Analysis of Parkinson’s disease patients with gastrointestinal symptoms using structural and functional magnetic resonance imaging

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This study aimed to investigate the neuroimaging mechanisms underlying gastrointestinal symptoms associated with Parkinson’s disease using functional connectivity and voxel-based morphometry. Methods : The study included 50 healthy controls, 71 Parkinson’s disease patients without gastrointestinal symptoms and 84 patients with gastrointestinal symptoms. Differences in gray matter volume among the three groups were assessed. Given a significant decrease in gray matter volume in the right cerebellar hemisphere, it was selected as the seed region for functional connectivity analysis. Results: The Parkinson’s disease patients with gastrointestinal symptoms showed significant differences in disease duration, levodopa equivalents daily dose, Hoehn and Yahr stage, unified Parkinson's disease rating scale part Ⅲ, Hamilton anxiety scale, Scales for Outcomes in Parkinson’s disease-Autonomic, non-motor symptom scale, Montreal cognitive assessment, and orthostatic hypotension compared to the patients without gastrointestinal symptoms (p<0.05). Lower gray matter volume was observed in the group with gastrointestinal symptoms, particularly in the bilateral cerebellum hemisphere and the left superior temporal gyrus. Compared to the group without gastrointestinal symptoms, functional connectivity between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus and left middle temporal lobe was significantly increased. Conclusions: Parkinson’s disease patients with gastrointestinal symptoms present with a prolonged disease course and increased severity of both motor and non-motor symptoms. The gastrointestinal symptoms in Parkinson’s disease patients may be associated with structural and functional brain alterations. Parkinson’s disease gastrointestinal symptoms voxel-based morphometry functional connectivity Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Research demonstrating the significant role of non-motor symptoms in Parkinson’s disease (PD) is increasing. Common non-motor symptoms in PD include gastrointestinal (GI) problems such as dysphagia, gastroparesis, and constipation [ 1 ] . A small percentage of PD patients may experience GI symptoms years before physical symptoms manifest, which can worsen over time, significantly impacting their quality of life [ 2 ] . The most common GI symptom in PD patients is constipation, characterized by decreased frequency of stools, difficulty defecating, and passage of dry, hard stools [ 3 ] . Constipation has been identified as an early indicator of PD. PD is 2–5 times more likely to occur in individuals with chronic constipation than those without [ 4 ] . Gastroparesis, characterized by a feeling of fullness and delayed stomach emptying after eating, can lead to malnutrition and weight loss [ 5 ] . Research has shown a correlation between the degree of dyskinesia and the severity of gastroparesis in PD patients [ 6 ] . Although the relationship between dysphagia and the clinical course of PD is not well-established, dysphagia is significantly associated with a higher risk of death and complications such as aspiration pneumonia, weight loss, dehydration, and malnutrition, which is believed to contribute to 70% of PD-related deaths [ 7 ] . Furthermore, studies have shown a bidirectional relationship between mental health in PD patients and gut health, with significant GI symptoms predicting severe anxiety-depression, while negative emotions may exacerbate GI dysfunction [ 8 ] . Another study suggests that GI problems in PD patients may indicate the onset of cognitive decline [ 9 ] . In recent years, more academics have recognized the gut as the "second brain" of mankind [ 10 ] . The enteric nervous system (ENS) and the central nervous system (CNS) communicate bidirectionally along the gut-brain axis through various immunological, inflammatory, and endocrine pathways [ 11 ] . Braak et al. (2003) reported that α-synuclein (α-syn) is initially deposited in the ENS and the dorsal nucleus of the vagal motor nucleus before appearing in the CNS, proposing six pathological phases in the development of PD [ 12 ] . These pathological changes primarily affect the structures of the dorsal nucleus of the medulla oblongata and the anterior olfactory bulb before progressing to the pons, midbrain, and neocortex, rather than beginning in the substantia nigra of the midbrain [ 13 ] . With advancements in neuroimaging techniques, magnetic resonance imaging (MRI) can now be used to investigate the pathophysiology of PD. Changes in structural and functional MRI of PD patients with GI symptoms warrant investigation, as there are limited and inconsistent imaging studies on GI symptoms in PD. GI complaints are among the most prevalent autonomic symptoms, which include GI symptoms, incontinence, hypotension, tachycardia or bradycardia, and cold and hot paresthesia. The Scales for Outcomes in Parkinson’s disease-Autonomic (SCOP-AUT) can help medical practitioners in understanding the autonomic dysfunction experienced by PD patients. Higher SCOP-AUT scores indicate more severe symptomatology, with items 5–7 assessing GI symptoms such as constipation, difficulty defecating, and fecal incontinence [ 14 ] . This study was aimed to improve our understanding of the pathophysiology by investigating the connection between PD with GI symptoms and alterations in brain structure and function. 2 Methods 2.1. Participants The Second Department of Neurology at the First Affiliated Hospital of Kunming Medical University recruited 155 PD patients and 50 healthy controls (HCs)between June 2022 and December 2023. Inclusion criteria for all participants were as follows: (1) clinically diagnosed with PD according to the Movement Disorder Society Clinical Diagnostic Criteria [15]; (2) no family history of PD in first-degree relatives; (3) no history of neurological disorders such as stroke, infection, poisoning, metabolic disorders, or trauma, or other serious illnesses; (4) no history of active epilepsy or brain surgery. Exclusion criteria included: (1) GI disorders or GI symptoms caused by medication; (2) past history of mental illness, currently being treated or having been treated with anti-anxiety and depression medication in the last six months; (3) contraindications for MRI scans; (4) significant brain atrophy or multiple cerebral white matter lesions observed on imaging; (5) left-handedness. PD patients were categorized into PD with GI symptoms group (PG-GI) and PD without GI symptoms group (PG-NGI) based on scores of items 5–7 of SCOP-AUT. HCs were individuals who were essentially matched to the sex and age of the PD patients collected during the same period. 