**3.1. Experimental results**

88 Thyroid Hormone

the drawing was monitored.

frequencies was determined.

for completion of the test was recorded (44).

of third grade difficulty (like: 23+11=?). Each result of a calculus task was assigned one of five colours (yellow, red, green, dark and light blue). After completing the calculation task the test persons were asked to fill a second form, consisting of an outline drawing containing 54 numbered areas, where each number equalled one of the results of the preceding calculus task (some numbers were used several times). The patients were handed coloured pencils and asked to assign the appropriate colour from the result of the calculus task to each of the numbers given in the drawing. This procedure finally resulted in the appearance of a meaningful picture (in this case a boat). The time taken by the patients to complete the calculus task and to assign the colours to the figures in

b. *Trail making*. The test consisted of a piece of DIN A4 paper, containing randomly distributed numbers (24 pt size, black, surrounded by a black circle). The paper was placed on a table in front of the test persons who were asked to connect the numbers from one to 25 (version A). In version B numbers from 1 to 13 and letters from A to L were distributed randomly and the test persons asked to connect them alternating between the numbers and the succession of the alphabet, e.g., 1-A 2-B- 3-C etc. The time needed

a. *Flicker fusion frequency*. Light flashes delivered with a sufficiently high frequency fuse to give the impression of a continuous light source. The lowest frequency at which an intermittent light source is perceived as a continuous one is termed the "flicker fusion frequency". A light source containing red (660nm), green (565 nm) or blue (470nm) diodes of 1 cm2 diameter with an intensity of 14 Cd m2 (determined with a Minolta luminance meter) was displayed to the test persons at a distance of 52 cm (to excite a 1° area of the visual field). The screen was positioned at the back of a 50 x 50 cm wide and 52 cm deep box with black walls. The flicker frequency was generated with a square wave pulse generator with a 50% duty cycle. The frequency could be changed with a dial. Test persons were asked to focus on the light with both eyes while the frequency was increased and to give a sign when they perceived the flashes to fuse to a continuous light source. Since it turned out to be too time-consuming to test the right or the left eyes, foveal and peripheral illumination separately and to use lights of different colours and since preliminary experiments showed no qualitative differences in the results, most patients were only retested with the red colour fixed by two eyes. The average value of three determinations of flicker fusion frequency always starting from low

b. *Red-Green fusion*. Changes in the perception of chromatic flicker were tested in addition to the critical flicker fusion frequency of luminance flicker. In this test a rotating disk of 12 cm diameter was shown to the test persons. The disk was diagonally partitioned into four sections which were painted alternatively in light red (Plaka Nr. 82) and light green (Plaka No. 90; 16 – 20 Cd/m2, determined with a Minolta LS 100 luminance meter). The speed of rotation was increased continuously and the number of rotations

*Tests to determine time resolution of visual perception and colour contrast perception:* 

*Speed of speech.* Figures 1A and B show digitized traces of speech records of a female test person in hypothyroidism (upper trace, a) and after hormone substitution (lower trace, b). After hormone substitution this test person pronounced the four words faster. As shown in Fig. 1C, on average the test persons needed a significantly longer time to pronounce the same words in the hypothyroid condition as compared to the euthyroid control persons or after thyroid hormone substitution. Figure 1D gives a more elaborate example of the development of the slowing of speech during hormone withdrawal and resubstitution. Here an additional test person was asked to repeat a short poem in regular intervals at maximal speed and the time taken to complete this poem was recorded. During hormone withdrawal the time needed to finish the poem became increasing longer. During resubstitution with thyroid hormone the time to finish the poem gradually decreased during the following month. To find out whether the increase in speed of speech during hormone resubstitution was accompanied by an increase in pitch a fast Fourier analysis was performed on the syllable "mus" (encircled by the rectangles in Fig. 1A). The analysis of the pronounciation of this syllable, consisting with predominant amplitude of the noun "u" showed several clear frequency peaks (Fig. 1B). The records from four of the five male subjects included in the study showed a peak between 100 and 200 Hz which was not seen in the records from any of the female test persons. Since the most prominent peak in all test persons was found between 200 and 300 Hz this peak was evaluated in hypothyroidism and after hormone substitution. As shown in Table 2 and illustrated in Fig. 1B the peak frequency was shifted by an average of about 30 Hz to higher frequencies by the hormone substitution. This shift was found in all subjects with the exception of one test person, aged 61, who suffered from paresis of the *n. recurrens.*

