Exploring The Brain Functional And Structural Changes In Patients With Chronic Pontine Infarction By Using Multimodal Magnetic Resonance Imaging

Pontine infarction accounts for about 7%of all patients with ischemic stroke and is the most common type of posterior circulation infarction.Due to the patients with various clinical manifestations and high incidence of neurological impairment in the acute stage,some patients in the chronic phase showed worse prognosis with motor and cognitive impairments.Previous studies have indicated that the recovery of neurological function in the chronic phase was correlated with brain tissue injury and reorganization after stroke.In addition,the injury and reorganization of brain function and structure not only occurred in the brain tissue around the infarction,but also caused abnormalities in the brain regions distant from the lesion.With the development of neuroimaging technology,especially the application of magnetic resonance imaging(MRI),it is possible to explore the pathophysiological mechanisms related to neuropsychiatric diseases by non-invasive,precise and multiple perspectives research.Resting state functional magnetic resonance imaging(rs-fMRI)can explore the changes in neurological activity of brain tissue in the resting state.Three-dimensional pseudo-continuous arterial spin labeling(3D-pc ASL)can non-invasive qualitative and quantitative analysis of brain perfusion using hydrogen protons in arterial blood as endogenous tracers.High resolution three-dimensional T1-weighted structure MRI imaging has high tissue resolution and could be segmented into different components to analyze the anatomical structure of brain tissue.Diffusion kurtosis imaging can describe the diffusion characteristics of water molecules in brain tissue by calculating multiple diffusion and kurtosis indicators,and then indirectly reflect the integrity and complexity of the white matter microstructure in brain tissue.Previous studies were often based on single-modal index to explore abnormal changes of brain tissue in patients with chronic pontine infarction.However,brain structure is the basis of function,and brain function is the embodiment of structure.The interaction and mutual influence between function and structure lead to injury and recovery of neurobehavioral after infarction.It is necessary to combine multiple modalities and multiple indicators to explore the mechanism of neurological impairment and recovery in patients with chronic pontine infarction from different pathophysiological aspects.Therefore,in this study,the functional and structural changes in patients with unilateral chronic pontine infarction were analyzed by using rs-fMRI,3D-pc ASL,3D-T1 and DKI multimodal MRI techniques,and the relationships between the changes of brain function and structure,and the impairment of neurological scores were further explored to provide the neuroimaging evidence for disease prognosis and specific treatment.Part 1 An MRI study of the changes of brain function and neurovascular coupling in patients with chronic pontine infarctionBackground and PurposeThe secondary functional damage and reorganization of remote-infarction brain regions may be an important neural mechanism for the damage and recovery of neurological function in patients with pontine infarction.Rs-fMRI can reflect the neurological activity and functional connectivity of brain regions by acquiring and analyzing the changes of blood oxygen level-dependent signals in the brain in the resting and non-task state.Amplitude of low frequency fluctuation(ALFF)and regional homogeneity(ReHo)are common analysis methods based on functional differentiation,while the brain functional connectivity strength(FCS)is a common indicator to analyze the changes of brain function from the functional integration.In addition,there are specific connections and interactions between micro vessels and neurons called neurovascular coupling,and the impairments of neurovascular coupling also play an important role in the development and prognosis of cerebral infarction.Therefore,the purpose of this part is to explore the damage and reorganization of brain function in chronic pontine infarction by analyzing the changes of ALFF,ReHo and FCS based on rs-fMRI.In addition,based on the CBF values calculated by 3D-pc ASL and the FCS values calculated by rs-fMRI,the CBF and FCS were further coupled to analyze the changes of neurovascular coupling in patients with chronic pontine infarction.Materials and MethodsIn this part,a total of 60 patients with chronic pontine infarction(PI)were recruited,and the patients were divided into the left pontine infarction(LPI)group with 33 patients and the right pontine infarction(RPI)group with 27 patients according to the infarction side.At the same time,30 healthy subjects matched with LPI and RPI groups in age,sex and the years of education were included as normal control(NC)group.Because the head movement exceeded the threshold,7 patients in the LPI group and 4 patients in the RPI group were excluded.Finally,26 patients in the LPI group