Sensory Learning Dysfunction Casual Factors

Underlying Mechanisms of Developmental Disorders by Dr. Christopher Jackson, PhD, DOM (FL)

The specific mechanisms by which developmental disorders evolve pre- and post-natally range from high-level metabolic processes to low-level cellular processes. These processes may affect cerebellar, vestibular, auditory, or optical processing. Several studies have pursued the underlying causes of disorders of cerebellar function and related sensory learning deficits. Studies explore the effects of hypo- and hyperthyroidism, endocrine disruptor effects on brain development, and the similarity of endocrine disruptor effects to the effects of thyroid hormone.

Thyroid hormone, particularly triiodothyronine (T3), may be under-appreciated in the medical community for its role in brain development. Generally the realm of endocrinologists rather than neurologists or developmental specialists, thyroid hormone actually appears to be involved in many roles beyond standard metabolic functions. According to Anderson (2008), referencing over 180 studies, deficiency of thyroid hormone pre- or post-natally may result in dysfunctions, cellular changes, and molecular variations via regulation of gene transcription. These actions are accomplished via binding of thyroid hormone, particularly T3, with thyroid hormone receptors that subsequently bind with thyroid hormone response element DNA sequences. Thyroid hormone may also induce neurotrophin gene expression, thereby indirectly activating genes (Anderson, 2008). Thus, there are many aspects to the involvement of thyroid hormone on brain development, including several influences on the cerebellum.

Abnormal cerebellar development may be commonly induced by perinatal hypothyroidism leading to reduced dendritic proliferation. This early hypothyroidism also may lead to reduced development of Purkinje cells and a reduction, and delay in myelination. These abnormalities may lead to impaired voluntary motor activity or strabismus, and may be avoided or reversed to some extent if thyroid hormone is replaced quickly enough after birth (Anderson, 2008). Koibuchi (2009) examined additional mechanisms via which thyroid hormones may affect brain development, particularly the cerebellum, including monocarboxylate transporter 8 (MCT8). The study explored the activity of various deiodinases in the conversion and breakdown of thyroid hormones within neurologic pathways, including conversion of thyroxine (T4) to active thyroid hormone T3 in astrocytes, tanycytes, and transfer to oligodendrocytes. Such molecular and neurological mechanisms appear to contribute significantly to the origins of developmental delays.

Other molecular and neurological mechanisms, related to thyroid dysfunction, have been studied to help isolate underlying causal factors for cerebellar developmental disorders. Li, Post, Koibuchi, and Sajdel-Sulkowska (2004) explored the role of diminished thyroid hormone in the distortion of cerebellar development. An attempt to understand the molecular mechanisms involved in regulation of the development of the cerebellum, the study focused on glial-neuronal interactions and specific proteins involved. The study used pregnant rats treated with propylthiouracil (PTU) to reduce thyroid function, then grouped the newborn rats by those remaining untreated and those receiving treatment with T4, comparing them with normal controls with euthyroid mothers. Cerebella of the newborns were dissected to examine the levels of proteins present in this section of their brains at various stages of development (days from birth). The data were analyzed statistically for a relationship between treatment and age using analysis of variance (ANOVA) and t-tests for any significant relationships. A significant functional decrease (expressed in protein levels) was observed at day 10, and full function was restored with T4 treatment (Li et al., 2004). The viability of treatment with T4 helps to confirm the significance of these pathways etiologically.

Other studies use treatment with thyroid hormone to examine causal relationships and pathways. A study engaged in the pursuit of related molecular and neurological mechanisms was Martinez, Eller, Viana, and Gomes (2011). The study explored the role of the pathway that includes thyroid hormone inducement of epidermal growth factor (EGF) secretion from cerebellar astrocytes, and the resultant effect on neuronal migration. The astrocyte cultures (25,000 cells in 96 cultures) were treated with T3 and compared with untreated control cultures maintained under similar environmental conditions. Cerebellar cultures (96 cultures from small pieces of cerebellar tissue) were treated using EGF. Bergmann glia (BG) fibers were extracted and grown in 96 similarly developed cultures. Divided portions of each of the BG and cerebellar cultured groups were treated with signal pathway inhibitors, while others were treated with antibodies that neutralized them against EGF. Treatment of the rat brain cultures with EGF induced significant increases in neuronal migration, whereas treatment with neutralizing antibodies against EGF or inhibition of EGF using bis-tyrphostin inhibited migration. According to this study, the results indicated that thyroid hormones, by inducing EGF secretion, promoted neuronal migration via elongation of BG fibers, bypassing the Purkinje cell layer (Martinez et al., 2011).

Since iodine is a major component of thyroid hormone, it is reasonable to consider the role of iodine deficiency in thyroid dysfunction. This consideration then leads to the important relationship between thyroid dysfunction and developmental issues or the relationship between iodine deficiency and brain damage (Delange & Lecomte, 2000). Concerns may be raised about the influence of iodine supplementation on rates of hyperthyroidism or thyrotoxicosis, but Delange and Lecomte (2000) evaluated these issues and concluded that it is better to supplement. The study thoroughly reviewed and analyzed over 60 studies for the possible ramifications of supplementation, including iodine-induced hyperthyroidism (thyrotoxicosis) or autoimmune thyroiditis, and weighed them against the results of not taking this action, including developmental issues and a debate over cancer incidence with or without supplementation (Delange & Lecomte, 2000).

