| Objective: Bipolar disorder(BPD)is a type of mood disorder characterized by either manic or hypomanic episodes and depressive episodes.Clinical features include significant change of the mood and activity levels twice at least,sometimes presented as higher mood swings,full of energy and increased activities,while sometimes as lowing mood,energy loss and decreased activities.According to the Diagnostic and Statistical Manual of Mental Disorders,Fifth edition(DSM-V),bipolar disorder is classified into two subtypes.BPD type I: meets the diagnostic criteria for manic episodes,with episodes of hypomania or major depression occurring before or after the manic episode;BPD type II: meets the diagnostic criteria for current or past episodes of hypomania and current or past episodes of major depression.No symptom is shown during the intervals of the attacks.The characteristics of the seizures is alternating mania and depression,or in a mixed way.The attack symptoms tend to last for a period of time,and the patients' daily life and social functions would be affected.Bipolar disorder is characterized by acute or subacute onset,and some of which can last for only a few days while others can last for more than 10 years.In some patients,the course of disease can be self-limited,and mild episodes with no treatment may be spontaneous remission with time.Although bipolar disorder is self-limiting,the recurrence rate is quite high with inappropriate treatment or without any treatment.In untreated patients,50% of whose symptoms can be remit spontaneously in the first year after the first onset.While less than a third of the rest could get remission in the later time.Long-term recurrent damage can lead to personality changes and impaired social functions.Research data suggested that in addition to genetic factors,nerve and biochemical factors and psychosocial factors,neuroimaging changes including brain structure and function can impact on the occurrence of the disease.In recent years,increasing scholars have devoted themselves to the neuroimaging studies of bipolar disorder and made some progress.However,the etiology and pathogenesis of the disease are still unknown.Based on the research evidence of imaging,deep brain stimulation and histopathology,some brain structures including prefrontal cortex,limbic system,thalamus and visual cortex,may play an important role of the pathophysiological mechanism of bipolar disorder.Structural imaging technique can reflect the biological physical properties of brain tissue.Researchers used to analyze the difference in brain structure between groups based on voxel-based morphometry method to explore the morphological and pathological changes of the bipolar disorder after performing high resolution T1 WI three-dimensional scanning.Despite of various research results of bipolar disorder,a consistent conclusion of the studies suggested that: more attention should be paid to the brain structure abnormalities in specific brain regions,rather than the whole brain structural abnormalities.In recent years,a number of studies have shown that the structural abnormalities of some specific brain regions are involved in the pathophysiological mechanism of bipolar disorder,which includes the prefrontal cortex,limbic system,thalamus and temporal lobe.Resting-state functional magnetic resonance imaging is a functional MR technique based on brain network under the resting state.It can reflect the brain spontaneous activity in the resting state and it has been widely used in the study of brain mechanism of various mental disorders because of its relatively simple operation.Additionally,it can eliminate the difference between individual subjects when performing the task and minimize the external stimuli.In recent years,many scholars have used resting-state functional magnetic resonance technology to study the pathophysiological mechanism of bipolar disorder in order to find out the relevant brain regions of dysfunction in patients with bipolar disorder,so as to explain its pathogenesis and clinical symptoms.Previous results of resting-state functional magnetic resonance studies suggested that: more attention should be paid to the brain structure abnormalities in specific brain regions.In various resting-state functional magnetic resonance imaging methods,regional homogeneity(Re Ho)is defined as a local measure for quantifying functional synchronizations between neighboring vertices from the perspective of functional integration.Abnormal Re Ho suggests that there are changes in spontaneous neuronal activity at the local level,which may be involved in the pathogenesis of disease.Previous studies on Re Ho using f MRI in patients with bipolar disorder were limited.Despite of various research results of bipolar disorder,a consistent conclusion of the studies suggested that patients with bipolar disorder have extensive abnormal baseline activity,i.e.functional abnormalities.In recent years,a number of studies have shown that the functional abnormalities of some specific brain regions are involved in the pathophysiological mechanism of bipolar disorder,which includes the prefrontal cortex,limbic system and temporal