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 91

40-46 days after beginning of thyroid hormone resubstitution

P (6 weeks after resubstitution versus 3 weeks after hormone withdrawal)

*Speed of visual perception*. In hypothyroidism, the frequency, at which patients first reported to perceive a flickering light source as a continuous one was slightly but insignificantly smaller than the frequency determined in the control group. The hypothyroid group showed no significant improvement after 6 weeks of hormone therapy (Figure 2Ab). In a single test person, where the flicker fusion frequency was recorded daily for blue, green and red light and both eyes tested separately, however, a significant decrease in flicker fusion frequency was shown in the third week after the arrest of hormone substitution. After six weeks of hormone resubstitution the flicker fusion frequency had significantly recovered with respect to the last week without the hormone

> P (1st week versus 3rd week)

12 37.4 0.4 12 36.6 0.6 0.27 12 40.6 0.3 0.000006

12 35.8 0.6 12 32.8 0.4 0.0003 12 36.3 0.3 0.0000002

**Table 1.** Critical flicker fusion frequency for three different colours (12 measurements on 2 eyes determined on 6 successive days were pooled from one test person, SEM: standard error of the mean,

The critical colour fusion frequency (CCFF), determined with a rotating wheel of alternating green and red sectors was significantly reduced in the hypothyroid test persons compared with the control subjects. The frequencies at which the rotating, red-green disk was perceived as starting to show a luminance flicker (Fig. 2 Ba) as well as the frequency at which a uniform yellow colour was reported (Fig. 2Bb) were both significantly smaller in the

*Cognitive performance*. Since several cognitive tests have been shown to be sensitive for thyroid hormone we here tested whether hypothyroidism for 4 weeks has an effect on calculation and visual-spatial orientation. A slight but insignificant slowing of the speed with which the hypothyroid persons completed the calculation task compared with the euthyroid control group was observed (Table 2, Figure 3A). A stronger effect was seen,

unpaired t-test), the original data for red light are displayed in Figure 2Aa.

hypothyroid test persons as compared to the control group.

12 35.3 0.6 12 29.9 0.5 0.0000004 12 37.2 0.3 <0.0000000001

Days 17-22 of hormone withdrawal

n mean SEM n mean SEM n mean SEM

(Table 1 and Figure 2 Aa).

CFF (Hz), green 2600 Cd/m2

CCF (Hz), red 100 Cd/m2

CCF (Hz), blue 30 Cd/m2

6 days during first week of thyroid hormone withdrawal

**Figure 1.** *Changes of speech during thyroid hormone withdrawal*. Original voltage traces of a record from a female test person (A) repeating four times the word "Apfelmus" as fast as possible after four weeks of thyroxine withdrawal (a) and after 10 weeks of hormone resubstitution (b). The darker yellow shadow indicates the time needed to pronounce the first word in the hypothyroid condition. B: Fast Fourier analysis of sections of the speech record shown within the squares in A. Inset: 100 ms long sections from the analysed traces. C: average time needed to pronounce the four words after hormone withdrawal (Hypo), resubstitution (Eu) and by control subjects (mean ± SE, n=6) asterisk: p<0.05, 2 asterisks: p<0.01. D: time needed to complete a short poem of an additional test person recorded daily during last 20 days of thyroxine withdrawal and during the following 60 days of resubstitution. Note the gradual decline in speed of speech with increasing time of thyroid hormone withdrawal.

*Speed of visual perception*. In hypothyroidism, the frequency, at which patients first reported to perceive a flickering light source as a continuous one was slightly but insignificantly smaller than the frequency determined in the control group. The hypothyroid group showed no significant improvement after 6 weeks of hormone therapy (Figure 2Ab). In a single test person, where the flicker fusion frequency was recorded daily for blue, green and red light and both eyes tested separately, however, a significant decrease in flicker fusion frequency was shown in the third week after the arrest of hormone substitution. After six weeks of hormone resubstitution the flicker fusion frequency had significantly recovered with respect to the last week without the hormone (Table 1 and Figure 2 Aa).

