impairment in 23 patients with primary hypothyroidism if treated in time but in 4 out of 7 cases if hormone substitution had been delayed. Besides the irreversible effects of thyroid hormone on the development of inner ear function, reversible changes of hearing acuity have already been described in early reports on the symptoms of adult-onset hypothyroidism (132, 133). Improvements of hearing threshold with treatment in some patients with hypothyroidism have since been shown with pure tone audiometric testing (25, 28, 29, 134, 135). Especially noteworthy in this context is the finding, that in 7- 11 year old, normal, but latently hypothyroid schoolchildren living in endemic areas of severe iodine deficiency iodine prophylaxis led to an average improvement of hearing (30 children tested in each village) by 15 db over the course of three years (136). Smaller changes in hearing threshold were reported after a total thyroid hormone withdrawal for a few weeks: 6 - 12 weeks after hormone withdrawal Post (137) reported 26 normal audiograms, decreased hearing thresholds which did not reverse after 3- 12 months of treatment in 5 patients and small, partially subjective improvements with hormone substitution in 4 patients from a total of 35 patients. No acute changes in hearing were also found by Mra and Wax (138) in 10 patients 2-6 weeks after total thyroidectomy. In contrast, Rubenstein et al. (120) described a case of a reversible hearing loss of 20 dB in a 5 year old child, that had been induced by stopping thyroid hormone therapy for four weeks. Another case report, where audiometric investigations were available 2 months before thyroidectomy a high frequency hearing loss started on the 40th day of hormone withdrawal, which was partially reversible after hormone substitution (139). These inconsistent findings correspond to our results of borderline significant increases in hearing thresholds of about 8 dB for high frequencies after

Animal experiments showed that in guinea pigs thyroid ablation caused decreased amplitudes of cochlear microphonic potentials (140) and cochlear action potentials of decreased amplitudes and increased delay when recorded four to eight months after administration of an ablative dose of radioactive iodine (124). Likewise, increased hearing thresholds have been observed in adult guinea pigs (125) at high frequencies of 8kHz (141) after 120 days of hypothyroidism. In contrast, Ritter (26) measured only deafness in five out of 166 experimental rats rendered hypothyroid on the 21st day of life. Interestingly, changes in the number of spines/per shaft of pyramidal neurones (indicating synaptic densities) could be shown in the auditory cortex of adult rats thyroidectomized at 120 days of age and investigated 120 days later (142). The authors note that in auditory pyramidal cells these changes develop much more slowly than in pyramidal cells of the visual cortex, which could indicate that the adult auditory system may respond to hypothyroidism on a slower time scale than the visual system. Perhaps these considerations could also explain why, in contrast to visual evoked potentials which consistently show slowing in hypothyroidism, some authors found no changes in auditory evoked potentials (24, 143) while other studies (18, 21, 22) found reversible increases in latencies of auditory evoked potentials in hypothyroidism.

4 weeks of thyroid hormone withdrawal.

Possible causes of a loss in smell during hypothyroidism have also been investigated in rats. Here prolonged hypothyroidism has been shown to result in deficits in migration of olfactory receptor neurones while the mitotic rates of basal cells remained unaltered in postnatal (106) as well as in adult rats (107). The effects of propylthiouracil (PTU) – induced hypothyroidism were reversed by thyroxine therapy. Further experiments could, however, not confirm increases in the threshold to olfactory and taste stimuli in adult rats rendered hypothyroid with PTU for 5 weeks (108, 109) in which only changes in taste preferences for sour, bitter and salty, not of detection threshold were found. Additional confusion arose from several case reports describing thyreostatic drugs to also induce decreases in the sense of taste and smell in patients (methylthiouracil, - (110); methimazole - (111); thiamazol and carbimazol, (112–114). Sometimes, only the sensation of taste, sometimes also olfaction was impaired. Some patients could have actually become hypothyroid, but in some patients no other symptoms of hypothyroidism were noted and the symptoms did not reappear during thyroidectomy-induced hypothyroidism (110). A histological examination showing destruction of the olfactory epithelium, sparing the basal cells already after 32 hours of methimazol administration to rats further substantiates the possibility of toxic effects of antithyroid medication (115), which lead to apoptosis of rat olfactory receptor neurons (116). However, in studies of methimazol toxicology effects of hypothyroidism should be carefully excluded. Likewise, we cannot presently exclude, that changes in taste, which have been reported to occur frequently in patients as side effects of a high dose 131I therapy (117) could also have resulted to some extent from the accompanying hypothyroidism, which also has been reported as a potential cause of a "bourning mouth symptom" (118).