2.2. Clinical Assessment General clinical and demographic data of all participants were collected, including gender, age, disease duration, age at onset, Hamilton Anxiety Scale (HAMA) score, Levodopa Equivalents Daily Dose (LEDD), Unified Parkinson's Disease Rating Scale Part Ⅲ(UPDRSⅢ) score, Hoehn and Yahr (H-Y) stage, Non-Motor Symptom Scale (NMSS) score, SCOP-AUT score, Montreal Cognitive Assessment (MOCA) score, Hamilton Depression Scale (HAMD) score, and Orthostatic Hypotension (OH). 2.3. Image Acquisition All subjects underwent imaging examinations at the First Affiliated Hospital of Kunming Medical University using a 3.0T magnetic resonance scanner. Foam padding was used to minimize head movement during data acquisition, and participants were instructed to remain awake and keep their eyes closed. PD patients were allowed to take levodopa before scanning if necessary to mitigate severe involuntary shaking. The scanning parameters for three-dimensional T1-weighted imaging (3D-T1WI) were as follows: slice thickness: 1 mm, voxel size: 1×1×1mm, repetition time (TR): 8.6 ms, echo time (TE): 3.2ms, inversion time: 450ms, flip angle: 12°, scanning field of view: 256mm, matrix: 256×256. The scanning parameters for resting-state functional MRI (RS-fMRI) were as follows: TR = 2000ms, TE = 35ms, slice thickness = 4.0mm, scanning matrix = 64×64, field of view = 240mm×240mm, voxel size = 3×3×3mm, time points = 240. 2.4. Image Processing 2.4.1. T1WI Image The 3D-T1WI images were processed using the SPM8 and VBM8 toolkits ( http://dbm.neuro.unijena.de/vbm ). Using segmentation techniques, the T1 images were matched to a standard template and then classified into three categories: gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Subsequently, the images were co-registered to the Montreal Neurological Institute (MNI) template and smoothed using a Gaussian kernel with a half-width (FWHM) of 8 mm. 2.4.2. Functional MRI (RS-fMRI) Image Data preprocessing was conducted using the DPABI software (version 4.5, http://rfmri.org/dpabi ) [ 16 ] . The pre-processing process included: (1) format conversion; (2) removal of the first 10 time points; (3) slice timing correction; (4) exclusion of participants with head motion displacement exceeding 2 mm or rotation exceeding 2°; (5) spatial standardization to the MNI standard space with voxel sizes of 3 mm × 3 mm × 3 mm; (6) regression of nuisance signals, including Friston 24 head motion parameters; (7) spatial smoothing using a Gaussian kernel (FWHM = 8 mm); (8) temporal band-pass filtering (0.01–0.08 Hz). Structural brain regions obtained were defined as regions of interest (ROIs). A seed-based functional connectivity (FC) analysis was conducted, centering at the coordinates of the peak value with an 8 mm radius. Correlation analysis between the average time series of each seed point and the time series of each voxel in the brain was performed. Functional connection maps for each seed point were generated, and a comprehensive Z-value map of the whole brain was created for each subject using Fisher-to-z transformation. 3 Statistical Analyses Demographic characteristics were analyzed using SPSS version 23.0 software. Normality of demographic data and clinical scales was tested. For normally distributed data, analysis of variance (ANOVA) was used for comparisons among all three groups, and independent samples t-test was used for comparisons between two groups, presented as mean ± standard deviation. Abnormally distributed data were reported as median (interquartile range), and non-parametric tests were applied. The chi-square test was used for count data, expressed as percentages. Differences with P < 0.05 were considered statistically significant. Imaging data were analyzed using a two-sample t-test in SPM12 software, with age, gender, and disease duration as covariates. Brain regions with statistical significance were identified after applying false discovery rate (FDR) correction (P < 0.05) and Gaussian random field (GRF) correction (P voxel < 0.005, P cluster < 0.05). 4 Results 4.1. Demographic Data Comparisons Compared to the PD-NGI group, PD-GI group showed the significant different age, disease duration, levodopa equivalents daily dose (LEDD), Hoehn-Yahr (H-Y) stage, unified Parkinson’s disease rating scale part Ⅲ(UPDRSⅢ) score, NMSS score, MOCA score, HAMD score, HAMA score, SCOP-AUT score, and OH incidence (p < 0.05) (Table 1 ). Table 1 Demographic and clinical characteristics Characteristic PD-GI PD-NGI HC P Participants 84 71 50 Gender(male) 48 (57.1%) 35 (49.3%) 20 (40.0%) 0.155 Age(years) 68 (62.25,74) 61 (54,71) 61.5(47,70) 0.000** Age of onset 63.335(53,70) 59 (51,69) NA 0.011* Disease duration 3 (1,6.75) 2 (1,3) NA 0.001** LEDD (mg/day) 375 (300,596.86) 337.5 (150,450) NA 0.008** H&Y stage 2(1,3) 1(1,2) NA 0.001** UPDRSIII 28 (19,43.75) 20 (14,35) NA 0.014* NMSS 49.5 (28,88.75) 27 (12,41) NA 0.000** MOCA 22 (28.75,26) 24 (19,27) NA 0.043* HAMD 10.5 (4,10.5) 5 (2,9) NA 0.000** HAMA 9.5 (3.25,22) 2 (0,12) NA 0.000** SCOP-AUT 17 (11,25) 6 (3,11) NA 0.000** OH (yes) 16 (19.0%) 5 (7.0%) NA 0.030* *P < 0.05, **P < 0.01. LEDD: Levodopa equivalents daily dose; UPDRSⅢ: unified Parkinson’s disease rating scale part Ⅲ; NMSS: non-motor symptom scale; MOCA: Montreal cognitive assessment; HAMD: Hamilton depression scale; HAMA: Hamilton anxiety scale; SCOP-AUT: scales for outcomes in Parkinson’s disease-autonomic; OH: orthostatic hypotension. 4.2. GMV Differences in Regions In the voxel-based morphometry (VBM) analysis, compared to the HC group, the PD-GI group demonstrated significantly decreased GMV in the right superior parietal gyrus, right inferior parietal gyrus and left caudate nucleus. Conversely, increased GMV was observed in the right middle temporal gyrus and left middle frontal gyrus. Additionally, decreased GMV was observed in the left cerebellar hemisphere (Cerebellum_9_L) in the PD-NGI group compared to the HC group. Furthermore, when compared to the PD-NGI group, the PD-GI group exhibited significantly decreased GMV in the bilateral hemispheres of the cerebellum (Cerebellum_Crus2_R, Cerebellum_6_L) and the left superior temporal gyrus (Table 2 , Fig. 1 ). Table 2 GMV differences in HCs group, PD-GI group, and PD-NGI group Brain region L/R Cluster size MNI coordinates T value X Y Z PD-GIHC Middle temporal gyrus R 360 60 -19.5 -15 4.4742 Middle frontal gyrus L 348 -49.5 39 16.5 3.8909 PD-NG<HC Cerebellum_9 L 348 -10.5 -39 -46.5 -3.8428 PD-GI<PD-NGI Cerebellum_Crus2 R 1592 34.5 -73.5 -49.5 -4.1577 Cerebellum_6 L 91 -24 -54 -33 -3.7506 Superior temporal gyrus L 422 -48 -4.5 1.5 -4.3756 MNI coordinates: Coordinates of primary peak locations in the Montreal Neurological Institute space; T values, GMV differences among two groups based on the two-sample t-test. 4.4. Regional FC Differences In the FC analysis, ROIs were defined using the right cerebellar hemisphere (Cerebelum_Crus2_R). Results indicated weaker FC between the right cerebellar hemisphere and the left middle frontal gyrus in the PD-GI group