90 Thyroid Hormone

paresis of the *n. recurrens.*

study showed a peak between 100 and 200 Hz which was not seen in the records from any of the female test persons. Since the most prominent peak in all test persons was found between 200 and 300 Hz this peak was evaluated in hypothyroidism and after hormone substitution. As shown in Table 2 and illustrated in Fig. 1B the peak frequency was shifted by an average of about 30 Hz to higher frequencies by the hormone substitution. This shift was found in all subjects with the exception of one test person, aged 61, who suffered from

**Figure 1.** *Changes of speech during thyroid hormone withdrawal*. Original voltage traces of a record from a female test person (A) repeating four times the word "Apfelmus" as fast as possible after four weeks of thyroxine withdrawal (a) and after 10 weeks of hormone resubstitution (b). The darker yellow shadow indicates the time needed to pronounce the first word in the hypothyroid condition. B: Fast Fourier analysis of sections of the speech record shown within the squares in A. Inset: 100 ms long sections from the analysed traces. C: average time needed to pronounce the four words after hormone withdrawal (Hypo), resubstitution (Eu) and by control subjects (mean ± SE, n=6) asterisk: p<0.05, 2 asterisks: p<0.01. D: time needed to complete a short poem of an additional test person recorded daily during last 20 days of thyroxine withdrawal and during the following 60 days of resubstitution. Note the gradual decline in

speed of speech with increasing time of thyroid hormone withdrawal.


**Table 1.** Critical flicker fusion frequency for three different colours (12 measurements on 2 eyes determined on 6 successive days were pooled from one test person, SEM: standard error of the mean, unpaired t-test), the original data for red light are displayed in Figure 2Aa.

The critical colour fusion frequency (CCFF), determined with a rotating wheel of alternating green and red sectors was significantly reduced in the hypothyroid test persons compared with the control subjects. The frequencies at which the rotating, red-green disk was perceived as starting to show a luminance flicker (Fig. 2 Ba) as well as the frequency at which a uniform yellow colour was reported (Fig. 2Bb) were both significantly smaller in the hypothyroid test persons as compared to the control group.

*Cognitive performance*. Since several cognitive tests have been shown to be sensitive for thyroid hormone we here tested whether hypothyroidism for 4 weeks has an effect on calculation and visual-spatial orientation. A slight but insignificant slowing of the speed with which the hypothyroid persons completed the calculation task compared with the euthyroid control group was observed (Table 2, Figure 3A). A stronger effect was seen, however, if a more complex performance task, like the correlation of numbers with colours and finding and colouring the appropriate numbered area, had to be accomplished (visualspatial orientation). Here the hypothyroid patients performed somewhat slower than the control subjects. After 6 weeks of hormone substitution the formerly hypothyroid persons showed a significantly improved performance (Figure 3B). Hypothyroid persons completed the trail making test insignificantly slower than the euthyroid controls or after hormone substitution, (Figure 3C, D).

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 93

**Figure 3.** *Performance in cognitive tests*. A: Average time needed by test persons after four weeks of hormone withdrawal (light bars), thyroid hormone resubstitution for at least nine weeks (grey bars) and by control subjects (black bars) to complete a set of simple calculations. B: Average time needed by the same subjects to combine numbers in an outline drawing with corresponding colours. C: Average time needed by the same subjects to complete the Trail A test and D: the Trail B test (mean ± SE, n=6).

*Sense of smell*. Finally, thyroid hormone might also affect the sense of smell. Of the six test persons tested one had been anosmic since childhood and a second subject did not want to repeat the smelling threshold test. Hence only 4 persons could be retested in the euthyroid state (Table 2). Using the odorant discrimination task, the hypothyroid test persons rated 66% of the presented flavours correctly. After hormone substitution they showed a slightly increased performance rating 72% of the presented flavours correctly, while the controls gave 70% correct answers. After four weeks of hypothyroidism, small but insignificant decreases in the threshold of odorant detection were found for both odorants which were

Although hypothyroid subjects performed on average slower in several tests it could have been possible that some test persons showed only a slowing of speech while others showed a slower resolution of visual signals. To find out whether some subjects were on average, slower or faster than others for each of seven tests, the speed of speech, calculation time, picture filling, Trail A, Trail B, critical flicker fusion frequency for red luminance flicker and fusion frequency for chromatic flicker, all twelve test persons were assigned numbers of 1 to 12 for each test, were the fasted was scored with 1 and the slowest with 12. If two persons showed the same speed of performance they were assigned an equal score, such that the highest value was less than 12 for several tests. For each test person the average score in the seven tests was calculated (Fig. 4). If differences in performance in the different tests were random, then the scores would scatter around a value of somewhere below 6.5 (assuming that in some tests several test persons showed the same speed). As Fig. 4 shows, this was not the case. As expected, the hypothyroid test persons were on average slower than the control subjects (Fig. 4A). As also somewhat

still below the thresholds determined for the control subjects (Table 2).