#### *Hearing*

Impairments of hearing have long been reported to occur in hypothyroidism (for reviews see (27, 119)). The incidence of decreases in hearing threshold observed in hypothyroid patients varies from study to study, ranging from 85% (28), 80% (29), 62% (120), 55% (121) 43% (122), 31% (80) to as low as 12% [98].

The only study showing no evidence of reversible hearing losses in hypothyroid patients (123) was performed on old patients between 61-92 years, in which the effects of presbyacusis may have a stronger effect on hearing threshold than those of thyroid hormone. The most dramatic hearing impairments arise if the thyroid hormone supply is insufficient during development, where irreversible structural impairments in the cochlea, presumably a disruption of the smooth fit of the tectorial membrane to the hair cells occurs (see e.g. (124–126). While a thyroid-hormone induced selective expression of neurotrophinreceptors could underly the morphogenetic changes shaping the inner ear (127) the acceleration of the expression of a fast potassium conductance (128) and the development of rapidly activating Ca2+- and voltage-activated K+ (BK) conductances in inner hair cells (129) could be necessary for the proper development of cochlear sensory transduction. Furthermore, hypothyroidism causes delays in the development of synaptic inhibition in the auditory brainstem (130). In line with a larger susceptibility of the immature auditory system to thyroid hormone deficiency Heinemann (131) reported no case of hearing impairment in 23 patients with primary hypothyroidism if treated in time but in 4 out of 7 cases if hormone substitution had been delayed. Besides the irreversible effects of thyroid hormone on the development of inner ear function, reversible changes of hearing acuity have already been described in early reports on the symptoms of adult-onset hypothyroidism (132, 133). Improvements of hearing threshold with treatment in some patients with hypothyroidism have since been shown with pure tone audiometric testing (25, 28, 29, 134, 135). Especially noteworthy in this context is the finding, that in 7- 11 year old, normal, but latently hypothyroid schoolchildren living in endemic areas of severe iodine deficiency iodine prophylaxis led to an average improvement of hearing (30 children tested in each village) by 15 db over the course of three years (136). Smaller changes in hearing threshold were reported after a total thyroid hormone withdrawal for a few weeks: 6 - 12 weeks after hormone withdrawal Post (137) reported 26 normal audiograms, decreased hearing thresholds which did not reverse after 3- 12 months of treatment in 5 patients and small, partially subjective improvements with hormone substitution in 4 patients from a total of 35 patients. No acute changes in hearing were also found by Mra and Wax (138) in 10 patients 2-6 weeks after total thyroidectomy. In contrast, Rubenstein et al. (120) described a case of a reversible hearing loss of 20 dB in a 5 year old child, that had been induced by stopping thyroid hormone therapy for four weeks. Another case report, where audiometric investigations were available 2 months before thyroidectomy a high frequency hearing loss started on the 40th day of hormone withdrawal, which was partially reversible after hormone substitution (139). These inconsistent findings correspond to our results of borderline significant increases in hearing thresholds of about 8 dB for high frequencies after 4 weeks of thyroid hormone withdrawal.

100 Thyroid Hormone

*Hearing* 

43% (122), 31% (80) to as low as 12% [98].

be possible, that the discordant findings of this report were due to the high median age of the investigated subjects (61 ± 16 years) which could already have displayed age-dependent declines in sensory function. In addition, the possibility exists, that only a fraction of the

