In the current study, we applied resting state fALFF to investigate the amplitude of spontaneous neuronal activity in newly diagnosed unmedicated patients with adult-onset hypothyroidism, and especially addressed the characteristics of the altered fractional amplitude in different frequency bands. Notably, left lingual gyrus and middle temporal gyrus exhibited lower fALFF values both in routine band and slow-5 band, indicating that the decreased fALFF observed in the group comparison was mostly contributed by the slow-5 oscillations. In addition, we discovered more significant brain regions in slow-5 band than in routine band in hypothyroid patients compared to HCs. These results demonstrated that abnormal spontaneous neuronal activity in the hypothyroid patients was involved multiple brain regions and the changes were frequency dependent.
The lingual gyrus is associated with wide variety of cognitive functions, including inhibition function and divergent thinking [25], visual memory processing [26], generation of vivid motion imagery [27, 28], and the processing of semantic relatedness [29] etc. In the present study, fALFF values of left lingual gyrus were lower in adult-onset hypothyroid patients compared to HCs both in routine band and slow-5 band, and the decreased fALFF values were negatively correlated with TSH levels, indicating that the lingual gyrus is an important and stable brain region which involved in neuropathological and physiological processes of hypothyroidism. A study of single photon emission computed tomography indicated even mild hypothyroidism could lead to significant reduction of cerebral blood flow in lingual gyrus, and alterations in cerebral blood flow associated with neurocognitive changes[30]. In addition, a task-based fMRI study had demonstrated patients with hypothyroidism showed abnormal activation in the lingual gyrus accompanied by impaired working memory function [31], which support our findings. Therefore, the decreased fALFF values in lingual gyrus might be a potential neuroimaging biomarker of brain impairment in adult-onset hypothyroidism.
The middle temporal gyrus is mainly involved in encoding and retrieving emotional memory, it performs complex and diverse functions including speech, learning, memory and cognition [32, 33]. In the current study, we found that the fALFF values in the left middle temporal gyrus were lower in hypothyroid patients in routine band and slow-5 band. This alteration might associate with the hemodynamic and anatomical basis in middle temporal gyrus in hypothyroid condition. It had been reported that regional cerebral blood flow in the temporal lobe was lower in hypothyroid patients [30]. Significant reduction in gray or white matter volume were found in the middle temporal gyrus of hypothyroid patients [34-36], associated with deficits in attention, memory, language, motor speed, and visual processing. These results implicated that the middle temporal gyrus was involved in the pathophysiological process of adult-onset hypothyroidism.
We also found decreased spontaneous neuronal activities in hypothyroid patients in precuneus and inferior occipital gyrus which are parts of visual cortical areas. These regions are typically involved in early visual memory and facial expression processing in healthy young adult population [37]. Our findings were highly correlated with a previous fMRI study that showed a significantly decreased functional connectivity within medial visual network (including occipital gyrus, precuneus cortex) in hypothyroid patients [6]. Further objective evidence is a recent report exhibited increased ReHo in precuneus and middle occipital gyrus after thyroidectomy and during thyroxine replacement therapy processing in hypothyroid patients, which were positively correlated with TSH levels [7], suggesting that TSH might affects the synchronization of neural BOLD signals. The abnormal spontaneous activity in the visual cortex might be one of the neural mechanisms of hypothyroidism.
Our study also found increased fALFF values in the right middle frontal gyrus and SMA in hypothyroid patients. The middle frontal gyrus has been implicated in attention, anger and auditory hallucination [38]. Earlier studies reported that the middle frontal gyrus showed a significant reduction in white or gray matter volume in hypothyroid patients[36, 39]. Besides, increased fALFF values were found in left middle frontal gyrus in mild hypothyroidism [39], which supporting our results to some extent, changes in structure may be the pathological basis for abnormality functions. Additionally, the SMA participates in the planning and execution of voluntary movement [40]. A previous fMRI study showed a much lower right index finger tapping rate in hypothyroid patients, and clusters of activation were found in SMA [41]. As reported in the literatures, hypothyroid patients showed a negative correlation between the functional connectivity in the SMA-cingulate gyrus and TSH values [6]. Moreover, a significant reduction in the gray matter volumes in SMA were found in hypothyroid patients [38]. Taken together, increased fALLF values in middle frontal gyrus and the SMA might be one of the neuropathological mechanisms of cerebral impairments in hypothyroid patients.
Interestingly, in the present study, the HAMD-24 scores were significantly higher in hypothyroid patients than HCs, suggesting that hypothyroidism might have higher risk of depressive symptoms, which might relate to the abnormal brain structure or function. Previous study reported that patients with severe depression showed decreased volume in the right lingual gyrus[42], and surface area of the lingual gyrus is related to the severity of anxiety and depression[43]. Alzheimer's disease patients with the depressive symptoms showed decreased functional connectivity between the dorsal anterior cingulate cortex and lingual gyrus[44]. Additionally, several studies have demonstrated that functional impairment of the middle temporal gyrus are associated with mood disorders, such as major depression disorder[45] and bipolar disorder[46], indicating that the impairment of lingual gyrus or middle temporal gyrus might related to the emotional dysregulation. However, we didn’t find any correlations between the abnormal fALFF values of theses brain regions and the HAMA or HAMD-24 scores, this maybe related with the relatively small sample size of the current study. Anyway, taken together, these results implicated that the lingual gyrus and middle temporal gyrus were related to the emotions regulation of adult-onset hypothyroidism.
Although the current study yielded promising results, it had some limitations. Firstly, the cross-sectional study design used did not support monitoring of the dynamic evolution process of brain function in hypothyroid patients. Secondly, although our sample sizes are comparable to that of previous neuroimaging studies in this field, a larger sample size, integrated multimodal neuroimaging technology and basic neuropathology research methods are needed to analyze the neuropathophysiological mechanisms in primary hypothyroid patients in future studies. Finally, we did not evaluate the structural changes which may underlie the abnormal intrinsic brain activity in hypothyroid patient.