Altered brain functional connectivity in patients with resistance to thyroid hormone ß.

To investigate changes in brain network organization and possible neurobehavioral similarities to attention-deficit hyperactivity disorder (ADHD), we measured changes in brain resting-state functional connectivity (rs-fMRI) and cognitive domains in patients with resistance to thyroid hormone ß (RTHß) and compared them with those in healthy control subjects. In this prospective case-control study, twenty-one participants with genetically confirmed RTHß were matched with 21 healthy controls. The Adult ADHD Self-Report Scale (ASRS-v1.1) and ADHD Rating Scale-IV were used to assess self-reported symptoms of ADHD. A voxel-wise and atlas-based approach was used to identify changes in the brain networks. The RTHß group reported behavioral symptoms similar to those of ADHD. We found evidence of weaker network integration of the lingual and fusiform gyri in the RTHß group, which was mainly driven by weaker connectivity to the bilateral insula and supplementary motor cortex. Functional connectivity between regions of the default mode network (angular gyrus/middle temporal gyrus) and regions of the cognitive control network (bilateral middle frontal gyrus) was increased in RTHß patients compared to healthy controls. Increased connectivity between regions of the default mode network and the dorsolateral prefrontal cortex is frequently reported in ADHD and is interpreted to be associated with deficits in attention. Our finding of weaker connectivity of the lingual gyrus to the bilateral insula (salience network) in RTHß patients has also been reported previously in ADHD and may reflect decreased habituation to visual stimuli and increased distractibility. Overall, our observations support the notion of neuropsychological similarities between RTHß and ADHD.

Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations.

BACKGROUND: Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. METHODS: High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). RESULTS: RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. CONCLUSION: RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined.

Reduced pituitary size in subjects with mutations in the THRB gene and thyroid hormone resistance.

Background: Thyroid hormone action is mediated by two forms of thyroid hormone receptors (α, ß) with differential tissue distribution. Thyroid hormone receptor ß (TRß) mutations lead to resistance to thyroid hormone action in tissues predominantly expressing the ß form of the receptor (pituitary, liver). This study seeks to identify the effects of mutant TRß on pituitary size. Methods: High-resolution 3D T1-weighted magnetic resonance images were acquired in 19 patients with RTHß in comparison to 19 healthy matched controls. Volumetric measurements of the pituitary gland were performed independently and blinded by four different raters (two neuroradiologists, one neurologist, one neuroscientist). Results: Patients with mutant TRß (resistance to thyroid hormone ß, RTHß) showed elevated free tri-iodothyronine/thyroxine levels with normal thyroid-stimulating hormone levels, whereas healthy controls showed normal thyroid hormone levels. Imaging revealed smaller pituitary size in RTHß patients in comparison to healthy controls (F(1,35) = 7.05, P = 0.012, partial η2 = 0.17). Conclusion: RTHß subjects have impaired sensitivity to thyroid hormones, along with decreased size of the pituitary gland.

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

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.

Patients with mutations of the Thyroid hormone beta-receptor show an ADHD-like phenotype for performance monitoring: an electrophysiological study.

Resistance to thyroid hormone beta (RTHß) is a syndrome of reduced responsiveness of peripheral tissue to thyroid hormone, caused by mutations in the thyroid hormone receptor beta (THRB). Its cognitive phenotype has been reported to be similar to attention deficit hyperactivity disorder (ADHD). This study used electrophysiological biomarkers of performance monitoring in RTHß to contribute further evidence on its phenotypical similarity to ADHD. Twenty-one participants with RTHß aged 18-67 years and 21 matched healthy controls performed a modified flanker task during EEG recording. The RTHß and control groups were compared on behavioural measures and components of event related potentials (ERPs), i.e. the error related negativity (ERN), the error positivity (Pe) and P3 component. There were no significant group differences with regard to behaviour. RTHß subjects displayed significantly reduced ERN and Pe amplitudes compared to the controls in the response-locked ERPs. In addition, we observed reduced P3 amplitudes in both congruent and incongruent trials, as well as prolonged P3 latencies in RTHß subjects in the stimulus-locked ERPs. Our findings reveal alterations in error detection and performance monitoring of RTHß patients, likely indicating reduced error awareness. The electrophysiological phenotype of RTHß subjects with regard to action monitoring is indistinguishable from ADHD.

Experimentally induced subclinical hypothyroidism causes decreased functional connectivity of the cuneus: A resting state fMRI study.

OBJECTIVE: The aim of this study was to experimentally evaluate the effects of subclinical mild hypothyroidism on brain network connectivity as determined by resting state fMRI (rsfMRI) which serves as a proxy for global changes in brain function. METHODS: Fifteen otherwise healthy patients with complete hypothyroidism under stable, long term levothyroxine substitution volunteered for the study. They reduced their pretest levothyroxine dosage by 30% for 52-56 days. Basally and after partial levothyroxine withdrawal, rsfMRI along with a neuropsychological analysis was performed. RsfMRI was subjected to graph-theory-based analysis to investigate whole-brain intrinsic functional connectivity. RESULTS: The desired subclinical hypothyroidism was achieved in all subjects. This was associated with a significant decrease in resting-state functional connectivity specifically in the cuneus (0.05 FWE corrected at cluster level) which was mainly caused by a weaker functional connectivity to the cerebellum and regions of the default mode network, i.e. the medial prefrontal cortex, the precuneus and the bilateral angular gyri. The decrease in cuneus connectivity was correlated to the increase in TSH serum levels. A working memory task showed a slightly longer reaction time and less accuracy after partial levothyroxine withdrawal. CONCLUSION: Even short-term partial levothyroxine partial withdrawal leads to deficits in working memory tasks and to a weaker integration of the cuneus within the default mode network.