The Influence of Thyroid Hormones on Brain Structure and Function in Humans

Abstract

The pleiotropic function of thyroid hormones (TH) is mediated by an organ specific expression of thyroid hormone transporters, deiodinases and TH receptors. In a series of studies we used the model of an experimentally induced hyper- or hypothyroidism in human volunteers to delineate TH action on the brain. A battery of neuropsychological testing paradigms was employed and complemented by structural and functional multimodal neuroimaging. Experimentally induced mild thyrotoxicosis for 6 weeks was associated with changes in brain structure (determined with voxel-based morphometry), resting state functional connectivity, and task-related functional activation in a working memory paradigm. Partial withdrawal of TH replacement in patients without thyroid (subclinical hypothyroidism) likewise lead to changes on multiple functional and structural brain measures. Importantly, the series of studies reviewed here identified the cerebellum as one crucial site of action.

Key words

thyroid hormones - voxel based morphometry - functional MRI - hyperthyroidism - hypothyroidism

Publication History

Received: 29 June 2019
Received: 03 January 2020

Accepted: 20 January 2020

Article published online:
10 February 2020

• References

• 1 Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007; 3: 249-259
• 2 Göbel A, Heldmann M, Göttlich M. et al. Effect of mild thyrotoxicosis on performance and brain activations in a working memory task. PLoS One 2016; 11: e0161552
• 3 Göbel A, Heldmann M, Sartorius A. et al. Mild thyrotoxicosis leads to brain perfusion changes: An arterial spin labelling study. J Neuroendocrinol 2017; DOI: 10.1111/jne.12446.
• 4 Göttlich M, Heldmann M, Göbel A. et al. Experimentally induced thyrotoxicosis leads to increased connectivity in temporal lobe structures: A resting state fMRI study. Psychoneuroendocrinology 2015; 56: 100-109
• 5 Göbel A, Heldmann M, Göttlich M. et al. Effect of experimental thyrotoxicosis on brain gray matter: A voxel-based morphometry study. Eur Thyroid J 2015; 4 (Suppl. 01) 113-118
• 6 Münte TF, Radamm C, Johannes S. et al. Alterations of cognitive functions induced by exogenous application of thyroid hormones in healthy men: A double-blind cross-over study using event-related brain potentials. Thyroid 2001; 11: 385-391
• 7 Liu B, Ran Q, Liu D. et al. Changes in resting-state cerebral activity in patients with hyperthyroidism: A short-term follow-up functional mr imaging study. Sci Rep 2017; 7: 10627
• 8 Zhang W, Song L, Yin X. et al. Grey matter abnormalities in untreated hyperthyroidism: A voxel-based morphometry study using the DARTEL approach. Eur J Radiol 2014; 83: e43-e48
• 9 Göbel A, Heldmann M, Göttlich M. et al. Partial withdrawal of levothyroxine treated disease leads to brain activations and effects on performance in a working memory task: A pilot study. J Neuroendocrinol 2019; DOI: 10.1111/jne.12707.
• 10 Göbel A, Göttlich M, Heldmann M. et al. Experimentally induced subclinical hypothyroidism causes decreased functional connectivity of the cuneus: A resting state fMRI study. Psychoneuroendocrinol 2019; 102: 158-163
• 11 Münte TF, Lill C, Otting G. et al. Cognitive changes in short-term hypothyroidism assessed with event-related brain potentials. Psychoneuroendocrinology 2004; 29: 1109-1118
• 12 Krausz Y, Freedman N, Lester H. et al. Regional cerebral blood flow in patients with mild hypothyroidism. J Nucl Med 2004; 45: 1712-1715
• 13 Nagamachi S, Jinnouchi S, Nishii R. et al. Cerebral blood flow abnormalities induced by transient hypothyroidism after thyroidectomy--analysis by tc-99m-HMPAO and SPM96. Ann Nucl Med 2004; 18: 469-477
• 14 Haji M, Kimura N, Hanaoka T. et al. Evaluation of regional cerebral blood flow in Alzheimerʼs disease patients with subclinical hypothyroidism. Dement Geriatr Cogn Disord 2015; 39: 360-367
• 15 Singh S, Kumar M, Modi S. et al. Alterations of functional connectivity among resting-state networks in hypothyroidism. J Neuroendocrinol 2015; 27: 609-615
• 16 Singh S, Modi S, Bagga D. et al. Voxel-based morphometric analysis in hypothyroidism using diffeomorphic anatomic registration via an exponentiated lie algebra algorithm approach. J Neuroendocrinol 2013; 25: 229-234
• 17 Lerch JP, Yiu AP, Martinez-Canabal A. et al. Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning. Neuroimage 2011; 54: 2086-2095
• 18 Golub Y, Kaltwasser SF, Mauch CP. et al. Reduced hippocampus volume in the mouse model of posttraumatic stress disorder. J Psychiatr Res 45: 650-659
• 19 Biedermann S, Fuss J, Zheng L. et al. In vivo voxel based morphometry: Detection of increased hippocampal volume and decreased glutamate levels in exercising mice. Neuroimage 2012; 61: 1206-1212
• 20 Keifer OP, Hurt RC, Gutman DA. et al. Voxel-based morphometry predicts shifts in dendritic spine density and morphology with auditory fear conditioning. Nat Commun 2015; 6: 7582
• 21 May A, Hajak G, Ganssbauer S. et al. Structural brain alterations following 5 days of intervention: Dynamic aspects of neuroplasticity. Cereb Cortex 2007; 17: 205-210
• 22 Pereira AC, Huddleston DE, Brickman AM. et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci USA 2007; 104: 5638-5643
• 23 Lerch JP, van der Kouwe AJ, Raznahan A. et al. Studying neuroanatomy using MRI. Nat Neurosci 2017; 20: 314-326
• 24 Porterfield SP, Hendrich CE. The role of thyroid hormones in prenatal and neonatal neurological development--current perspectives. Endocrine Rev 1993; 14: 94-106
• 25 Morte B, Manzano J, Scanlan T. et al. Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 2002; 99: 3985-3989
• 26 Fauquier T, Chatonnet F, Picou F. et al. Purkinje cells and Bergmann glia are primary targets of the TRα1 thyroid hormone receptor during mouse cerebellum postnatal development. Development 2014; 141: 166-175
• 27 Zsarnovszky A, Kiss D, Jocsak G. et al. Thyroid hormone- and estrogen receptor interactions with natural ligands and endocrine disruptors in the cerebellum. Front Neuroendocrinol 2018; 48: 23-36
• 28 Chatonnet F, Guyot R, Picou F. et al. Genome-wide search reveals the existence of a limited number of thyroid hormone receptor alpha target genes in cerebellar neurons. PLoS One. 2012; 7: e30703
• 29 Korevaar TI, Muetzel R, Medici M. et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: A population-based prospective cohort study. Lancet Diabetes Endocrinol 2016; 4: 35-43
• 30 Hugdahl K, Raichle ME, Mitra A. et al. On the existence of a generalized non-specific task-dependent network. Front Hum Neurosci 2015; 9: 430
• 31 Hoche F, Guell X, Vangel M. et al. The cerebellar cognitive affective/ Schmahmann syndrome scale. Brain 2018; 141: 248-270