lobe.Despite of some achievements in the previous studies,there are still many issues to be explored.Specifically,most of the studies focus on prefrontal-limbic system,which overlap with abnormal brain regions of schizophrenia,unipolar disorder or other mental diseases.Additionally,previous studies only focused on the brain functional analysis,but we speculated there should be some kind of relationship between brain structure and function.It becomes necessary for us to explore the relationship between brain structure and function at the same time in order to improve the understanding of the pathophysiological mechanism of bipolar disorder and the developing new treatment for bipolar disorder.We look forward to exploring new abnormal brain regions in patients with bipolar disorder to further explore the pathophysiological mechanisms using new research methods.The objective of the present study is to uncover the abnormal locations of the brain in bipolar patients with abnormal structure and local homogeneity of neuron activity based on the brain anatomy and function.We expect to provide direct evidence of the close relationship between brain morphological anatomy and brain function abnormalities in patients with bipolar disorder.Methods: 71 patients with bipolar disorder was selected from the psychiatric outpatient in the First Hospital of China Medical University and Mental Health Center of Shenyang as bipolar disorder group(BPD group): 49 subjects with BPD type I,22 subjects with BPD type II.All participants were between ages 13 and 46.The course of the disease was less than 2 years,and no antipsychotic medication was given in the past 3 months.All patients were currently experiencing a clinically stable mood status for the MRI scan.The BPD diagnosis for adult patients was individually determined by two professional psychiatrists with the use of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders,fourth edition(DSM-IV)criteria.Adolescent patients were diagnosed via the Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime Version(K-SAD-PL).Exclusion criteria for all participants includes(1)severe physical illness and neurological disorders;(2)head trauma with loss of consciousness lasting more than 5 minutes;(3)history of drug and alcohol abuse;(4)any contraindications for MRI.Healthy control(n=113)were recruited from the community of Shenyang,and the age,gender and handedness were matched with BPD group.HC group excluded the(1)DSM-IV axis disease in the primary relatives and(2)met all the exclusion criteria for bipolar disorder.All subjects were assessed by the Young Mania Rating Scale(YMRS)to evaluate the mood state right before scanning.The Ethics Committee of the First Hospital of China Medical University approved this study.After receiving a complete outline of the study,all adult participants,and parents of adolescent participant,provided written informed consent.Each participant was scanned with a GE Signa HDX 3.0 Tesla MR Scanner.Head motion was reduced by applying foam pads.All participants were instructed to lie still with their eyes closed and to let their mind wander during the scan.Each participant was performed(1)T1-weighted images of high resolution were collected in a sagittal plane by use of a Fast Spoiled Gradient Echo(FSPGR)sequence;(2)Functional resting-state images were acquired with the use of a Gradient Echo planar imaging(EPI)sequence.Processing procedure for the structural image data include magnetic field inhomogeneity correction,standardization of organization and spatial segmentation using the software package of voxel-based morphometry8(VBM8)of Statistical Parametric Mapping(SPM8)based on Matrix Laboratory(MATLAB).According to the default parameters of VBM8 tool kit,the image space was standardized to the space of Montreal Neurological Institute(MNI),and then the voxel in the same direction of 1.5mm3 was re-sampled.The volume of gray matter of each subject was adjusted by nonlinear transformation,and the adjusted voxel value was the relative volume of local tissue after brain size correction.Finally,Gaussian smoothing was performed on the image data with a full width at half maximum(FWHM)of 8mm3.Imaging data after the final segmentation,standardization,nonlinear transformation and spatially smoothing are prepared for statistical analysis of voxel-based levels.Processing procedure for the functional image data: For each participant,all image data were preprocessed in the Connectome Computation System(CCS;http://zuolab.psych.ac.cn/ccs.html),which was based on FCP scripts(http://www.nitrc.org/frs/downloadlink.php/2628).The structural image processing steps are as follows:(1)MR image spatial noise removal;(2)intensity correction;(3)brain extraction and tissue segmentation;(4)cutting plane generation;(5)mesh tessellation and deformation;and(6)individual surface normalization.The functional image processing steps consist of:(1)time series despiking;(2)slice timing;(3)volume aligning;(4)4D global mean imaging intensity normalization;(5)head motion and noise elimination;(6)multiple linear regression;(7)temporal filtering;and(8)aligning spatial correspondences between individual