**1. Introduction**

84 Thyroid Hormone

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Although thyroid hormone effects on the brain are most prominent in development, also in adult-acquired hypothyroidism symptoms such as sensory impairments, disagreeable smells and taste, slowness of thought and action, changes of speech, irritability, headaches, sleep disturbances, confusion up to delusions and hallucinations, impairments of memory, of vision as well as of hearing frequently occur. This involvement of the nervous system was already discussed in the first reports on myxoedema (1–3) and a systematic description included in the first extensive investigation by the Committee of the Clinical Society of London (4). Many of these symptoms have since been studied in considerable detail. The conspicuous slowing of movements of hypothyroid subjects has been shown to correlate with peripheral sensory and motor nerve dysfunctions and abnormal neuromuscular transmission (5–10). The slowing of thoughts and mental function occurs concomitant with a decrease in the frequency of the alpha rhythm of the EEG (11–15). In addition to the slowing of the alpha-rhythm increased latencies of visual, auditory and somatosensory evoked potentials in adult-onset hypothyroidism indicate a slowed conduction of information in the central nervous system (16–24). In addition to a slowing of neuronal conduction velocity, changes in the threshold of hearing (25–29) and of the sensation of smell have been reported (30, 31). Cognitive and memory tests revealed impaired performances, which could at least partially be reversed by hormone substitution (24, 32–34). The extent of the reversibility of these symptoms is still a matter of debate (35).

Since many of the neurological symptoms observed in hypothyroidism point to a conspicuous mental slowing as leading symptom of hypothyroidism, we here were

© 2012 Dietzel et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

interested to test in a small sample of 6 patients, whether already a transient hypothyroid state, induced by 4 weeks of total thyroid hormone withdrawal, would result in detectable changes in the speed of sensory perception and cognitive functions. For this aim we combined different psychophysical tests shown to be sensitive in previous studies of hypothyroidism with some new examinations. While cognitive tests, such as the trail making test as well a calculation task showed a non-significant tendency toward slowing, a more complex visual- spatial performance test revealed a significant slowing of mental function after four weeks of hypothyroidism. The speed of speech was significantly reduced and a fast Fourier analysis showed a shift to lower frequencies in the hypothyroid test persons. A significant decrease in red-green colour fusion frequency was found, indicating an impaired temporal resolution of visual stimuli. Smelling of two odorants tested, odorant discrimination (Sniffin`sticks) and the hearing thresholds were slightly, but insignificantly impaired in the hypothyroid test persons. The results of these tests indicate that the most prominent and first significant clinical symptom to develop in hypothyroidism is a slowing of speech and of visual perception.

Thyroid Hormone Effects on Sensory Perception,

Mental Speed, Neuronal Excitability and Ion Channel Regulation 87

conduction velocity and in the EEG (15). Furthermore, subjective impairments of the quality of life (38–40) as well as changes in mood (41, 42) and decreases in working memory (43)

*Test persons*. A test battery was developed to allow a relatively fast examination of several aspects of sensory and cognitive function. To integrate the investigation into the normal clinical examination procedures the whole testing protocol was designed to be completed within 1.5 hours. All tests were carried out on 6 patients after thyroid hormone withdrawal for 26 to 28 days and on 6 healthy volunteers which were age (maximal difference: 3 years) and sex matched (with the exception of one female control person for a male patient). Patients were retested after at least 6 weeks of hormone substitution, after obtaining low TSH values. To elaborate the optimal test parameters some of the tests had been performed in more detail on an additional hypothyroid test person, the data of which are included in the appropriate results sections. In the 7 test persons (age 42-64, 4 female, 3 male) TSH-suppressive thyroid hormone substitution after total thyroidectomy and radioiodine therapy for thyroid carcinoma had been discontinued for 26-28 days for routine diagnostic application of 131I. Thyroid hormone levels measured in hypothyroidism were FT3: < 2.0 pmol/l, FT4: <2.6 pmol/l in 6 patients and FT3: 2.6 pmol/l, FT4: 4.8 pmol/l in the remaining patient, TSH was > 80 mU/l in three patients and 48.7 ± 10.4 mU/l (mean ± SE) in the remaining four patients. After 6 - 10 weeks of hormone substitution these values were: FT3: 6.2 ± 0.5 pmol/l, FT4: 26.0 ± 3.0 pmol/l and TSH: 0.09 ± 0.04 mU/l, n=7 (normal ranges: FT3: 3.4 - 7.6 pmol/l (SPART, Amerlex MAB, Johnson & Johnson); FT4: 11 - 23 pmol/l (SPART, Amerlex MAB, Johnson & Johnson), TSH: 0.3 - 4.0 mU/l (IRMA, Dynotest, Brahms). Results are given as means ± standard error. Statistical analysis was performed using paired Student`s t-test. Informed consent was obtained from all

*Speed of speech*. To investigate possible changes in the speed of speech we asked the test persons to repeat four times the same word as fast as possible (in this case the word "Apfelmus"). They were asked the repeat the series of four words four times and were encouraged to accelerate their speech as much as possible. The four series of words were stored on magnetic tape with a SONY WTC-D6C stereo cassette recorder and analysed offline using a Digidata 1200A analog-digital converter with "Axoscope" software (Axon Instruments). The time needed to pronounce the four words was then read from a digital storage oscilloscope. In addition a fast Fourier analysis was performed on the record of the second syllable ("mus") selected from the two fastest traces obtained from each test person in the hypothyroid and the euthyroid condition. The section of the record to be analysed

a. *Calculation and Correlation*. To test more complex mental performances patients were first handed a sheet of paper and asked to complete a set of 24 simple calculation tasks

was selected with "Axoscope" and then analysed with "Origin 5" software.

have been reported.

individuals before performing the tests.

*Tests of cognitive performance*:

**3. Methods** 

Slowing of conduction velocity can be explained by a reduced myelination. A second mechanisms is a decrease in voltage-gated sodium current density, leading to a slowed charging of the membrane capacitor thus resulting in a decreased slope of the action potential upstroke velocity which in turn decreases conduction velocity. Although several investigations support the concept that thyroid hormone affects myelination, recently evidence has accumulated, that thyroid hormone also increases sodium current density in neurons from several species. We will thus discuss reports on the regulation of voltage gated ion currents in neurons and muscle cells later in the chapter, which could offer an explanation for the observed slowing of thoughts and movements at the cellular and molecular level.

Furthermore, it has been known for a long time, that thyroid hormone regulates energy expenditure (see also Yehuda-Shnaidman et al. in this issue). Pumping of Na+ out of the cells has been accounted for the expense of 40% of energy consumed at rest (36, 37). Thus an increased influx of Na+ due to enhanced voltage-gated Na+-influx will most likely also stimulate Na+/K+-ATPase activity, and could also account at least to some extent for the stimulation of an enhanced expression of Na+/K+-ATPase subunits in the membranes. We thus conclude the chapter by reviewing data on the regulation of Na+/K+-ATPase by thyroid hormone in the brain and its potential link to Na+ current regulation.