*Age-dependence of thyroid hormone effects*

Asterisk: p<0.05

**Figure 2.** *Speed of visual perception*. Aa: critical flicker fusion frequency for a luminance flicker of red light, 100 Cd/m2 measured once daily at the same time in the morning in a test person during the last 20 days of thyroxine withdrawal and during resubstitution. Note the gradual continuous decrease in CFF with increased time of thyroxine withdrawal and the gradual increase after hormone resubstitution. Dark red symbols: right eye, light red symbols: left eye. Ab: average critical flicker fusion frequency determined in six separate test persons after four weeks of hormone withdrawal (green bars), resubstitution (violet bars) and in control subjects (pink bars). B: critical colour fusion frequency in same test persons for luminance flicker of red and green sectors of a rotating disk (a) and fusion of the redgreen sectors to homogenous yellow (b) (mean ± SE, n=6) asterisk: p<0.05.

*Hearing threshold*. Since thyroid hormone has been reported to also affect the auditory system here we tested whether thyroid hormone withdrawal for several weeks has a measurable effect on hearing thresholds. No changes in hearing threshold were obvious for frequencies below 8 kHz. Hence only the measurements at 1 kHz and 8 kHz were evaluated (Table 2). If data from both ears were pooled, the improvement of 8 dB seen after hormone substitution at the test frequency of 8 kHz just reached significance.

**Figure 3.** *Performance in cognitive tests*. A: Average time needed by test persons after four weeks of hormone withdrawal (light bars), thyroid hormone resubstitution for at least nine weeks (grey bars) and by control subjects (black bars) to complete a set of simple calculations. B: Average time needed by the same subjects to combine numbers in an outline drawing with corresponding colours. C: Average time needed by the same subjects to complete the Trail A test and D: the Trail B test (mean ± SE, n=6). Asterisk: p<0.05

*Sense of smell*. Finally, thyroid hormone might also affect the sense of smell. Of the six test persons tested one had been anosmic since childhood and a second subject did not want to repeat the smelling threshold test. Hence only 4 persons could be retested in the euthyroid state (Table 2). Using the odorant discrimination task, the hypothyroid test persons rated 66% of the presented flavours correctly. After hormone substitution they showed a slightly increased performance rating 72% of the presented flavours correctly, while the controls gave 70% correct answers. After four weeks of hypothyroidism, small but insignificant decreases in the threshold of odorant detection were found for both odorants which were still below the thresholds determined for the control subjects (Table 2).

#### *Age-dependence of thyroid hormone effects*

92 Thyroid Hormone

substitution, (Figure 3C, D).

however, if a more complex performance task, like the correlation of numbers with colours and finding and colouring the appropriate numbered area, had to be accomplished (visualspatial orientation). Here the hypothyroid patients performed somewhat slower than the control subjects. After 6 weeks of hormone substitution the formerly hypothyroid persons showed a significantly improved performance (Figure 3B). Hypothyroid persons completed the trail making test insignificantly slower than the euthyroid controls or after hormone

**Figure 2.** *Speed of visual perception*. Aa: critical flicker fusion frequency for a luminance flicker of red light, 100 Cd/m2 measured once daily at the same time in the morning in a test person during the last 20 days of thyroxine withdrawal and during resubstitution. Note the gradual continuous decrease in CFF with increased time of thyroxine withdrawal and the gradual increase after hormone resubstitution. Dark red symbols: right eye, light red symbols: left eye. Ab: average critical flicker fusion frequency determined in six separate test persons after four weeks of hormone withdrawal (green bars),

resubstitution (violet bars) and in control subjects (pink bars). B: critical colour fusion frequency in same test persons for luminance flicker of red and green sectors of a rotating disk (a) and fusion of the red-

*Hearing threshold*. Since thyroid hormone has been reported to also affect the auditory system here we tested whether thyroid hormone withdrawal for several weeks has a measurable effect on hearing thresholds. No changes in hearing threshold were obvious for frequencies below 8 kHz. Hence only the measurements at 1 kHz and 8 kHz were evaluated (Table 2). If data from both ears were pooled, the improvement of 8 dB seen after hormone

green sectors to homogenous yellow (b) (mean ± SE, n=6) asterisk: p<0.05.

substitution at the test frequency of 8 kHz just reached significance.