compared to the HC group. Conversely, the PD-NGI group exhibited increased connectivity between the right cerebellar hemisphere and the left paracentral lobule compared to the HC group. Furthermore, the PD-GI group demonstrated significantly increased FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, compared to the PD-NGI group (Table 4 , Fig. 3 ). Table 3 Regional FC differences in PD-GI group, PD-NGI group, and HCs group ROI MNI coordinates Brain region L/R Cluster size MNI coordinates T value X, Y, Z X Y Z PD-GIHC paracentral lobule L 99 -27 -30 63 3.8643 PD-GI>PD-NGI medial and lateral cingulate gyrus R 36 9 -18 33 3.9236 middle temporal gyrus L 35 -48 -51 12 3.9236 MNI coordinates: Coordinates of primary peak locations in the Montreal Neurological Institute space; T values, GMV differences among two groups based on the two-sample t-test; ROI, region of interest. The figure illustrates differences in FC among three groups, including cross-sectional and sagittal brain views. Weakened FC is depicted in blue, while enhanced FC values are represented in red. The lines connecting blue bars indicate T-values, with positive T-values shown in red and negative T-values in blue. (A): PD-GI group vs HC group; (B): PD-NGI group vs HC group; (C) & (D): PD-GI group vs PD-NGI group; (E): Weaker FC between Cerebelum_Crus2_R and the left middle frontal gyrus in the PD-GI group compared to the HC group; (F): Increased connectivity of Cerebelum_Crus2_R with the left paracentral lobule in the PD-NGI group compared with the HC group; (G): The PD-GI group exhibited significantly increased FC between Cerebelum_Crus2_R and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, compared with the PD-NGI group. FC: functional connectivity; HC: healthy control; PD-GI: PD patients with GI symptoms; PD-NGI: PD patients without GI symptoms. 4.5. Correlation between clinical data and different brain regions In the structural MRI analysis, GMV in the right cerebellar hemisphere was negatively correlated with age and SCOP-AUT; besides, GMV in the left cerebellar hemisphere also showed negative correlations with age, disease duration, and SCOP-AUT. Additionally, negative correlations were observed between the left superior temporal gyrus and age, disease duration, LEDD, H-Y stage, UPDRSⅢ, and SCOP-AUT. Furthermore, in the functional MRI analysis, FC values between the right cerebellar hemisphere and the right median cingulate and paracingulate gyrus were positively correlated with LEDD and SCOP-AUT (Fig. 4 ). The colored band on the right indicates the correlation coefficient, with blue representing a positive correlation and red representing a negative correlation. CRBLCris2.R: Cerebellum_Crus2; CRBL6.L: Cerebellum_6; STG.L :the left superior temporal gyrus; DCG.R :the right median cingulate and paracingulate gyrus; MTG.L :the left Middle temporal gyrus. 4.6 Independent risk factors and logistic regression model of GI symptoms Binary logistic regression analysis and receiver operating characteristic (ROC) curve were employed to assess independent risk factors in PD patients with GI symptoms. Results suggest that disease duration, H-Y stage, and NMSS may be independent risk factors for PD with GI symptoms. When combined with clinical characteristics such as disease duration, H-Y stage, and NMSS, along with VBM and FC data, the area under the curve (AUC) reached its maximum value. (Table 5, Fig. 5) Table 4 Binary logistic regression B Exp(B) EXP(B)95%confidence interval of EXP༈B༉ P lower limit upper limit Age(years) 0.051 1.052 0.957 1.156 0.293 Age of onset 0.036 1.037 0.945 1.138 0.446 Disease duration 0.190 1.210 1.019 1.436 0.030* LEDD 0.001 1.001 0.999 1.003 0.303 H-Y stage 0.487 1.627 1.044 2.536 0.031* UPDRSⅢ -0.009 0.991 0.965 1.018 0.500 NMSS 0.025 1.025 1.008 1.042 0.004** MOCA 0.049 1.050 0.973 1.134 0.212 HAMD 0.033 1.033 0.950 1.124 0.447 HAMA -0.020 0.981 0.918 1.047 0.558 OH -0.093 0.911 0.237 3.506 0.893 *: P < 0.05, **: P < 0.01 The basic model includes clinical features such as disease duration, H-Y stage, and NMSS. The Basic + VBM model incorporates VBM data, including GMV of the right cerebellar hemisphere, left cerebellar hemisphere, and left superior temporal gyrus. The Basic + VBM + FC model adds functional connectivity (FC) data, including FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, to the previous model. AUC: area under receiver operating curve; PD-GI: PD patients with GI symptoms; PD-NGI: PD patients without GI symptoms. 5 Discussion Analysis of clinical data revealed that the PD-GI group exhibited more pronounced motor and non-motor symptoms compared with the PD-NGI group. This is consistent with previous findings suggesting that PD patients with GI symptoms tend to have a prolonged disease course, increased severity of both motor and non-motor symptoms, and a higher likelihood of experiencing cognitive impairment, anxiety, and depression [ 8 , 9 , 17 , 18 ] . We observed decreased GMV in the bilateral cerebellar hemispheres and left superior temporal gyrus in the PD-GI group. Subsequently, using the right cerebellum as the seed point for FC analysis, we identified significantly increased FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus in the PD-GI group compared to the PD-NGI group. In fact, the cerebellum, cingulate gyrus, and temporal lobe are implicated in processing visceral emotion and nociceptive stimuli [ 19 – 22 ] . Several scholars have suggested that the cerebellum regulates visceral activity through the cerebellar-hypothalamic circuit, which may serve as a potential neuroanatomical basis for the connection between the cerebellum and GI symptoms [ 23 – 26 ] . Neuroinflammation triggers injury and disease responses mediated by the anterior cingulate cortex (ACC), leading to autonomic nervous system activation, worsening immune dysfunction, and exacerbating gut damage [ 27 ] . Additionally, Soulier et al. demonstrated a significant correlation between the stimulation of brain regions such as the temporal pole and temporo-mesial structures and visceral emotional perception [ 22 ] . Thus, we speculated that the pathways involving the cerebellar-cingulate gyrus, cerebellar-temporal lobe, and cerebellar-hypothalamic may contribute to the pathophysiological mechanism of GI symptoms in PD patients. However, there is a scarcity of imaging studies concerning GI symptoms in PD. Interestingly, Zheng et al. reported that PD patients with constipation exhibited significantly higher Amplitude of Low-Frequency Fluctuation (ALFF) in the right dorsal pons extending into the cerebellum and the right insula (INS), along with stronger functional connections between the superior temporal gyrus (STG) and cerebellum [ 28 ] . This appears to be similar to our conclusion. Most previous studies of PD have focused on the basal ganglia region, often overlooking the cerebellum and temporal lobe. Nevertheless, the cerebellum influences