structural and functional images by use of a boundary-based registration(BBR)algorithm.Following the preprocessing steps to exclude the subjects from the subsequent analysis with low-quality multimodal imaging datasets,CCS pipeline provides a quality control procedure(QCP;http://zuolab.psych.ac.cn/ccs/QC.html).The QCP included image screenshots for visual inspection of:(1)skull stripping or brain extraction;(2)segmentation of brain tissue;(3)head motion blurring during rf MRI;(4)reconstruction of pial and white surfaces;(5)functional image registration based on BBR and some quality metrics.All the participants passed the QCP for subsequent analysis.To calculate2 d Re Ho for a given vertex on the surface grid of interest(fsaverage5),surface-based2 d Re Ho metrics were applied to characterize the local short-range functional homogeneity on the cortical surface.This procedure was repeated for each vertex in the global brain surface to form a vertex-wise 2d Re Ho map.Spatial smoothing steps were followed for all the participants,with a Gaussian kernel with 10mm3 full width at half maximum on fsaverages5.Statistical analysis for the structural image data: SPSS 20.0 was used to compare differences between groups.A chi-square test was used for gender ratio comparison between the BPD and HC groups.Unpaired two-sample t-tests were performed to examine the differences in age and neuropsychological test comparisons between the two groups.The level of two-tailed statistical significance was set at p<0.05 for the test.SPM8 were used for t-test analysis of preprocessed data following the preprocessing steps,and the brain region with abnormal gray matter volume was obtained based on Talairach-coordinates.The level of statistical significance was set at p<0.001 for the test.Statistical analysis for the functional image data: Voxelwise one-way ANCOVA tests(covariates: age,gender,mc BBR,and rms FD)were used for analyses of 2d Re Ho differences between the BPD and HC groups.To correct for multiple comparisons,we employed a cluster-level correction algorithm.Specifically,this algorithm used a threshold of the uncorrected p < 0.001 to format the clusters,which were further cleaned by a family-wise error(FWE)correction of P < 0.05.The Pearson and Spearman correlation coefficients between each vertex on the surface and age were calculated.For this analysis,we again employed a cluster-level FEW correction of P < 0.05 for multiple comparisons.Results: 1.Based on the voxel-based morphological analysis method,the volume of gray matter in the brain between the patients with bipolar disorder and the healthy controls was quantitatively analyzed.The results showed that there was a significant difference in the volume of gray matter between the patients with BPD and HC group.Surface-based regional homogeneity of patients with BPD was significantly lower than that of HC.Compared with HC group,the volume of grey matter in the left ventral visual cortex(left inferotemporal cortex)and right occipital cortex(P<0.001*)was reduced in BPD group.The results showed no significant increase of the volume of gray matter in patients with BPD compared with HC.2.By using resting-state functional magnetic resonance imaging,based on the methods of surface-based regional homogeneity,surface-based regional homogeneity in patients with BPD and HC was analyzed.The results showed that there was significant difference in the two-dimensional regional homogeneity between the two groups both at the global level and cluster level.The regional homogeneity of gray matter in patients with BPD was significantly lower than that in HC.At global level,the 2d Re Ho value of BPD group was significantly reduced compared with the HC group(P=0.045*).At cluster level,the 2d Re Ho value of the left ventral visual cortex(left occipital lobe)in BPD group was significantly lower than that in HC group(P<0.001*).The results showed there was no significant increase of2 d Re Ho of the gray matter in patients with BPD compared with HC.3.Both in BPD and HC group,the correlation analysis of age and the 2d Re Ho value of all participants showed that there was a significant correlation between age and 2d Re Ho values in both groups at the global level.The surface-based 2d Re Ho value across the cortical surface was significantly correlated with age negatively both in the BPD and HC group at the global level(BPD:r=-0.363,p=0.002*;HC:r=-0.232,p=0.013*).Conclusion: There were structural abnormalities in the left ventral visual cortex(left temporal lobe)and right occipital cortex in patients with bipolar disorder.BPD group had an abnormal decreased functional regional homogeneity in the whole cerebral cortex;Additionally,the BPD group had a significant reduction in the brain functional regional homogeneity in the left ventral visual cortex(left occipital lobe).Brain functional regional homogeneity was significantly decreased with age during brain development.Based on the conclusion of the above,the present study indicated that the ventral visual cortex is likely to play an important role in the pathophysiological mechanism of bipolar disorder. |
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