fMRI revealed neural substrate for reversible working memory dysfunction in subclinical hypothyroidism.

Cognitive impairments have been found in thyroid hormone-related diseases (e.g. hyperthyroidism and hypothyroidism) for a long time. However, whether and how subclinical hypothyroidism (SCH) causes any deficits in brain functions, and whether a hormone-replacement treatment is necessary for SCH patients, still remain controversial subjects. In the present study, functional MRI (fMRI) was used to measure brain functions by asking euthyroid subjects, hyperthyroid patients and SCH patients to perform the widely used digit n-back working memory task. After having been treated with l-thyroxine for approximately 6 months, the SCH patients were asked to do the same fMRI experiment. The hypothyroid and SCH patients scored significantly lower in the 2-back task than either the hyperthyroid patients or the euthyroid subjects (P < 0.012). The fMRI showed that a common frontoparietal network, including bilateral middle/inferior frontal gyri (M/IFG), bilateral dorsolateral prefrontal cortex (DLPFC), bilateral premotor areas (PreMA), the supplementary motor area/anterior cingulate cortex (SMA/ACC) and bilateral parietal areas (PA), was activated by the n-back task in all the subjects. Further quantitative analysis showed that the load effect of blood oxygen level-dependent (BOLD) response appeared in all the five regions of interest (ROIs) in the euthyroid and hyperthyroid subjects. In the pre-treatment SCH patients, however, the load effect of BOLD response was only found in the PA and PreMA, but not in other frontal cortex ROIs [general linear model (GLM), F < 2.6, P > 0.1]. After an approximately 6 month treatment with LT4, the SCH patients exhibited the same load effects in all five ROIs as the euthyroid subjects (GLM, F > 6, P < 0.05) along with an improvement of performance in n-back task. These results suggest that working memory (but not other memory functions) is impaired in SCH patients, mainly as far as disorders of the frontoparietal network were concerned. Both the memory performance and frontal executive functions were improved after an l-thyroxine-replacement treatment.