both motor and non-motor symptoms in PD patients. Firstly, PD patients with dysphagia showed significantly increased FC between the cerebellum, frontal lobe, temporal lobe, anterior ACC, and INS [ 29 ] .Secondly, abnormal diffusion in cerebellar white matter correlated with olfactory dysfunction in patients with PD [ 30 ] . Thirdly, positive FC between the cerebellar vermis Ⅷ and Ⅹ and relevant brain networks in PD patients with visuospatial disorders may serve as a compensatory mechanism [ 31 ] . Additionally, gray matter loss was found extensively in the cerebellum and corticolimbic network in non-demented patients with PD [ 32 ] . Furthermore, the cerebellum has been implicated in other diseases featuring GI symptoms. Ding et al. reported that individuals with major depressive disorder (MDD) and GI symptoms exhibited higher connectivity within the cerebellar-anterior default mode network (DMN), with connectivity between the right Crus and right STG associated with the severity of both GI symptoms and depression in all MDD patients [ 33 ] . Increased Regional Homogeneity (ReHo) in the bilateral cerebellum Crus Ⅱ was also found in MDD patients with GI symptoms [ 34] . Additionally, the left cerebellum exhibited higher centrality in individuals with irritable bowel syndrome (IBS) and low somatization compared to those with high somatization and HCs [ 35 ] . Patients with Crohn's disease (CD) showed decreased activity in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) [ 36 ] . However, functional MRI studies investigating temporal lobe changes in GI diseases remain limited, and the underlying mechanisms remain unclear. MDD patients with GI symptoms exhibited increased ReHo in the left superior temporal gyrus compared to those without GI symptoms [ 37 ] . Patients with IBS exhibited reduced ALFF values in the left superior frontal gyrus, right hippocampus, and right superior temporal pole [ 38 ] . These findings suggest a potential correlation between the temporal lobe and GI symptoms. Our study also found that PD patients with GI symptoms exhibited more pronounced anxiety and depression, consistent with previous research linking the temporal lobe to mood disorders [ 39 – 41 ] . However, the precise role of the pathways involving the cerebellar-cingulate gyrus and cerebellar-temporal lobe remains unknown, necessitating further research to validate our hypotheses. Furthermore, our findings suggest that the course of the disease, H-Y stage, and NMSS may be independent risk factors for PD patients with GI symptoms. When integrated with clinical features and imaging results, this combined approach demonstrates strong predictive capability for identifying GI symptoms in PD. This underscored the importance of heightened awareness and consideration of GI symptoms in the clinical diagnosis and management of PD, particularly in patients with longer disease duration, higher H-Y stage, and more severe non-motor symptoms. Our study has certain novel highlights; However, it also has its limitations. Firstly, considering that the PD-GI group exhibited more pronounced anxiety and depression symptoms, we cannot completely disregard the potential influence of emotional factors on the imaging results. However, we addressed this concern by making necessary adjustments during regression analysis and confirmed through correlation analysis that structural and functional brain regions were not significantly associated with anxiety and depression. Secondly, the demographic factors were not fully matched between groups. Although we minimized the impact of age on imaging results by including it as a covariate in MRI analysis, this limitation should be acknowledged. Additionally, due to the limited number of cases, we did not assess the impact of disease severity on imaging results in the PD-GI group through further subgrouping based on H-Y stage. Despite these limitations, our study sheds light on the role of abnormalities in the structure and function of the cerebellum, cingulate gyrus, and temporal lobe in contributing to the manifestation of GI symptoms in PD. Declarations Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Finding This research was supported by Applied Basic Research Foundation of Yunnan Province[grant numbers:202301AS070045,202101AY070001-115],National Natural Science Foundation of China [grant numbers: 81960242],Yunnan Province Clinical Research Center for Geriatric Disease [grant number: 202102AA310069],The Innovative Team of Yunnan Province (202305AS350019). References Fasano A, Visanji N P, Liu L W, Lang A E, Pfeiffer R F. Gastrointestinal dysfunction in Parkinson’s disease [J]. Lancet Neurol, 2015, 14(6): 625-639. 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Voxel-based analysis of diffusion tensor indices in the brain in patients with ‘Parkinson’s disease’ [J]. Eur J Radiol, 2011, 77(2): 269-273. Yin K, Zhou C, Yin L, Zhu Y, Yin W, Lu Y, Liu B, Ren H, Xu Z, Yang X. Resting-state functional magnetic resonance imaging of the cerebellar vermis in patients with ‘Parkinson’s disease’ and visuospatial disorder [J]. Neurosci Lett, 2021, 760: 136082. Nishio Y, Hirayama K, Takeda A, Hosokai Y, Ishioka T, Suzuki K, Itoyama Y, Takahashi S, Mori E. Corticolimbic gray matter loss in ‘Parkinson’s disease’ without dementia [J]. Eur J Neurol, 2010, 17(8): 1090-1097. Ding Y, Ou Y, Yan H, Fu X, Yan M, Li H, Liu F, Guo W. Disrupted Cerebellar-Default Mode Network Functional Connectivity in Major Depressive Disorder With Gastrointestinal Symptoms [J]. Front Cell Neurosci, 2022, 16: 833592. Yan M, Chen J, Liu F, Li H, Huang R, Tang Y, Zhao J, Guo W. Disrupted Regional Homogeneity in Major Depressive Disorder With Gastrointestinal Symptoms at Rest [J]. Front Psychiatry, 2021, 12: 636820. Grinsvall C, Van Oudenhove L, Dupont P, Ryu H J, Ljungberg M, Labus J S, Törnblom H, Mayer E A, Simrén M. Altered Structural Covariance of Insula, Cerebellum and Prefrontal Cortex Is Associated with Somatic Symptom Levels in Irritable Bowel Syndrome (IBS) [J]. Brain Sci, 2021, 11(12). Thapaliya G, Eldeghaidy S, Radford S J, Francis S T, Moran G W. An examination of resting-state functional connectivity in patients with active Crohn's disease [J]. Front Neurosci, 2023, 17: 1265815. Liu P, Li G, Zhang A, Yang C, Liu Z, Sun N, Kerang Z. Brain structural and functional alterations in MDD patient with gastrointestinal symptoms: A resting-state MRI study [J]. J Affect Disord, 2020, 273: 95-105. Ma X, Li S, Tian J, Jiang G, Wen H, Wang T, Fang J, Zhan W, Xu Y. Altered brain spontaneous activity and connectivity network in irritable bowel syndrome patients: A resting-state fMRI study [J]. Clin Neurophysiol, 2015, 126(6): 1190-1197. Adolphs R. Neural systems for recognizing emotion [J]. Curr Opin Neurobiol, 2002, 12(2): 169-177. Barbas H. Flow of information for emotions through temporal and orbitofrontal pathways [J]. J Anat, 2007, 211(2): 237-249. Dzafic I, Oestreich L, Martin A K, Mowry B, Burianová H. Stria terminalis, amygdala, and temporoparietal junction networks facilitate efficient emotion processing under expectations [J]. Hum Brain Mapp, 2019, 40(18): 5382-5396. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 15 Aug, 2024 Reviewers invited by journal 31 Jul, 2024 Editor assigned by journal 22 Jul, 2024 First submitted to journal 20 Jul, 2024 Editorial decision: Revise and Resubmit as Letter 03 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4575490","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":334373321,"identity":"202e1e08-7eb8-4115-9e91-c915a2800b1a","order_by":0,"name":"Yuchao TAI","email":"","orcid":"","institution":"Kunming Medical University First Affiliated Hospital: First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuchao","middleName":"","lastName":"TAI","suffix":""},{"id":334373322,"identity":"49af208c-9e70-42a3-beb2-b756aa525b5b","order_by":1,"name":"Wei Huang","email":"","orcid":"","institution":"First People's Hospital of Yunnan","correspondingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Huang","suffix":""},{"id":334373323,"identity":"dae8f893-dc32-45a8-852f-2c94300ac787","order_by":2,"name":"Yongyun Zhu","email":"","orcid":"","institution":"First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yongyun","middleName":"","lastName":"Zhu","suffix":""},{"id":334373324,"identity":"1a2bcb4e-c066-4581-b759-4a9dcb6cc9a9","order_by":3,"name":"Bin Liu","email":"","orcid":"","institution":"Kunming Medical University First Affiliated Hospital: First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bin","middleName":"","lastName":"Liu","suffix":""},{"id":334373325,"identity":"038c732c-a05b-4600-85ad-b1f6bc59a497","order_by":4,"name":"Fang Wang","email":"","orcid":"","institution":"Kunming Medical University First Affiliated Hospital: First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Wang","suffix":""},{"id":334373326,"identity":"37e72c4b-c0e3-47ac-a71e-fbb98322a52a","order_by":5,"name":"Zhaochao Liu","email":"","orcid":"","institution":"Kunming Medical University First Affiliated Hospital: First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhaochao","middleName":"","lastName":"Liu","suffix":""},{"id":334373327,"identity":"9888275a-2bdb-40ab-a1bb-027fa64a51e6","order_by":6,"name":"Chunyu Liang","email":"","orcid":"","institution":"Kunming Medical University First Affiliated Hospital: First Affiliated Hospital of Kunming Medical University","correspondingAuthor":false,"prefix":"","firstName":"Chunyu","middleName":"","lastName":"Liang","suffix":""},{"id":334373328,"identity":"ffea46b9-ce60-48b8-aa0e-8511232adebe","order_by":7,"name":"Jin 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University","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Ren","suffix":""},{"id":334373331,"identity":"7e024dbe-2fed-44a9-9bc7-bd5f788aa33f","order_by":10,"name":"Xinglong Yang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAs0lEQVRIiWNgGAWjYFAC5gYJBgYJHn5m5sMPiNTCCNJiISPZzpZmQIqWChuD8zwKEkRpMLiR2HjjQ40Ej/FhHgYDhhqbaMJazhxstpxxTILH7DDvgQcMx9JyGwhqOd7YJs3bANLCl2DA2HCYCC2HGSFajJt5DCSI0wKzxYCZWC2SML9IHAYGcgIxfuG7kXwQGGJ19vz9hw8/+FBjQ1iLwgFkXgIh5SAgT9DQUTAKRsEoGAUAeCs8bt3tGmMAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-5801-5211","institution":"Kunming Medical University First Affilliated Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xinglong","middleName":"","lastName":"Yang","suffix":""}],"badges":[],"createdAt":"2024-06-13 10:27:51","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4575490/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4575490/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":64006044,"identity":"5e0f89e6-90a6-46dd-894c-8a70b8f70cbc","added_by":"auto","created_at":"2024-09-04 21:45:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":206200,"visible":true,"origin":"","legend":"\u003cp\u003e(a) PD-GI group vs. HC group; (b) PD-NGI group vs. HC group; (c) PD-GI group vs. PD-NGI group. Increased GMV is represented by the red, while decreased GMV is represented by the blue. Color bars indicate T values based on the two-sample t-test, with positive values in red indicating increased GMV, and negative values in blue indicating decreased GMV.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4575490/v1/a6b0b48de883f9b426b1600f.png"},{"id":64006910,"identity":"bd8b0006-8f8f-4031-9f80-99611f7062f5","added_by":"auto","created_at":"2024-09-04 21:53:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":206162,"visible":true,"origin":"","legend":"\u003cp\u003eThe figure illustrates differences in FC among three groups, including cross-sectional and sagittal brain views. Weakened FC is depicted in blue, while enhancedFC values arerepresented in red. The lines connecting blue bars indicate T-values, with positive T-values shown in red and negative T-values in blue. (A): PD-GI group vs HC group; (B): PD-NGI group vs HC group; (C) \u0026amp; (D): PD-GI group vs PD-NGI group; (E): Weaker FC between Cerebelum_Crus2_R and the left middle frontal gyrus in the PD-GI group compared to the HC group; (F): Increased connectivity of Cerebelum_Crus2_R with the left paracentral lobule in the PD-NGI group compared with the HC group; (G): The PD-GI group exhibited significantly increased FC between Cerebelum_Crus2_R and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, compared with the PD-NGI group. FC: functional connectivity; HC: healthy control; PD-GI: PD patients with GI symptoms; PD-NGI: PD patients without GI symptoms.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4575490/v1/6368193569a9771a07e0111b.png"},{"id":64006047,"identity":"5865b700-b604-45a3-9c5f-aebbb6e23944","added_by":"auto","created_at":"2024-09-04 21:45:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122484,"visible":true,"origin":"","legend":"\u003cp\u003ecorrelation analysis\u003c/p\u003e\n\u003cp\u003e*: P \u0026lt; 0.05, **: P \u0026lt; 0.01,***P＜0.001\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4575490/v1/6bd68a945d72b2416067d639.png"},{"id":64006043,"identity":"445634ac-9cd6-457e-8ffb-69c2188d832a","added_by":"auto","created_at":"2024-09-04 21:45:03","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":13048,"visible":true,"origin":"","legend":"\u003cp\u003eROC curve\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4575490/v1/5a1f968d87b222c81a09e9f6.png"},{"id":64007559,"identity":"f9edf854-fbca-4af6-ab66-91f4f350d099","added_by":"auto","created_at":"2024-09-04 22:01:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1209860,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4575490/v1/c525b2c9-a29c-490e-a9bd-6cc16db17aae.pdf"}],"financialInterests":"","formattedTitle":"Analysis of Parkinson’s disease patients with gastrointestinal symptoms using structural and functional magnetic resonance imaging","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eResearch demonstrating the significant role of