Possible causes of a loss in smell during hypothyroidism have also been investigated in rats. Here prolonged hypothyroidism has been shown to result in deficits in migration of olfactory receptor neurones while the mitotic rates of basal cells remained unaltered in postnatal (106) as well as in adult rats (107). The effects of propylthiouracil (PTU) – induced hypothyroidism were reversed by thyroxine therapy. Further experiments could, however, not confirm increases in the threshold to olfactory and taste stimuli in adult rats rendered hypothyroid with PTU for 5 weeks (108, 109) in which only changes in taste preferences for sour, bitter and salty, not of detection threshold were found. Additional confusion arose from several case reports describing thyreostatic drugs to also induce decreases in the sense of taste and smell in patients (methylthiouracil, - (110); methimazole - (111); thiamazol and carbimazol, (112–114). Sometimes, only the sensation of taste, sometimes also olfaction was impaired. Some patients could have actually become hypothyroid, but in some patients no other symptoms of hypothyroidism were noted and the symptoms did not reappear during thyroidectomy-induced hypothyroidism (110). A histological examination showing destruction of the olfactory epithelium, sparing the basal cells already after 32 hours of methimazol administration to rats further substantiates the possibility of toxic effects of antithyroid medication (115), which lead to apoptosis of rat olfactory receptor neurons (116). However, in studies of methimazol toxicology effects of hypothyroidism should be carefully excluded. Likewise, we cannot presently exclude, that changes in taste, which have been reported to occur frequently in patients as side effects of a high dose 131I therapy (117) could also have resulted to some extent from the accompanying hypothyroidism, which also has

hypothyroid subjects shows changes in taste thresholds (105).

been reported as a potential cause of a "bourning mouth symptom" (118).

Impairments of hearing have long been reported to occur in hypothyroidism (for reviews see (27, 119)). The incidence of decreases in hearing threshold observed in hypothyroid patients varies from study to study, ranging from 85% (28), 80% (29), 62% (120), 55% (121)

The only study showing no evidence of reversible hearing losses in hypothyroid patients (123) was performed on old patients between 61-92 years, in which the effects of presbyacusis may have a stronger effect on hearing threshold than those of thyroid hormone. The most dramatic hearing impairments arise if the thyroid hormone supply is insufficient during development, where irreversible structural impairments in the cochlea, presumably a disruption of the smooth fit of the tectorial membrane to the hair cells occurs (see e.g. (124–126). While a thyroid-hormone induced selective expression of neurotrophinreceptors could underly the morphogenetic changes shaping the inner ear (127) the acceleration of the expression of a fast potassium conductance (128) and the development of rapidly activating Ca2+- and voltage-activated K+ (BK) conductances in inner hair cells (129) Animal experiments showed that in guinea pigs thyroid ablation caused decreased amplitudes of cochlear microphonic potentials (140) and cochlear action potentials of decreased amplitudes and increased delay when recorded four to eight months after administration of an ablative dose of radioactive iodine (124). Likewise, increased hearing thresholds have been observed in adult guinea pigs (125) at high frequencies of 8kHz (141) after 120 days of hypothyroidism. In contrast, Ritter (26) measured only deafness in five out of 166 experimental rats rendered hypothyroid on the 21st day of life. Interestingly, changes in the number of spines/per shaft of pyramidal neurones (indicating synaptic densities) could be shown in the auditory cortex of adult rats thyroidectomized at 120 days of age and investigated 120 days later (142). The authors note that in auditory pyramidal cells these changes develop much more slowly than in pyramidal cells of the visual cortex, which could indicate that the adult auditory system may respond to hypothyroidism on a slower time scale than the visual system. Perhaps these considerations could also explain why, in contrast to visual evoked potentials which consistently show slowing in hypothyroidism, some authors found no changes in auditory evoked potentials (24, 143) while other studies (18, 21, 22) found reversible increases in latencies of auditory evoked potentials in hypothyroidism.

Taken together, the auditory system may lose its sensitivity to thyroid hormone with increasing age and this may also depend on an individual susceptibility. In addition, effects on hearing may develop only after a thyroid hormone withdrawal for more than five weeks in the adult.