Although hypothyroid subjects performed on average slower in several tests it could have been possible that some test persons showed only a slowing of speech while others showed a slower resolution of visual signals. To find out whether some subjects were on average, slower or faster than others for each of seven tests, the speed of speech, calculation time, picture filling, Trail A, Trail B, critical flicker fusion frequency for red luminance flicker and fusion frequency for chromatic flicker, all twelve test persons were assigned numbers of 1 to 12 for each test, were the fasted was scored with 1 and the slowest with 12. If two persons showed the same speed of performance they were assigned an equal score, such that the highest value was less than 12 for several tests. For each test person the average score in the seven tests was calculated (Fig. 4). If differences in performance in the different tests were random, then the scores would scatter around a value of somewhere below 6.5 (assuming that in some tests several test persons showed the same speed). As Fig. 4 shows, this was not the case. As expected, the hypothyroid test persons were on average slower than the control subjects (Fig. 4A). As also somewhat expected the speed of performance showed a tendency to decline with age, such that the older test persons, displayed at the right side of the series of columns in Fig 4A, scored on average higher than the younger subjects. In comparison of the performance of the test persons during hormone substitution with the control subjects an increase in overall speed of performance of the formerly hypothyroid subjects was seen, such that the average speed of the substituted test persons became indistinguishable from that of the controls (Fig. C). Interestingly, the relative increase in speed seemed to be larger in the younger than the older test persons (compare Fig. 4A with Fig. 4B).

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 95

**Figure 4.** *Effects of age and thyroid status on speed of performance of individual test persons*. Mean scores obtained by the 12 test and control subjects in 7 tests. A: Comparison of speed of performance in the sum of 7 tests in hypothyroid subjects with control subjects. Smallest score: fastest person, largest score: slowest person. B: Comparison of former hypothyroid subjects after at least 6 weeks of hormone substitution (a) with controls (b). C: Mean values of scores of all six persons after thyroid hormone withdrawal compared with control subjects (a) and of test persons after hormone replacement with controls (b). Light bars: test persons after hormone withdrawal, grey bars: test persons after hormone resubstitution, black bars: control subjects.\*\*: p<0.01.D: Overall improvement in speed of performance after hormone substitution. For each of the 6 test persons the number of tests in which performance was speeded minus the number of tests in which performance was slowed was determined (maximal value of improvement: 8, maximal value of slowing: -8). While 5 persons considerably increased their speed of performance (e.g. an increase in speed in 6 tests and a decrease in performance in 1 test) only 1 test

To investigate whether only the younger test persons responded with an increase in the speed of neuronal information processing to thyroid hormone we evaluated the individual change in performance of each test person. For each of the 6 test persons and eight tests (the speed of speech, pitch of speech, calculation time, picture filling, Trail A, Trail B, critical flicker fusion frequency for red luminance flicker and fusion frequency for chromatic flicker) we rated an increase in the speed of performance in a test assigning a 1 to an increase in

person showed no average increase in speed.


Speed and pitch of speech: the two fastest measurements of each test and control persons were included. CFF: critical flicker fusion frequency, CCFF: critical colour fusion frequency, Smell thresholds: a lower threshold of smell corresponds to a higher test score: Phe: Phenylethylalcohole, Eu: Eugenol: Pyr: pyridine, hearing thresholds: data from right and left ears were pooled, SEM: standard error of the mean, paired t-Test

**Table 2.** Summary of the effects of hypothyroidism on performance in the different psychophysical tests in hypothyroid test persons, hormone substituted hypothyroid test persons and euthyroid control subjects.

Thyroid Hormone Effects on Sensory Perception, Mental Speed, Neuronal Excitability and Ion Channel Regulation 95

94 Thyroid Hormone

Visual-spatial orientation/s

Odour recognition

Smell threshold (eugenol)

Smell threshold

Smell threshold

Hearing threshold for 8 kHz /-dB

Hearing threshold for 1 kHz /-dB

(%)

(Phe)

(Pyr)

subjects.

