The Effect of Thyroid Hormones on the Hippocampus
There have been a number of new studies that have found that thyroid hormone (TH) deficiencies can have a serious impact on certain regions of the brain. One specific area affected is the hippocampus (Smith, Evans, Costall, & Smythe, 2002). The hippocampus is located within the medial temporal lobe in a region called the limbic system, which contains some brain regions that are relevant to memory and the processing thereof. These regions consist of the hippocampus, amygdala, thalamus, and hypothalamus (Reisberg, 2013). The hippocampus plays an important role in the transference of short-term memory to long-term memory, which also regulates spatial memory and behavior (Reisberg, 2013). In addition, certain THs are essential for the development and function of the brain within the hippocampus (Smith et al., 2002). Iodine is taken in by the thyroid gland and converted into thyroxine (T-4) and triiodthyronine (T-3). However, thyroid stimulating hormones (TSH) are produced by the pituitary gland, which tells the thyroid gland when to produce THs (Smith et al., 2002). Furthermore, the hypothalamus produces a TSH releasing hormone (TRH) that informs the pituitary gland to stimulate the thyroid gland by releasing TSH (Smith et. al. 2002). In addition, patients with hypothyroidism (HYPO) have higher than normal levels of TH, and patients with hyperthyroidism (HYPER) have a lower level of TH. These hormone levels play an important role in brain development, brain functioning, and other systems within the body and central nervous system. With evidence showing thyroid hormones as having an effect on the hippocampus, this research attempts to answer: what affect do thyroid hormones have on the hippocampus?
One study shows TH deficiencies cause damage to the episodic memory in children born with congenital hypothyroidism (CH). One method used in this study is a Children’s Autobiographical Interview (CAI). The CAI is a modified variant of the Autobiographical Interview (AI). This modified version is implemented to better serve children for this study. The CAI allows the experimenter to assess the participant’s episodic and semantic autobiographical memories (AM) by asking them to recall specific incidents in their lives within the last three years. The recall is measured by the amount of detail the participant is able to recite. Those measurements are compared with a CH group, HYPO group, and a control group of healthy children of similar age and sex. They found that the control group recalled more episodic details than the CH group. This study concluded its results by indicating that the ability to encode and/or retrieve visual information is affected by lack of TH in early development. Furthermore, it is noted that both CH and HYPO groups had problems recalling main event details, which suggests that visual memory may be affected by TH deficiencies (Willouhby, McAndrews, & Rovet, 2013). Another method used in this study is the Wechsler Abbreviated Scale of Intelligence (WASI). This test is used to evaluate intellectual ability based on a vocabulary test, given orally and visually, and a reasoning test. The higher scores on this test indicate a higher intellectual ability. They found no significant difference between IQs and episodic AM. Furthermore, this study found that TH deficiency can have a similar affect as a patient with hippocampal damage (Willouhby et al., 2013). These results suggest that TH deficiencies affect the hippocampus in areas where episodic memories are stored.
Another study concluded that THs affect the functioning of the hippocampus by causing it to rely on other parts of the brain area to perform a visuospatial paired-associates task during object pairing and spatial location activities. A functional magnetic resonance imaging (fMRI) was used in conjunction with a visuospatial paired-associates task (Wheeler, McAndrews, Sheard, & Rovet, 2012). The fMRI is used to measure brain activity while detecting the changes in the blood flow within the brain. Furthermore, the visuospatial paired-associates task is a method used in relation to visual perception of spatial association among objects. The participants were asked to pair a couple of items in a computer game and then respond to whether the pairs were new or previously examined (Wheeler et al., 2012). These tests were performed on children and adolescents with congenital hypothyroidism. It was noted in another study by Wheeler and associates that CH children were found to have a reduced size and maturation of the hippocampus, which affected the performance during certain memory tasks (Wheeler et al., 2007, as cited in Wheeler, 2012). These measurements are compared to typically developing (TD) children. These results show both groups performed similarly during the visuospatial associative memory task. However, fMRI results showed a difference in the hippocampal activation patterns; whereas, the CH group showed an increase in hippocampal activity, in both left and right hemisphere of the hippocampi, compared to the TD group. This study indicates an effect on the hippocampus by causing it to need recruitment of additional hippocampal resources during visuospatial paired-associates tasks consisting of object pairing and spatial location activities (Wheeler et al., 2012). Therefore, an impairment of the hippocampus can be recognized in participants with thyroid deficiencies during the developmental stage of the hippocampus.