non-motor symptoms in Parkinson\u0026rsquo;s disease (PD) is increasing. Common non-motor symptoms in PD include gastrointestinal (GI) problems such as dysphagia, gastroparesis, and constipation \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. A small percentage of PD patients may experience GI symptoms years before physical symptoms manifest, which can worsen over time, significantly impacting their quality of life\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. The most common GI symptom in PD patients is constipation, characterized by decreased frequency of stools, difficulty defecating, and passage of dry, hard stools \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. Constipation has been identified as an early indicator of PD. PD is 2\u0026ndash;5 times more likely to occur in individuals with chronic constipation than those without \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Gastroparesis, characterized by a feeling of fullness and delayed stomach emptying after eating, can lead to malnutrition and weight loss \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Research has shown a correlation between the degree of dyskinesia and the severity of gastroparesis in PD patients \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Although the relationship between dysphagia and the clinical course of PD is not well-established, dysphagia is significantly associated with a higher risk of death and complications such as aspiration pneumonia, weight loss, dehydration, and malnutrition, which is believed to contribute to 70% of PD-related deaths \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Furthermore, studies have shown a bidirectional relationship between mental health in PD patients and gut health, with significant GI symptoms predicting severe anxiety-depression, while negative emotions may exacerbate GI dysfunction \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Another study suggests that GI problems in PD patients may indicate the onset of cognitive decline \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn recent years, more academics have recognized the gut as the \"second brain\" of mankind \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The enteric nervous system (ENS) and the central nervous system (CNS) communicate bidirectionally along the gut-brain axis through various immunological, inflammatory, and endocrine pathways \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Braak et al. (2003) reported that α-synuclein (α-syn) is initially deposited in the ENS and the dorsal nucleus of the vagal motor nucleus before appearing in the CNS, proposing six pathological phases in the development of PD \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. These pathological changes primarily affect the structures of the dorsal nucleus of the medulla oblongata and the anterior olfactory bulb before progressing to the pons, midbrain, and neocortex, rather than beginning in the substantia nigra of the midbrain \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. With advancements in neuroimaging techniques, magnetic resonance imaging (MRI) can now be used to investigate the pathophysiology of PD.\u003c/p\u003e \u003cp\u003eChanges in structural and functional MRI of PD patients with GI symptoms warrant investigation, as there are limited and inconsistent imaging studies on GI symptoms in PD. GI complaints are among the most prevalent autonomic symptoms, which include GI symptoms, incontinence, hypotension, tachycardia or bradycardia, and cold and hot paresthesia. The Scales for Outcomes in Parkinson\u0026rsquo;s disease-Autonomic (SCOP-AUT) can help medical practitioners in understanding the autonomic dysfunction experienced by PD patients. Higher SCOP-AUT scores indicate more severe symptomatology, with items 5\u0026ndash;7 assessing GI symptoms such as constipation, difficulty defecating, and fecal incontinence \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study was aimed to improve our understanding of the pathophysiology by investigating the connection between PD with GI symptoms and alterations in brain structure and function.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Participants\u003c/h2\u003e \u003cp\u003eThe Second Department of Neurology at the First Affiliated Hospital of Kunming Medical University recruited 155 PD patients and 50 healthy controls (HCs)between June 2022 and December 2023. Inclusion criteria for all participants were as follows: (1) clinically diagnosed with PD according to the Movement Disorder Society Clinical Diagnostic Criteria [15]; (2) no family history of PD in first-degree relatives; (3) no history of neurological disorders such as stroke, infection, poisoning, metabolic disorders, or trauma, or other serious illnesses; (4) no history of active epilepsy or brain surgery. Exclusion criteria included: (1) GI disorders or GI symptoms caused by medication; (2) past history of mental illness, currently being treated or having been treated with anti-anxiety and depression medication in the last six months; (3) contraindications for MRI scans; (4) significant brain atrophy or multiple cerebral white matter lesions observed on imaging; (5) left-handedness. PD patients were categorized into PD with GI symptoms group (PG-GI) and PD without GI symptoms group (PG-NGI) based on scores of items 5\u0026ndash;7 of SCOP-AUT. HCs were individuals who were essentially matched to the sex and age of the PD patients collected during the same period.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Clinical Assessment\u003c/h2\u003e \u003cp\u003eGeneral clinical and demographic data of all participants were collected, including gender, age, disease duration, age at onset, Hamilton Anxiety Scale (HAMA) score, Levodopa Equivalents Daily Dose (LEDD), Unified Parkinson's Disease Rating Scale Part Ⅲ(UPDRSⅢ) score, Hoehn and Yahr (H-Y) stage, Non-Motor Symptom Scale (NMSS) score, SCOP-AUT score, Montreal Cognitive Assessment (MOCA) score, Hamilton Depression Scale (HAMD) score, and Orthostatic Hypotension (OH).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Image Acquisition\u003c/h2\u003e \u003cp\u003eAll subjects underwent imaging examinations at the First Affiliated Hospital of Kunming Medical University using a 3.0T magnetic resonance scanner. Foam padding was used to minimize head movement during data acquisition, and participants were instructed to remain awake and keep their eyes closed. PD patients were allowed to take levodopa before scanning if necessary to mitigate severe involuntary shaking. The scanning parameters for three-dimensional T1-weighted imaging (3D-T1WI) were as follows: slice thickness: 1 mm, voxel size: 1\u0026times;1\u0026times;1mm, repetition time (TR): 8.6 ms, echo time (TE): 3.2ms, inversion time: 450ms, flip angle: 12\u0026deg;, scanning field of view: 256mm, matrix: 256\u0026times;256. The scanning parameters for resting-state functional MRI (RS-fMRI) were as follows: TR\u0026thinsp;=\u0026thinsp;2000ms, TE\u0026thinsp;=\u0026thinsp;35ms, slice thickness\u0026thinsp;=\u0026thinsp;4.0mm, scanning matrix\u0026thinsp;=\u0026thinsp;64\u0026times;64, field of view\u0026thinsp;=\u0026thinsp;240mm\u0026times;240mm, voxel size\u0026thinsp;=\u0026thinsp;3\u0026times;3\u0026times;3mm, time points\u0026thinsp;=\u0026thinsp;240.