Cortical excitability in patients with resistance to thyroid hormone compared to patients with hypothyroidism and euthyroid controls: a transcranial magnetic stimulation study

C. Terranova, V. Rizzo, A. Calamuneri, L. Bartolone, F. Morgante, D. Bruschetta, V. Roberto, P. Girlanda, S. Benvenga, A. Quartarone


Resistance to thyroid hormone (RTH) describes a rare syndrome in which serum levels of thyroid hormones are elevated but serum levels of thyroid stimulating hormone (TSH) are unsuppressed. The importance of thyroid hormones for the normal function of the adult brain is corroborated by the frequent association of thyroid dysfunctions with neurological and psychiatric symptoms. In this study we investigated whether adult thyroid hormone resistance affects cortical excitability and modulates inhibitory and excitatory intracortical circuitries by using transcranial magnetic stimulation. Cortical excitability was probed with transcranial magnetic stimulation in 4 patients with thyroid hormone resistance, 10 patients affected by overt hypothyroidism (OH) and 10 age-matched healthy controls. We tested motor thresholds, motor evoked potential recruitment curve, cortical silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation. In both OH and RTH patients, the inhibitory cortical circuits were affected compared with euthyroid controls, but in opposite ways. In OH patients, CSP was prolonged and SICI was decreased. On the contrary, in RTH patients CSP was shortened and SICI was increased. Thyroid hormones may influence cortical excitability and cortical inhibitory circuits.


Resistance to thyroid hormone; hypothyroidism; Cortical excitability; transcranial magnetic stimulation.

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Acharya, M. M. and S. S. Katyare (2005). "Structural and functional alterations in mitochondrial membrane in picrotoxin-induced epileptic rat brain." Exp Neurol 192(1): 79-88.

Alzoubi, K. H., N. Z. Gerges and K. A. Alkadhi (2005). "Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies." Exp Neurol 195(2): 330-341.

Aszalos, Z. (2007). "Some neurologic and psychiatric complications in endocrine disorders: the thyroid gland." Orv Hetil 148(7): 303-310.

Bauer, M. (2002). "Thyroid hormone augmentation with levothyroxine in bipolar depression." Bipolar Disord 4 Suppl 1: 109-110.

Bauer, M., E. D. London, N. Rasgon, S. M. Berman, M. A. Frye, L. L. Altshuler, M. A. Mandelkern, J. Bramen, B. Voytek, R. Woods, J. C. Mazziotta and P. C. Whybrow (2005). "Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression." Mol Psychiatry 10(5): 456-469.

Bauer, M., E. D. London, D. H. Silverman, N. Rasgon, J. Kirchheiner and P. C. Whybrow (2003). "Thyroid, brain and mood modulation in affective disorder: insights from molecular research and functional brain imaging." Pharmacopsychiatry 36 Suppl 3: S215-221.

Calza, L., L. Aloe and L. Giardino (1997). "Thyroid hormone-induced plasticity in the adult rat brain." Brain Res Bull 44(4): 549-557.

De Jong, F. J., T. den Heijer, T. J. Visser, Y. B. de Rijke, H. A. Drexhage, A. Hofman and M. M. Breteler (2006). "Thyroid hormones, dementia, and atrophy of the medial temporal lobe." J Clin Endocrinol Metab 91(7): 2569-2573.

Dratman, M. B. and J. T. Gordon (1996). "Thyroid hormones as neurotransmitters." Thyroid 6(6): 639-647.

Dumitrescu, A.M. and S. Refetoff (2013). "The syndromes of reduced sensitivity to thyroid hormone." Biochim Biophys Acta 1830(7): 3987-4003.

Dumitrescu A.M., Refetoff. S. (2013). Reduced sensitivity to thyroid hormone: defects of transport, metabolism, and action. In Werner & Ingbar’s The thyroid: a fundamental and clinical text. Philadelphia, Wolters Kluwer, Lippincott Williams & Wilkins: 845-873

Ferrara, A. M., K. Onigata, O. Ercan, H. Woodhead, R. E. Weiss and S. Refetoff (2012). "Homozygous thyroid hormone receptor beta-gene mutations in resistance to thyroid hormone: three new cases and review of the literature." J Clin Endocrinol Metab 97(4): 1328-1336.

Gadea, A. and A. M. Lopez-Colome (2001). "Glial transporters for glutamate, glycine, and GABA III. Glycine transporters." J Neurosci Res 64(3): 218-222.

Garcia, M. L. and E. E. Strehler (1999). "Plasma membrane calcium ATPases as critical regulators of calcium homeostasis during neuronal cell function." Front Biosci 4: D869-882.

Gilbert, D. L., K. M. Isaacs, M. Augusta, L. K. Macneil and S. H. Mostofsky (2011). "Motor cortex inhibition: a marker of ADHD behavior and motor development in children." Neurology 76(7): 615-621.