An alternative way of studying the effect of TH deficiencies found in HYPER patients is to access their decision making performance by using the Iowa Gambling Test (IGT). The IGT is a computerized gambling task that stimulates decisions made in real-life by assessing the participant’s selection of advantageous and disadvantageous cards from four decks. This study found an irregular performance in HYPER patients during the decision making under uncertain conditions. The HYPER patients were unable to effectively use the information provided to them from previous choices and; therefore, chose the decks with instant reward regardless of any higher future loss during the gamble (Yuan, Tian, Zhang, Ma, & Chen, 2015). In addition, a Stroop Color-Word Test is performed, which is based on how fast an individual can read words and colors. Both tests were taken by and compared to a healthy group and a group of HYPER patients (Yuan et al., 2015). A Zung Self-Rating Anxiety Scale (Z-SAS) is also used to determine the anxiety levels of all participants in the study. It is noted that the HYPER patients scored higher on the Z-SAS, which means they experienced a higher anxiety level. Furthermore, the HYPER patients show a slower reaction time when switching task conditions and exhibit poorer performance on the IGT and Stroop Color-Word Test. This study reveals HYPER patients as showing a decrease in specific THs and that the lack of THs cause HYPER patients to have difficulties in decision making under certain conditions (Yuan et al., 2015). While this study does not pinpoint the hippocampus, it does note that the limbic system is affected by the TH deficiencies, which is the same system that the hippocampal functions reside.
Another way in which TH functioning has been assessed is with the use of lab rats. One experiment used twelve adult lab rats that were divided into a control group and HYPER induced group of rats. A stimulation recording device was placed on the rats to measure their excitability during a behavior test by way of a Y-Maze to assess spatial-memory. The Y-Maze had three identical arms where the rats would start at one end and choose one of the other two directions to explore. There were no reinforcements used, but visual cues were used to differentiate the different arms on the “Y”. The rats did several trial runs where some arms were blocked and they started at different ends. The measurement of this test is based on the rat’s natural curiosity to explore new areas (Taskin, Artis, Soner, & Dolus, 2011). Furthermore, the HYPER induced rats were treated with T-3 or T-4 hormones over time to measure the change in the rat’s performance. Elevated T-3 and/or T-4 levels are considered HYPER, while the lower levels are HYPO. The treated rats were given dosage levels of T-4 that would allow the THs to resume normal levels. The results showed that the HYPER rats showed a depressed behavior because their amplitudes were lower than the control group. In addition, the HYPER rats were unable to retain spatial information for either short or long periods of time. It was noted that the T-3 treated rats performed poorly in the spatial task, but showed improvement over time with the treatment of T-4 hormones, which prompted the rats’ THs to resume normal levels (Taskin et. al., 2011). This study shows the effect on the rats’ hippocampal region by inducing HYPER rats with T-3 hormones and then changed the effect by inducing T-4 hormones. Spatial learning, a function found in the hippocampus, was shown to be affected by an increase in THs and deficiencies. Furthermore, it provides evidence that both an increase and deficiencies of THs can cause a depressed behavior.