Thyroid Hormone Effects on Sensory Perception, Mental Speed, Neuronal Excitability and Ion Channel Regulation 103

also explain the occurrence of slow EEG waves (159) as well as the cognitive impairments frequently seen in hypothyroid subjects. A regulation of cholinergic function also fits to the observation of a regulation of nerve growth factor which has been suggested to be involved in maintaining the function of cholinergic hippocampal projections by thyroid hormone in adult rat brain (160). Thyroid hormone, however, does not seem to interfere exclusively with cholinergic forebrain neurons but to regulate the balance of a variety of other neurotransmitters in a region-specific manner. Hence dopamine levels were found to be increased in the midbrain of hyperthyroid rats (161) and decreased in hypothyroid rats (162). Also the dopaminergic input into striatal neurons could be upregulated by thyroid hormone (163). Furthermore, a differential regulation of serotonin levels (162, 164) as well as 5-HT2 receptors have been found (165). Regulations of various adrenoceptors as well as GABAreceptors have been described see e.g. (166–168). In addition T3 could act as a cotransmitter to modulate noradrenergic action (169) or as a modulator of endogenous benzodiazepine action (170). While it is believed that thyroid hormone exerts its effects predominantly via nuclear receptors possible direct effects on membrane receptors further complicate the picture (157, 171, 172). In addition to a membrane action via αVβ3intergins, high doses of 20 µM T3 or T4 have been shown to directly act on GABA receptors to down-regulate GABAergic postsynaptic currents in cultured hippocampal neurons (173, 174), which could explain acute increases in neuronal excitability induced by iontophoretecally injected T4 and T3 (171). Although the regulatory influences exerted by thyroid hormone are complex it seems that T3 regulates to some extent the release of neurotransmitters such as acetylcholine, dopamine, 5-HT and noradrenalin in specific pathways as well as the density of the corresponding receptors (166).

A stimulating effect of thyroid hormone on transmitter synthetic enzymes or precursoruptake systems as well as the protein synthesis of the receptors could in principle explain the decrease in cerebral responsiveness in hypothyroid subjects. Furthermore, a downregulation of postsynaptic inhibitory currents in hyperthyroidism, as suggested by Puia and Losi (174), could account for the increased irritability seen in hyperthyroid subjects. A diminished postsynaptic current density due to a decrease in transmitter release or receptor density or activation could also explain some of the increased latencies since a smaller current density would lead to a delay in the charging of the membrane capacitance. However, investigations using transcranial magnetic stimulation provided evidence that in hypothyroid patients the cortical excitability as such is decreased (145). Furthermore, experiments on peripheral nerves of hyperthyroid rats indicated enhanced afferent spikes and a drop in the chronaxia for direct activation of action potentials in rat peripheral nerves (175). Hence thyroid hormone could also influence neuronal excitability directly, which

*Changes in conduction velocity, action potential waveform and the regulation of voltage-gated ion* 

Changes in Achilles tendon reflexes and the slowing of peripheral conduction velocity in hypothyroidism have so far mostly been explained by a reduction in myelination, and the gene for myelin basic protein is, in fact, regarded as one of the few genes known to be directly regulated by thyroid hormone (for review see (176)). However, a decrease in

could secondarily result in a decrease in transmitter release.

*currents by thyroid hormone*

#### *Effects of thyroid hormone on sensory perception and brain function*

The present tests performed on a small number of patients indicate that the most prominent symptom after 4 weeks of thyroid hormone withdrawal is a beginning decline in the speed of central neuronal information processing, which was reflected in decreases in the speed of visual perception, speed of speech as well as of visual-spatial orientation. Hearing and smelling thresholds were only slightly changed, and in the context with the publications discussed above this indicates that auditory and olfactory perception may change only with thyroid dysfunctions of longer duration or are more sensitive to thyroid hormone in development. The experiments illustrated here complement previous findings, that hypothyroidism slows peripheral conduction velocity (144), reduces EEG frequencies and increases latencies of evoked potentials (73). The conception that thyroid hormone deficiency causes a general decrease in neuronal excitability was recently supported by the observation of a decreased cortical excitability and increased motor thresholds using transcranial magnetic stimulation in adult patients (145). Accordingly, in a small percentage of epileptic seizures in humans (146) thyrotoxicosis was identified as sole cause of the seizures and the seizures were found to fully subside after restoration of euthyroidism, again indicating an effect of thyroid hormone on cortical excitability. An increased susceptibility to seizures was also noticed in hyperthyroid animals such as cats (147) and mice (148).