Gordon, J. T., D. M. Kaminski, C. B. Rozanov and M. B. Dratman (1999). "Evidence that 3,3',5-triiodothyronine is concentrated in and delivered from the locus coeruleus to its noradrenergic targets via anterograde axonal transport." Neuroscience 93(3): 943-954.

Grasberger, H., U. Ringkananont, M. Croxson and S. Refetoff (2005). "Resistance to thyroid hormone in a patient with thyroid dysgenesis." Thyroid 15(7): 730-733.

Hauser, P., A. J. Zametkin, P. Martinez, B. Vitiello, J. A. Matochik, A. J. Mixson and B. D. Weintraub (1993). "Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone." N Engl J Med 328(14): 997-1001.

Howland, R. H. (1993). "Thyroid dysfunction in refractory depression: implications for pathophysiology and treatment." J Clin Psychiatry 54(2): 47-54.

Ilic, T. V., A. Korchounov and U. Ziemann (2002). "Complex modulation of human motor cortex excitability by the specific serotonin re-uptake inhibitor sertraline." Neurosci Lett 319(2): 116-120.

Kapaki, E., I. Ilias, G. P. Paraskevas, I. Theotoka and I. Christakopoulou (2003). "Thyroid function in patients with Alzheimer's disease treated with cholinesterase inhibitors." Acta Neurobiol Exp (Wars) 63(4): 389-392.

Kujirai, T., M. D. Caramia, J. C. Rothwell, B. L. Day, P. D. Thompson, A. Ferbert, S. Wroe, P. Asselman and C. D. Marsden (1993). "Corticocortical inhibition in human motor cortex." J Physiol 471: 501-519.

Le Donne, M., S. Settineri and S. Benvenga (2012). "Early pospartum alexithymia and risk for depression: relationship with serum thyrotropin, free thyroid hormones and thyroid autoantibodies." Psychoneuroendocrinology 37(4): 519-533.

Losi, G., G. Garzon and G. Puia (2008). "Nongenomic regulation of glutamatergic neurotransmission in hippocampus by thyroid hormones." Neuroscience 151(1): 155-163.

Moll, G. H., H. Heinrich, G. Trott, S. Wirth and A. Rothenberger (2000). "Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate." Neurosci Lett 284(1-2): 121-125.

Olateju, T. O. and M. P. Vanderpump (2006). "Thyroid hormone resistance." Ann Clin Biochem 43(Pt 6): 431-440.

Plewnia, C., J. Hoppe, C. Hiemke, M. Bartels, L. G. Cohen and C. Gerloff (2002). "Enhancement of human cortico-motoneuronal excitability by the selective norepinephrine reuptake inhibitor reboxetine." Neurosci Lett 330(3): 231-234.

Prange, A. J., Jr. (1996). "Novel uses of thyroid hormones in patients with affective disorders." Thyroid 6(5): 537-543.

Refetoff, S. and A. M. Dumitrescu (2007). "Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination." Best Pract Res Clin Endocrinol Metab 21(2): 277-305.

Rizzo, V., D. Crupi, S. Bagnato, A. Quartarone, S. Benvenga, L. Bartolone, M. F. Ghilardi, F. Trimarchi, P. Girlanda and F. Battaglia (2008). "Neural response to transcranial magnetic stimulation in adult hypothyroidism and effect of replacement treatment." J Neurol Sci 266(1-2): 38-43.

Sandrini, M., A. V. Vergoni and A. Bertolini (1993). "No modifications of GABAA and benzodiazepine receptors following experimental dysthyroidism in rats." Pharmacol Res 28(1): 47-52.

Stern, R. A., J. D. Davis, B. L. Rogers, K. E. Smith, C. J. Harrington, B. R. Ott, I. M. Jackson and A. J. Prange, Jr. (2004). "Preliminary study of the relationship between thyroid status and cognitive and neuropsychiatric functioning in euthyroid patients with Alzheimer dementia." Cogn Behav Neurol 17(4): 219-223.

Vara, H., J. Munoz-Cuevas and A. Colino (2003). "Age-dependent alterations of long-term synaptic plasticity in thyroid-deficient rats." Hippocampus 13(7): 816-825.

Weiss, R. E., Y. Hayashi, T. Nagaya, K. J. Petty, Y. Murata, H. Tunca, H. Seo and S. Refetoff (1996). "Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor." J Clin Endocrinol Metab 81(12): 4196-4203.

Ziemann, U., B. J. Steinhoff, F. Tergau and W. Paulus (1998). "Transcranial magnetic stimulation: its current role in epilepsy research." Epilepsy Res 30(1): 11-30.

Zylinska, L. and M. Soszynski (2000). "Plasma membrane Ca2+-ATPase in excitable and nonexcitable cells." Acta Biochim Pol 47(3): 529-539.



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