Hypothyroid

expected the speed of performance showed a tendency to decline with age, such that the older test persons, displayed at the right side of the series of columns in Fig 4A, scored on average higher than the younger subjects. In comparison of the performance of the test persons during hormone substitution with the control subjects an increase in overall speed of performance of the formerly hypothyroid subjects was seen, such that the average speed of the substituted test persons became indistinguishable from that of the controls (Fig. C). Interestingly, the relative increase in speed seemed to be larger in the

> Substituted Test Persons (SubTP)

Speed of speech / s 12 2.09 0.05 12 1.91 0.04 0.03 12 1.88 0.05 0.003 Pitch of "u" /Hz 12 236 13 12 263 10 0.008 12 264 10 0.16 NS CFF /Hz 6 28.3 1.0 6 28.2 1.1 0.90 NS 6 30.3 1.6 0.38 NS CCFF I /Hz 6 22.0 1.2 6 23.0 2.1 0.73 NS 6 27.3 2.4 0.03 CCFF II /Hz 6 26.2 1.8 6 30.8 1.8 0.21 NS 6 31.8 2.3 0.02 Calculation time /s 6 146 42 6 142 40 0.75 NS 6 118 19 0.51 NS

Trail A /s 6 122 25 6 105 26 0.16 NS 6 96 16 0.40 NS Trail B /s 6 203 40 6 163 44 0.13 NS 6 189 36 0.79 NS

n mean SEM n mean SEM n mean SEM

6 576 56 6 478 71 0.02 6 504 74 0.44 NS

5 66 6 5 72 6 0.32 NS 5 70 6 0.48 NS

5 6.7 0.6 4 6.9 1.2 0.91 NS 5 7.8 0.5 0.19 NS

5 5.9 1.1 4 6.7 0.5 0.54 NS 5 7.8 0.5 0.23 NS

5 5.1 0.5 4 5.4 0.8 0.37 NS 5 5.9 1.1 0.50 NS

12 32 5 12 24 6 0.05 12 25 4 0.24 NS

12 22 3 12 21 4 0.43 NS 12 23 2 0.83 NS

Speed and pitch of speech: the two fastest measurements of each test and control persons were included. CFF: critical flicker fusion frequency, CCFF: critical colour fusion frequency, Smell thresholds: a lower threshold of smell

corresponds to a higher test score: Phe: Phenylethylalcohole, Eu: Eugenol: Pyr: pyridine, hearing thresholds: data from

**Table 2.** Summary of the effects of hypothyroidism on performance in the different psychophysical tests in hypothyroid test persons, hormone substituted hypothyroid test persons and euthyroid control

right and left ears were pooled, SEM: standard error of the mean, paired t-Test

P (HypoTP versus SubTP)

Controls P (HypoTP

versus Controls)

younger than the older test persons (compare Fig. 4A with Fig. 4B).

Test Persons (HypoTP)

**Figure 4.** *Effects of age and thyroid status on speed of performance of individual test persons*. Mean scores obtained by the 12 test and control subjects in 7 tests. A: Comparison of speed of performance in the sum of 7 tests in hypothyroid subjects with control subjects. Smallest score: fastest person, largest score: slowest person. B: Comparison of former hypothyroid subjects after at least 6 weeks of hormone substitution (a) with controls (b). C: Mean values of scores of all six persons after thyroid hormone withdrawal compared with control subjects (a) and of test persons after hormone replacement with controls (b). Light bars: test persons after hormone withdrawal, grey bars: test persons after hormone resubstitution, black bars: control subjects.\*\*: p<0.01.D: Overall improvement in speed of performance after hormone substitution. For each of the 6 test persons the number of tests in which performance was speeded minus the number of tests in which performance was slowed was determined (maximal value of improvement: 8, maximal value of slowing: -8). While 5 persons considerably increased their speed of performance (e.g. an increase in speed in 6 tests and a decrease in performance in 1 test) only 1 test person showed no average increase in speed.

To investigate whether only the younger test persons responded with an increase in the speed of neuronal information processing to thyroid hormone we evaluated the individual change in performance of each test person. For each of the 6 test persons and eight tests (the speed of speech, pitch of speech, calculation time, picture filling, Trail A, Trail B, critical flicker fusion frequency for red luminance flicker and fusion frequency for chromatic flicker) we rated an increase in the speed of performance in a test assigning a 1 to an increase in

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 hormone resubstitution in this test person.

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 97

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

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

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

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

to luminance flicker already starts to arise at the level of the retina (56).

*Speed of processing of visual signals* 

to a direct effect of thyroid hormone.

cognitive tests in old age (70).

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 (49).
