This study found different short-term and moderate-term effects of TIPS insertion on cirrhotic patients, i.e., both impairment and compensatory mechanism of brain function in peri-TIPS and continuous impairment of brain function in 3 months following TIPS.
Amplitude of low frequency fluctuation (ALFF) developed by Zang et al
is a new index for brain functional analysis, which has been widely used in studies of various mental disorders e.g., schizophrenia 
, attention deficit hyperactivity disorder 
, and Alzheimer's disease 
. Although the exact biological mechanism of ALFF remains unclear to date, many scholars consider that these spontaneous low-frequency fluctuation changes in blood oxygenation level dependent signal are associated with local neuronal activity 
. It should be noted that different fMRI analysis algorithms may reflect different aspects of comprehensive brain functions. Compared with other algorithms such as functional connectivity analysis, ALFF has the advantage of directly reflecting the amplitude or intensity of spontaneous activity, as shown in the present study and several other studies 
In this study, pre-TIPS patients already had widespread aberrant spontaneous brain activities. The results were quite consistent with a recent fMRI study of HE with ALFF analysis 
. It should be noted that many regions with decreased ALFF were located in the default mode network (DMN), including MPFC, ACC and PCu, which is consistent with a recent rs-fMRI study with ALFF in HE patients 
. DMN 
is thought to engage in the maintenance of the baseline brain activities, which are related to cognitions of self-awareness, episodic memory and interactive modulation between the internal mind activities and external tasks. The DMN abnormalities in patients with or without HE have been reported in a few task-driven 
and rs-fMRI studies 
. The present findings of decreased spontaneous brain activity in DMN suggested that pre-TIPS cirrhotic patients already had abnormal brain function.
Following TIPS, 2 of the 3 pre-TIPS MHE patients in our study had episodes of HE in the median 3-month follow-up, this is consistent with one previous report that patients with HE before TIPS had increased risk of post-TIPS HE 
. In addition, patients who underwent the median 8-day follow-up rs-fMRI showed bilaterally changed (either decreased or increased) regional ALFF values, while in the median 3-month follow up observation, patients displayed persistently decreased regional ALFF values. These findings suggested that TIPS insertion may have different short-term and moderate-term effects on cirrhotic patients. In particular, there might co-exist impairment and compensatory mechanisms of brain functions in peri-TIPS and continuous impairment of brain function in 3 months following TIPS. Two recent fMRI studies with ALFF analysis algorithm also reported both decreased and increased regional ALFF values in cirrhotic patients 
. However, in a prospective PET study, Iversen et al
measured cerebral blood flow (CBF) by [15
O]-water PET in 9 cirrhotic patients before and median 11-day post TIPS, but found no significant CBF changes. The discrepancy between ours and the above-mentioned PET study might be due to differences in imaging techniques. Resting-state fMRI using in this study has been used in detecting the slight brain function changes 
, e.g., in the early phase of Alzheimer's disease 
and HE 
ACC in the present study showed increased brain activity in the median 8-day follow-up while decreased brain activity in the median 3-month following TIPS. ACC is a center involved in a form of attention which severs to regular both cognitive and emotional processing 
. Interestingly, attention defect is a fundamental aspect of HE 
, and abnormal ACC function in cirrhotic patients had been reported by a previous PET study 
. The dynamically changed ACC activity may be partially supported by the dynamic changes of blood ammonia in the present study, whose levels showed an increasing trend of median 8 day follow-up < pre-TIPS < median 3-month follow-up. Ammonia plays an important role in the pathogenesis of HE. The ammonia-related cellular alterations are considered to be important for the development of HE 
. Additionally, of 10 patients undergoing the median 8-day follow-up, only one patient who showed minimum increase rate of the ACC activity (<10%) had some episodes of HE in the 3-month follow-up. All other nine patients with larger increase rate (>20%) did not experience HE. If these results are confirmed by further studies with more patients, they may imply that patients with slight increase rate of the ACC activity shortly after TIPS might have propensity to develop into overt HE, suggesting that rs-fMRI might have a potential to predict the development of postsurgical HE.
The current study has some limitations. First, as a preliminary study, our results are limited to a small patient cohort, and the follow-up examinations are only available for some of the patients after TIPS insertion, especially in the median 3-month follow-up the sample size is small, thus, the statistical power for the data analysis in this study is limited, and further studies with more patients in each follow up period are warranted to confirm these findings. Second, not all post-TIPS patients performed all the follow-up test procedures, and the results of longer follow-up MR examinations were not included in this study. Third, it is possible that brain function change may be a consequence of HE, and ideally we need to include a control group of cirrhotic patients who did not undergo TIPS. However, based on the fact that none of cirrhotic patients had overt HE pre-TIPS and during the short-term follow-up, and the brain function of patients with TIPS insertion was already changed compared to pre-TIPS studies, we believe that this altered brain function is primarily due to the TIPS procedure itself. Fourth, the exact biologic mechanism of ALFF we used here remains unclear to date, in addition, the dynamic changes of ALFF values and blood ammonia levels in patients after TIPS treatment in the present study need to be confirmed by further studies.
In conclusion, the present study showed that TIPS insertion altered patients' brain function, which might have different short-and moderate-term effects. Resting- state fMRI with ALFF analysis might potentially supply a novel way to understand the neuro-pathophysiological mechanism of TIPS's effects on brain function.