Iodine deficiency and its effect on psychiatric function were examined in a 2001 study. Lederbogen, Hermann, Hewer, and Henn (2001) was a study of psychiatric in-patients throughout a calendar year. The parameters studied were total T4, free thyroxine index (FTI), and thyrotrophin stimulating hormone (TSH). Participants with thyroid dysfunction indicated by at least one parameter (243 of 880) were initially included, but the population was reduced to 848 and legitimate (not by other cause, such as drug-induced) thyroid dysfunction was determined in a resultant 100 participants. As measures of T4 and/or FTI provided no essential information in 854 patients (97% of tested), they found that in most cases the determination of TSH alone was sufficient for demonstrating normal thyroid function.

This study made the statement that TSH was sufficient measure in most cases. This is quite debatable, since TSH has been shown to be inaccurate in other studies (Schwartz, Morelli, & Holtorf, 2011). The assumption is linked to the lack of usefulness of T4 and FTI, which only illustrates the invalidity of those values. FTI is a calculated value as opposed to a measured value. Also, the active thyroid hormone is T3 and this has not been measured in any form in this study. An alternative approach would be to test the free-floating forms free triiodothyronine (FT3) and free thyroxine (FT4) to indicate the actual availability of thyroid hormone, a more direct measure of thyroid function. Therefore, this study may have miscalculated the effect.

Developmental issues, such as memory and learning disorders, may extend beyond clinical hypothyroidism to subclinical hypothyroidism, measured by the same parameters but at low normal functional levels rather than clinically low levels. Ge, Peng, Hu, and Wu (2012) suggested extending treatment to subclinical hypothyroidism, largely due to deficits in learning exhibited by lab-created subclinically hypothyroid rats. The study used 36 male rats divided randomly into 3 groups of 12 each, induced through cauterization to be clinically hypothyroid or subclinically hypothyroid, compared to non-affected controls. Thyroid function levels were measured directly using TSH, FT3, and FT4, as opposed to the calculation of FTI. The study concluded that there is a need for treatment of subclinical hypothyroidism to help prevent developmental disorders (Ge et al., 2012).

Thyroid dysfunction and endocrine disruptors may affect production of the important sex hormones progesterone and estrogen. According to Koibuchi (2008), abnormal development of the cerebellum may result from inappropriate sex hormone levels due to thyroid dysfunction. Hormonal imbalances of estrogen and progesterone may be involved, since they may be affected by production of the hormones within the Purkinje cells of the cerebellum. Additionally, rapid action of these hormones may be induced by receptor activity at cell membranes, possibly modulating the activity of neurotransmitters (Koibuchi, 2008).

Development of the cerebellum may be affected by many other factors. According to Koibuchi (2008), several inherent elements may lead to aberrant cerebellar development. Mutations of receptors may occur due to the actions of prescription drugs or environmental toxins, including endocrine disruptors, as well as the actions of hypothalamic hormones thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH), which may modulate Purkinje cell function via related receptors (Koibuchi, 2008). CRH and TRH are precursors to hormones adrenocorticotropic hormone (ACTH) and TSH which are released from the anterior pituitary to stimulate thyroid and adrenal activity in a concerted effort to balance our metabolisms. This suggests that TSH and ACTH should be used to assess metabolic activity and the status of hormones pre- and post-natally.

A rather interesting and widely-debated contributor that may affect thyroid-related developmental pathways is thimerosal. A study by Sulkowski, Chen, Midha, Zavacki, and Sajdel-Sulkowska (2012) examined the effect of ethylmercury (Et-Hg) from thimerosal on the developing brain. This is particularly interesting because of the wide distribution of vaccines containing thimerosal. In the study, pregnant rats were exposed to thimerosal during pregnancy and lactation, and their offspring were examined for auditory, motor, thyroid, and cerebellar (oxidative stress) dysfunction. The study hypothesized that perinatal exposure to thimerosal impaired development of the cerebellum, and central nervous system (CNS) as a whole, via oxidation. Dysfunctions such as a delayed startle response and significant cerebellar oxidative stress were found. In male offspring, specifically spontaneously hypertensive rats, a significant reduction in type 2 deiodinase (a selenoenzyme involved in the conversion of T4 to T3) was an evident mechanism, likely related to T3 deficiency in the cerebellum (Sulkowski et al., 2012). Thus, we have further confirmation of the effects of low T3 on the cerebellum, as well as the contribution of thimerosal (in vaccines) to developmental disorders.