Rats have been used in other studies to look at hippocampal functions. One such study explores the reduced growth and the alteration of the hippocampal structure in newborn rats with abnormal levels of TH, T-4 and T-3. A Porsolt Swimming Test (or forced swimming) was used to establish a normal behavior between a depressive-like behavior when placed under stressful circumstances. The test is based on the assumption that the rats will try to find a way out of the stressful situation. It is measured by how long the rats spend trying to escape before giving up. If the rat gives up quickly, it is considered to show a depressed behavior. The rats are placed in a cylinder full of water while their actions were being recorded (Montero-Pedrazuela et al., 2006). In addition, an Object Recognition Task was performed. The rats were individually placed in an open box and were assessed by the amount of time spent exploring new or familiar objects (Montero-Pedrazuela et al., 2006). Furthermore, the brain structures were examined after the experiment to determine any proliferating cells or impaired hippocampal neurogenesis. A euthyroid (normal), HYPO, and a treated HYPO group were used. The study concluded that THs did affect the hippocampal neurogenesis (Montero-Pedrazuela et al., 2006). This shows hippocampal functions rely on the proper amount of THs. Also, the results found, in comparison to the euthyroid (normal) rats, HYPO rats showed a depressive behavior in the Porsolt Swimming Test. Furthermore, the treated HYPO rats showed a reverse in their depressive behavior after treatment to provide a normal level of THs (Montero-Pedrazuela et al., 2006). In relation to TH effects on the hippocampus, this study provides several aspects showing that the hippocampal region can be affected and the cause it has on the behavior of lab rats. While the hippocampal neurogenesis is effected, a depressive-like behavior can be found in rats with TH abnormalities. Furthermore, this study shows that treatment for TH abnormalities can repair the depressive behavior that was presented by the HYPO rat.
While TH research has only recently been at the forefront of certain studies, there seems to be a good amount of information available showing its connection to hippocampal functions. TH abnormalities have been shown to affect the episodic autobiographical memory with the inability to encode and/or retrieve visual information (Willoughby et al., 2013). With the help of fMRI technology, CH patients showed an increased activity in both left and right hemispheres of the hippocampal region during visuospatial paired-associates task and spatial location activities. This provides some evidence that the TH levels have an effect on the functioning of the hippocampus and that it has to rely on other parts of the brain to sufficiently perform such tasks (Wheeler et al., 2012). Furthermore, poor decision making and slower reaction time during task switching is found in HYPER patients (Yuan et al., 2015). In TH studies using rats, both high (HYPER) and low (HYPO) levels of TH is found to affect the hippocampus causing the rats to have poor spatial and object recognition abilities. Both HYPER and HYPO rats are found to display depressive-like behavior, but show an improvement once the TH levels are restored to normal levels (Taskin et al., 2011 and Montero-Pedrazuela et al., 2006).
There are many ways to study the effect on hippocampus caused by the abnormal levels of THs. However, there are ethical guidelines that must be followed when performing studies on human participants. On the other hand, lab rats can be studied in ways that can prove to be more effective and convincing. Researchers can alternate the rats’ THs while assessing their behavior with and without abnormal TH levels. Also, the researchers are able to surgically remove and dissect the brains in order to study the hippocampus of normal rats and compare them to rats with TH abnormalities. During these studies, it is evident that the hippocampal growth and the development of nervous tissue is affected by TH abnormalities (Montero-Pedrazuela et al., 2006). The most compelling evidence is found when the rats’ TH levels are altered causing a similar effect found in patients with abnormal TH levels. In addition, the researchers are able to reverse the effects of abnormal TH levels on lab rats by inducing normal levels of THs. This type of evidence provides a cause for the correlation between the two; whereas, the human experiments can only provide a possible connection.
While these studies provide a good starting point in finding the effects of THs on the hippocampus, more research should be done because it is possible that the connections between the hypothalamus, pituitary gland, and thyroid gland are disrupted. Although proper levels of THs are important, it may be abnormal because of other reasons beyond the thyroid gland. The thyroid gland can only do its job properly if the other connecting systems provide the necessary information needed. The hypothalamus should be looked at and studied first because it is the first branch that produces and releases TRHs that inform the pituitary gland on the next step needed in producing the right amount of TSH. Next, the pituitary gland should be studied in conjunction with the hypothalamus to make sure the correct information is being received before stimulating the thyroid gland to produce the desired amount of THs. Since iodine is the contributing factor, it should be collected during the first two stages to determine whether the two systems are properly communicating between each other. However, the evidence presented in this paper provides enough compelling evidence to show that THs does have an effect on the hippocampus, and the many ways it is affected thereof.
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Yuan, L., Tilan, Y., Zhang, F., Ma, H., Chen, X. et. al. (2015). Decision-making in patients with hyperthyroidism: A neuropsychological study. PLoS One, 10(6): e0129773. doi:10.1371/journal.pone.0129773.