and 23 patients in the RPI group were included.Rs-fMRI images,3D-T1 and 3D-pcASL images were acquired for all subjects with a GE 3.0 T Discovery MR 750 magnetic resonance scanner.All subjects were assessed for motor function using the Fugl-Meyer Test.In addition,rey auditory verbal learning test,digital working memory 1-back and spatial working memory 1-back test were used to assess cognitive function after MRI scanning.The preprocessing and analysis steps were as follows:1.First,the resting-state BOLD-fMRI images were preprocessed based on DPARSF toolbox in the MATLAB software package,and the ALFF and ReHo maps at the whole brain level were calculated.2.Based on the preprocessed BOLD-fMRI images,the whole brain FCS maps were calculated,then the global-FCS maps were further divided into the short-and long-FCS maps with an anatomical distance of 75 mm as the segmentation value.3.The ALFF,ReHo and different range-FCS maps were further converted into z-value maps by subtracting the mean and dividing by the standard deviation of the global brain and then were spatially smoothed using a Gaussian kernel of 6-mm full width at half-maximum(FWHM).4.The 3D-pc ASL images were preprocessed and standardized based on the SPM12 toolbox in the MATLAB software package to get zCBF maps.5.For a subject,the correlation coefficient between the preprocessed zCBF and zFCS with different distances were calculated as the neurovascular coupling(CBF-FCS coupling)at the whole-brain level to the subject.The CBF/FCS ratio were computed based on the original CBF and FCS maps without z-transformation to evaluate the amount of cerebral blood flow consumption per unit of connectivity strength.6.The differences of functional parameters in the LPI group and RPI group compared with the NC group were analyzed.Two-sample t-test was used to compared the zALFF,zReHo,zFCS,zCBF,and zCBF/FCS ratio between the unilateral PI groups and the NC group,respectively.The age,sex,years of education and the mean FD as covariates.The results were further corrected using the Gaussian Random Field(GRF)method with cluster level P<0.05 and voxel level P<0.001.Differences in CBF-FCS coupling values between the unilateral PI groups and the NC group were compared using a two-sample t-test.7.The functional parameters of abnormal brain regions with significant differences between PI and NC groups were extracted and the correlations between abnormal function parameters and behavioral scores were calculated.The significance threshold was set at P<0.05.Results1.The results of ALFF analysis:compared with NC group,there was no significant difference between LPI and NC groups.In the RPI group,significantly increased ALFF values were found in the left inferior temporal gyrus,left orbital part of superior frontal gyrus,right middle occipital gyrus and left caudate nucleus(GRF correction,voxel level P<0.001 and cluster level P<0.05).2.The results of ReHo analysis:compared with NC group,there was no significant difference between LPI and NC groups.The patients in the RPI group showed significantly increased ReHo values in the left orbital part of superior frontal gyrus and decreased ReHo values in the left middle temporal gyrus(GRF correction,voxel level P<0.001 and cluster level P<0.05).3.The results of FCS analysis:compared with NC group,the LPI group showed significantly increased FCS values in the left inferior temporal gyrus and decreased FCS values in the right angular gyrus.The RPI group showed significantly increased FCS in the left middle and inferior temporal gyrus.Distance-dependent results demonstrated that the patients with PI had more abnormal brain regions with abnormal changes in the long FCS and less abnormal brain regions in the short FCS(GRF correction,voxel level P<0.001 and cluster level P<0.05).4.The results of CBF analysis:compared with NC group,the LPI group showed significantly decreased CBF in the left superior temporal gyrus and the RPI group showed decreased CBF in the left cerebellar CrusI(GRF correction,voxel level P<0.001 and cluster level P<0.05).5.The results of neurovascular coupling analysis:compared with NC group,the results of global-CBF-FCS coupling showed significant decrease in LPI and RPI groups(P<0.05).Distance-dependent analysis demonstrate that significantly decreased long-CBF-FCS coupling in LPI and RPI groups,and only the patients in RPI group showed significant decreased short-CBF-FCS coupling(P<0.05).The analysis of global CBF/FCS ratio showed significantly decreased global CBF/FCS ratio in the left middle and inferior temporal gyrus and the left orbital part of superior frontal gyrus in the RPI group(GRF correction,voxel level P<0.001 and cluster level P<0.05).Distance-dependent analysis demonstrated that PI had more brain regions with abnormal changes of the long CBF/FCS ratio and fewer brain regions with significant changes of short CBF/FCS ratio.6.Behavioral correlation analysis showed that the changes of ALFF value,FCS value and CBF/FCS ratio in abnormal brain regions were significantly correlated with the scores of motor and cognitive