Despite the many affirmative study results, there has been at least one study questioning these results. Grabe et al. (2005) concluded that evidence was limited for a pathogenic role of thyroid disorders in mental disorders. The study sampled 3,790 participants from the general population, testing the hypothesis that hypo- and hyperthyroidism were associated with mental and physical complaints, testing 38 complaints in total. The study used reasonable measures of thyroid function, directly measuring FT4 and FT3, rather than using the calculated value of FTI. Particularly, the study showed no association between psychiatric diagnoses and subclinical hypothyroidism or subclinical hyperthyroidism. However, both mental and physical problems were associated with autoimmune thyroiditis (Grabe et al., 2005).

The results from Grabe et al. (2005) and Lederbogen et al. (2001) relied on diagnosis of disorders at the functional (psychiatric) level, which could certainly be interpreted as a less precise measure, as opposed to looking directly at brain cell activity, albeit typically in rat studies of brain activity rather than human studies. An additional area of needed research is highlighted as a phenotype discrepancy between mice and human beings, which may bring some question to results yielded by Ge et al. (2012), Lederbogen et al. (2001), Li et al. (2004), Martinez et al. (2011), and Sulkowski et al. (2012), experiments with lab mice (Koibuchi, 2009). It was duly noted in Sulkowski et al. (2012) that the applied dosage of 200 mcg per kg of body weight used in the study was approximately 10 times that used in human applications, making these results somewhat suspect.

Additionally, the study by Martinez et al. (2011) was interpreted to indicate that thyroid hormones, by inducing EGF secretion, promoted neuronal migration via elongation of BG fibers, bypassing the Purkinje cell layer. However, this implies that the actions of these cultures are directly indicative of development that takes place in a closed and synergistic environment that may rely on feedback mechanisms beyond the single part, single role mechanistic model portrayed by the study. Further investigation of these roles in a more naturally-occuring environment would be appropriate. Thus, there is much room for further exploration of these mechanisms, particularly for a human study, perhaps in cadavers of former psychiatric patients with developmental disorders. According to studies such as Koibuchi (2008), estrogen and/or progesterone imbalance may be involved in cerebellar dysfunction and developmental issues. Endocrine disruptors are found in particular drugs, pesticides, parabens in makeup, industrial by-products, and heat-exposed water bottles. Therefore, the role, significance, and specific pathways of endocrine disruptors in developmental disorders may be an important area of research. In other words, the specific contribution level of endocrine disruptors to the ever more prevalent presence of developmental disorders, particularly in children with mothers exposed to these disruptors while carrying these children, is at question.

Copyright April 18, 2014

References

Anderson, G. (2008). Thyroid hormone and cerebellar development. Cerebellum (London, England), 7(1), 60-74. doi:10.1007/s12311-008-0021-4

Delange, F., & Lecomte, P. (2000). Iodine supplementation: benefits outweigh risks. Drug Safety: An International Journal of Medical Toxicology and Drug Experience, 22(2), 89-95.

 

Ge, J., Peng, L., Hu, C., & Wu, T. (2012). Impaired learning and memory performance in a subclinical hypothyroidism rat model induced by hemi-thyroid electrocauterisation. Journal of Neuroendocrinology, 24(6), 953-961. doi:10.1111/j.1365-2826.2012.02297.x

 

Grabe, H., Völzke, H., Lüdemann, J., Wolff, B., Schwahn, C., John, U., & ... Freyberger, H. (2005). Mental and physical complaints in thyroid disorders in the general population. Acta Psychiatrica Scandinavica, 112(4), 286-293.

Koibuchi, N. (2008). The role of thyroid hormone on cerebellar development. Cerebellum (London, England), 7(4), 530-533. doi:10.1007/s12311-008-0069-1

 

Koibuchi, N. (2009). Animal models to study thyroid hormone action in cerebellum. Cerebellum (London, England), 8(2), 89-97. doi:10.1007/s12311-008-0089-x

 

Lederbogen, F., Hermann, D., Hewer, W., & Henn, F. (2001). Thyroid function test abnormalities in newly admitted psychiatric patients residing in an iodine-deficient area: patterns and clinical significance. Acta Psychiatrica Scandinavica, 104(4), 305-310.

Li, G., Post, J., Koibuchi, N., & Sajdel-Sulkowska, E. (2004). Impact of thyroid hormone deficiency on the developing CNS: cerebellar glial and neuronal protein expression in rat neonates exposed to antithyroid drug propylthiouracil. Cerebellum (London, England), 3(2), 100-106.

Martinez, R., Eller, C., Viana, N., & Gomes, F. (2011). Thyroid hormone induces cerebellar neuronal migration and Bergmann glia differentiation through epidermal growth factor/mitogen-activated protein kinase pathway. The European Journal of Neuroscience, 33(1), 26-35. doi:10.1111/j.1460-9568.2010.07490.x

Sulkowski, Z., Chen, T., Midha, S., Zavacki, A., & Sajdel-Sulkowska, E. (2012). Maternal thimerosal exposure results in aberrant cerebellar oxidative stress, thyroid hormone metabolism, and motor behavior in rat pups; sex- and strain-dependent effects. Cerebellum (London, England), 11(2), 575-586. doi:10.1007/s12311-011-0319-5