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Image Processing\u003c/h2\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e2.4.1. T1WI Image\u003c/h2\u003e \u003cp\u003eThe 3D-T1WI images were processed using the SPM8 and VBM8 toolkits (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dbm.neuro.unijena.de/vbm\u003c/span\u003e\u003cspan address=\"http://dbm.neuro.unijena.de/vbm\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Using segmentation techniques, the T1 images were matched to a standard template and then classified into three categories: gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). Subsequently, the images were co-registered to the Montreal Neurological Institute (MNI) template and smoothed using a Gaussian kernel with a half-width (FWHM) of 8 mm.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e2.4.2. Functional MRI (RS-fMRI) Image\u003c/h2\u003e \u003cp\u003eData preprocessing was conducted using the DPABI software (version 4.5, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://rfmri.org/dpabi\u003c/span\u003e\u003cspan address=\"http://rfmri.org/dpabi\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. The pre-processing process included: (1) format conversion; (2) removal of the first 10 time points; (3) slice timing correction; (4) exclusion of participants with head motion displacement exceeding 2 mm or rotation exceeding 2\u0026deg;; (5) spatial standardization to the MNI standard space with voxel sizes of 3 mm \u0026times; 3 mm \u0026times; 3 mm; (6) regression of nuisance signals, including Friston 24 head motion parameters; (7) spatial smoothing using a Gaussian kernel (FWHM\u0026thinsp;=\u0026thinsp;8 mm); (8) temporal band-pass filtering (0.01\u0026ndash;0.08 Hz).\u003c/p\u003e \u003cp\u003eStructural brain regions obtained were defined as regions of interest (ROIs). A seed-based functional connectivity (FC) analysis was conducted, centering at the coordinates of the peak value with an 8 mm radius. Correlation analysis between the average time series of each seed point and the time series of each voxel in the brain was performed. Functional connection maps for each seed point were generated, and a comprehensive Z-value map of the whole brain was created for each subject using Fisher-to-z transformation.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"3 Statistical Analyses","content":"\u003cp\u003eDemographic characteristics were analyzed using SPSS version 23.0 software. Normality of demographic data and clinical scales was tested. For normally distributed data, analysis of variance (ANOVA) was used for comparisons among all three groups, and independent samples t-test was used for comparisons between two groups, presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Abnormally distributed data were reported as median (interquartile range), and non-parametric tests were applied. The chi-square test was used for count data, expressed as percentages. Differences with P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003cp\u003eImaging data were analyzed using a two-sample t-test in SPM12 software, with age, gender, and disease duration as covariates. Brain regions with statistical significance were identified after applying false discovery rate (FDR) correction (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and Gaussian random field (GRF) correction (P voxel\u0026thinsp;\u0026lt;\u0026thinsp;0.005, P cluster\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"4 Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1. Demographic Data Comparisons\u003c/h2\u003e\n \u003cp\u003eCompared to the PD-NGI group, PD-GI group showed the significant different age, disease duration, levodopa equivalents daily dose (LEDD), Hoehn-Yahr (H-Y) stage, unified Parkinson\u0026rsquo;s disease rating scale part Ⅲ(UPDRSⅢ) score, NMSS score, MOCA score, HAMD score, HAMA score, SCOP-AUT score, and OH incidence (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eDemographic and clinical characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePD-GI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePD-NGI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eParticipants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGender(male)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (49.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.155\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (62.25,74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61 (54,71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61.5(47,70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge of onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63.335(53,70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e59 (51,69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.011*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1,6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (1,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLEDD (mg/day)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e375 (300,596.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e337.5 (150,450)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.008**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH\u0026amp;Y stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2(1,3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1(1,2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUPDRSIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (19,43.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (14,35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.014*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNMSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e49.5 (28,88.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27 (12,41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMOCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (28.75,26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (19,27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.043*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.5 (4,10.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (2,9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.5 (3.25,22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (0,12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSCOP-AUT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (11,25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (3,11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.000**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOH (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (19.