functions to patients with chronic PI(P<0.05).Conclusions1.The analyses of multiple functional indicators showed significant abnormalities in the remote-infarction brain regions in patients with chronic PI.That is,the distant brain areas showed secondary damage and reorganization.2.The patients with chronic PI have obvious damage to neurovascular coupling,and the damage of long-distance neurovascular coupling is more obvious than shortdistance coupling.3.The functional parameters and neurovascular coupling values of abnormal brain regions were significantly correlated with the motor and cognitive function scores of PI groups,which indicated that the secondary injury and reorganization after stroke may be the important neural mechanism for the injury and recovery of the patient’s neurological function.4.The left middle and inferior temporal gyrus and the left orbital part of superior frontal gyrus of patients with RPI showed significant changes of the neurological function parameters and neurovascular coupling,which were correlated with the cognitive scores.It provided the possible target regions to treat impaired cognitive function.Part 2 An MRI study of structural impairment and abnormal structural covariance network in chronic pontine infarctionBackground and PurposeImpaired motor and cognitive function are common sequelae in patients with chronic PI.Previous studies have confirmed that there are not only impairment and reorganization of brain function but also abnormal brain structure in distant brain regions after infarction.Abnormal changes of gray matter structure may be the anatomical basis of the changes of brain function after PI.The purpose of this section is to explore the changes of gray matter volume(GMV)and the secondary gray matter covariation network in patients with chronic PI.Materials and MethodsIn this part,a total of 60 patients with chronic PI were recruited and further divided into the LPI group with 33 patients and the RPI group with 27 patients according to the infarction side.30 healthy subjects matched with LPI and RPI groups in age,sex and the years of education were included as the NC group.3D-T1 were acquired for all subjects with a GE 3.0 T Discovery MR 750 magnetic resonance scanner.All subjects were assessed for motor and cognitive function after MRI scanning.The preprocessing and analysis steps were as follows:1.The 3D-T1 images were preprocessed using the CAT 12 toolbox in the SPM12.After preprocessing,the images were smoothed using the 8mm Gaussian smoothing kernel.2.The differences of GMV between the unilateral PI groups and the NC group were separately analyzed using a two-sample t-test,with age,sex,education,and total brain volume as covariates.The results were further corrected using GRF method with cluster level P<0.05 and voxel level P<0.001.3.The brain regions with significantly altered GMV were extracted as seed regions of interest in the LPI group and RPI group.Then,the GMV of seed regions were obtained as regression variables and brought into the multiple linear regression equation with family wise error correction(P<0.05).Finally,the brain regions covariant with the seed regions were obtained.4.The structural covariance network was constructed that the covariant brain regions were extracted as nodes and the correlation coefficient were calculated as edges.Then,the differences of covariance network properties between the PI and NC groups were further analyzed.5.The correlations between the abnormal changes of GMV,and the scores of motor and cognitive functions in the PI group was calculated.P<0.05 was considered as the significant correlation.Results1.Compared with the NC group,the patients in the LPI group showed significantly decreased GMV in the left cerebellar posterior lobe(CrusⅠ,CrusⅡ,Ⅶb,Ⅷ)and the right cerebellar posterior lobe(CrusⅡ,Ⅶb,Ⅷ).While the patients in the RPI group showed significantly decreased GMV in the left cerebellar anterior and posterior lobe(CrusⅠ,CrusⅡ,Ⅳ_Ⅴ,Ⅵ,Ⅶb,Ⅷ)and the right cerebellar posterior lobe(CrusⅠ,CrusⅡ,Ⅵ,Ⅶb,Ⅷ).2.The correlation analyses between the abnormal changes of GMV and clinical symptoms showed that the significantly atrophied GMV was significantly correlated with impaired motor and cognitive function in patients with PI.3.The analyses of structural covariance showed the covariant brain regions were located in bilateral cerebral hemispheres in LPI and NC groups.While compared with the NC group,the RPI group showed significantly increased the number of covariant brain regions and located in bilateral cerebral and cerebellar cortex.In addition,the number of connections of the structural covariant networks in the RPI group were significant increase.Conclusions1.The patients with chronic PI showed significantly atrophic GMV in the bilateral cerebellar hemispheres and the abnormal GMV was significantly correlated with the behavioral scores.2.The patients in the RPI group showed significantly abnormal covariation patterns with significantly increased the number of covariant brain regions and connections between covariant brain