Experimentally induced thyrotoxicosis leads to increased connectivity in temporal lobe structures: A resting state fMRI study
Introduction
Changes in thyroid hormone levels have been shown to lead to profound effects on cognitive functions. Whereas hypothyroidism in adults leads to attentional and memory deficits that can mimic dementia (Dugbartey, 1998, Pilhatsch et al., 2011), hyperthyroidism is associated with a range of symptoms including inattentiveness, cognitive function deficits and hyperarousal (Larisch et al., 2004, Bunevicius and Prange, 2006, Bauer et al., 2008). During development, but likely also in the adult organism, thyroid hormones impact a wide range of processes such as neurogenesis, development of glia, myelination, synaptogenesis and dendritic proliferation (Zoeller and Rovet, 2004, Bernal, 2007, Williams, 2008). In the human, the structural and functional changes of the brain, brought about by either hypo- or hyperthyroidism, are understudied. One study using voxel-based morphometry (VBM) applied to T1-weighted MR images revealed a reduction in grey matter volume (GMV) in the left postcentral gyrus and the cerebellum in ten hypothyroid patients compared to healthy controls (Singh et al., 2013). Hypothyroidism was also associated with white matter volume reduction in the cerebellum, the right inferior and middle frontal gyrus, right precentral gyrus, right inferior occipital gyrus and right temporal gyrus (Singh et al., 2013). Zhang et al., 2014a, Zhang et al., 2014b investigated GMV alterations in 51 patients with Graves’ disease compared to 51 healthy controls. In hyperthyroidism, GMV was reduced in the bilateral hippocampus, parahippocampal gyrus, calcarine region, lingual gyrus, and left temporal pole, whereas the GMV was increased in the supplementary motor area bilaterally. In a group of healthy volunteers who took thyroxin or placebo in a double blind crossover design, late cognitive event-related potentials were significantly altered during the execution of visual search tasks (Münte et al., 2001) in the hyperthyroid state.
Fluorodeoxyglucose (FDG) PET revealed decreased glucose metabolism in the temporal poles (bilateral) in Graves’ disease (Schreckenberger et al., 2006) or in the parahippocampus (bilateral), fusiform gyrus (bilateral), cingulate gyrus (left) and in the frontal lobes (left middle and superior frontal gyrus) in untreated patients with hyperthyroidism (Miao et al., 2011).
In the present investigation we evaluated the effects of levothyroxine treatment (250 μg per day over eight week) on intrinsic brain connectivity as measured by resting-state fMRI. More specifically, to quantify connectivity changes we applied graph-theory-based analyses and calculated the degree centrality as a measure of connectivity on a voxel-level. The degree of a voxel is defined as the number of connections to other voxels in the brain. It is thus a measure for the connectedness of a voxel within the brain network and particularly suited to detect localized effects. This method is superior to region of interest (ROI) analyses which are biased by the choice of the ROIs. Recently, the voxel-degree method has successfully been used as a marker for altered connectivity in Alzheimer's disease (Buckner et al., 2009), Parkinson's disease (Göttlich et al., 2013), bilateral vestibular failure (Göttlich et al., 2014) and Obsessive Compulsive Disorder (Beucke et al., 2013). We first identified regions of altered connectivity during experimental thyrotoxicosis applying rigorous statistical thresholds to the voxel degree maps. To further explore altered connectivity we used the regions identified by whole brain voxel degree analysis as seeds for functional connectivity analyses. Both, PET and structural data associated structures of the limbic system, the temporal and frontal lobes with thyrotoxicosis. We hypothesized that also the functional connectivity in these regions should be affected. We also hypothesized that participants with induced mild hyperthyroidism may show elevated mood as well as subtle improvements in attention and memory (Samuels et al., 2008). Based on the literature, we did not expect changes in executive functions.
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Subjects
The ethics committee of the University of Lübeck had cleared all procedures and all subjects gave their written informed consent prior to the study. Twenty-nine healthy male right-handed subjects (median age 30 years, range 21–49 years) were recruited. One participant had to be excluded due to extensive bodybuilding and the resulting impact on the thyroid gland. All subjects were screened prior to the study for general health, medicines, drug abuse, thyroid status (hormone levels, anti-thyroid
Clinical and neuropsychological characteristics
After 8 weeks, the intake of levothyroxine led to a significant increase in free thyroxine (fT4, p < 0.001) and free triiodothyronine (fT3, p < 0.001) and a significant decrease in the thyroid-stimulating hormone (TSH, p < 0.001). Systolic and diastolic blood pressures were not significantly altered. Mean heart rate significantly rose by 6 beats per minute (p = 0.016) on average. All clinical characteristics are summarized in Table 1.
After discontinuation of treatment, all parameters went back to the
Discussion
The aim of this study was to demonstrate whether short term application of thyroid hormones resulting in a thyrotoxic state leads to changes of resting state connectivity which in turn could underlie the well-known cognitive effects of hyperthyroidism. In contrast to this well-defined onset and extent of thyrotoxicosis, spontaneous hyperthyroidism as encountered in patients is uncontrolled particularly in the duration of the disease and is as well frequently associated with other medical
Conclusions
Short-term hyperthyroidism leads to increased resting-state functional connectivity in the rostral temporal lobes which is caused by an increased functional connectivity to the cognitive control network. The increased connectivity may facilitate prefrontal control over limbic areas. This mechanism may underlie the successful use of thyroid hormones as an augmentation therapy of depression.
Financial disclosures
The authors declare no financial conflicts.
Role of the funding source
The funding source had no influence on the design, analysis and publication of the study.
Conflict of interest statement
None declared.
Acknowledgment
Supported by DFG grant MU1311/16-1 awarded to TFM and GB and by intramural funding of the University of Lübeck.
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