regions.3.Significantly atrophic GMV and the abnormal covariant pattern may be important neural mechanisms of neurobehavioral impairment in patients with chronic PI.Part 3 The changes of white matter microstructure in Patients withChronic Pontine Infarction Based on Diffusion Kurtosis Imaging Background and ObjectiveAs the relay station of the central nervous system,the white matter is the basis for information exchange and communication between the brain gray matter.In the first two parts of this study,we have found that significantly abnormal changes of functional indicators and gray matter volume in the whole brain regions after PI,while the secondary changes of white matter microstructure are still unclear.Diffusion Kurtosis Imaging(DKI)can quantitatively describe the non-Gaussian diffusion distribution of water molecule,which could accurately describe the changes of white matter microstructure.Therefore,in this study,DTI and DKI models were constructed to explore the abnormality of cerebral white matter microstructure in patients with chronic PI,and the sensitivity of different diffusion models in identifying abnormal white matter fiber tracts was compared.Materials and MethodsThe subjects in this part were the same as those in the second part,including 33 patients in the LPI group and 27 patients in the RPI group.30 healthy subjects matched with LPI and RPI groups in age,sex and the years of education were included as the NC group.DKI and 3D-T1 were collected with a GE 3.0 T Discovery MR 750 magnetic resonance scanner.All subjects were assessed for motor and cognitive function after MRI scanning.The preprocessing and analysis steps were as follows:1.The DKI images were preprocessed and analyzed by using PANDA software.Three b-values(b=0,1000,2000)were used to fit the DKI model and then calculated the diffusion and kurtosis parameters.Two b-values(b=0,1000)were used to fit the DTI model and calculated the DTI-derived diffusion parameters.2.A general linear model was constructed based on the tract-based spatial statistics(TBSS)and nonparametric permutation test with 5000 times permutations to analyze the differences of parameter values between PI and the NC groups with age,sex,and the years of education as covariates.The statistical results were corrected using the threshold-free cluster enhancement(TFCE)correction at the FWE level,and the significance threshold was set to P<0.01.3.Analyzing the sensitivity of different parameters calculated by DTI and DKI model to identify abnormal white matter fibers.4.The diffusion and kurtosis parameters of abnormal white matter microstructure in the PI group were extracted and the correlations with the motor and cognitive function scores of the patients was calculated,and the threshold value of the obvious correlation was set at P<0.05.Results1.DTI and DKI models were constructed,and the TBSS analysis of different DTI-and DKI-derived diffusion and kurtosis parameters showed significantly decreased FA and MK values and increased MD and RD values of the extensive white matter fiber tracts in LPI and RPI groups.2.The sensitivity analysis of DTI-derived and DKI-derived diffusion and kurtosis parameters to identify abnormal white matter fiber tracts in patients with chronic PI showed that the sensitivity of DTI-derived diffusion parameters(FADTI,MDDTI,RDDTI)was 27.3%,40.0%,and 46.0%in the LPI group,respectively.While in the RPI group,the sensitivity of FADTI,MDDTI and RDDTI was 1.7%,0%and 19.7%,respectively.In addition,in the LPI group,the sensitivity of DKI-derived diffusion and kurtosis parameters(FAdDTI,MDDTI,RDDTI and MKDTI)was 34.6%,40.2%,47.9%and 0.58%and the sensitivity of DKI-derived diffusion and kurtosis parameters(FADTI,MDDTI,RDDTI and MKDTI)in the RPI group was 6.9%,0.6%,24.1%and 0.56%,respectively.The sensitivity of DKI-derived diffusion parameters to identify the abnormal white matter microstructure in patients with chronic PI is higher than that of the DTI-derived diffusion parameter value.The kurtosis parameters were more sensitive to detect abnormal white matter fiber tracts with complex fiber arrangement.3.The diffusion and kurtosis parameters of abnormal white matter fiber tracts were significantly correlated with the motor and cognitive scores in PI group(P<0.05).Conclusions1.The patients with chronic PI showed extensive white matter microstructure impairment in supratentorial and infratentorial brain regions,and the diffusion and kurtosis parameters of abnormal white matter fiber tracts were significantly correlated with motor and cognitive function in PI groups.This phenomenon suggested that anterograde and retrograde disruption of white mater microstructure may be the white matter structural basis for neurobehavioral impairment in patients with chronic PI.2.The sensitivity of DKI-derived diffusion parameters to identify the abnormal white matter microstructure in patients with chronic PI was higher than that of the diffusion parameters calculated by the DTI model and the kurtosis parameters were more sensitive to identify the impairment of the complex fiber arrangement.