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (7.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.030*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e*P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **P\u0026thinsp;\u0026lt;\u0026thinsp;0.01.\u003c/p\u003e\n \u003cp\u003eLEDD: Levodopa equivalents daily dose; UPDRSⅢ: unified Parkinson\u0026rsquo;s disease rating scale part Ⅲ; NMSS: non-motor symptom scale; MOCA: Montreal cognitive assessment; HAMD: Hamilton depression scale; HAMA: Hamilton anxiety scale; SCOP-AUT: scales for outcomes in Parkinson\u0026rsquo;s disease-autonomic; OH: orthostatic hypotension.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2. GMV Differences in Regions\u003c/h2\u003e\n \u003cp\u003eIn the voxel-based morphometry (VBM) analysis, compared to the HC group, the PD-GI group demonstrated significantly decreased GMV in the right superior parietal gyrus, right inferior parietal gyrus and left caudate nucleus. Conversely, increased GMV was observed in the right middle temporal gyrus and left middle frontal gyrus. Additionally, decreased GMV was observed in the left cerebellar hemisphere (Cerebellum_9_L) in the PD-NGI group compared to the HC group. Furthermore, when compared to the PD-NGI group, the PD-GI group exhibited significantly decreased GMV in the bilateral hemispheres of the cerebellum (Cerebellum_Crus2_R, Cerebellum_6_L) and the left superior temporal gyrus (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGMV differences in HCs group, PD-GI group, and PD-NGI group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBrain region\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eL/R\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCluster size\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMNI coordinates\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eT value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eZ\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003ePD-GI\u0026lt;HC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior prietal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e734\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-61.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-5.5037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eInferior parietal, but supramarginal and angular gyri\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e135\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-5.3158\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCaudate nucleus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.9803\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ePD-NGI\u0026gt;HC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMiddle temporal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e360\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-19.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.4742\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMiddle frontal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-49.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.8909\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-NG\u0026lt;HC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebellum_9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e348\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-46.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.8428\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003ePD-GI\u0026lt;PD-NGI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebellum_Crus2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1592\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-73.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-49.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.1577\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCerebellum_6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-3.7506\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperior temporal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e422\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-4.3756\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eMNI coordinates: Coordinates of primary peak locations in the Montreal Neurological Institute space; T values, GMV differences among two groups based on the two-sample t-test.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e4.4. Regional FC Differences\u003c/h2\u003e\n \u003cp\u003eIn the FC analysis, ROIs were defined using the right cerebellar hemisphere (Cerebelum_Crus2_R). Results indicated weaker FC between the right cerebellar hemisphere and the left middle frontal gyrus in the PD-GI group compared to the HC group. Conversely, the PD-NGI group exhibited increased connectivity between the right cerebellar hemisphere and the left paracentral lobule compared to the HC group. Furthermore, the PD-GI group demonstrated significantly increased FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, compared to the PD-NGI group (Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eRegional FC differences in PD-GI group, PD-NGI group, and HCs group\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"9\"\u003e\u003c/colgroup\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eROI MNI coordinates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eBrain region\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eL/R\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eCluster size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"3\"\u003e\n \u003cp\u003eMNI coordinates\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eT value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eX, Y, Z\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eX\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eY\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eZ\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-GI\u0026lt;HC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003eCerebelum_Crus2_R\u003c/p\u003e\n \u003cp\u003e(34.5, -73.5, -49.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emiddle frontal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3.6375\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePD-NGI\u0026gt;HC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eparacentral lobule\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.8643\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003ePD-GI\u0026gt;PD-NGI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emedial and lateral cingulate gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emiddle temporal gyrus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3.9236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eMNI coordinates: Coordinates of primary peak locations in the Montreal Neurological Institute space; T values, GMV differences among two groups based on the two-sample t-test; ROI, region of interest.\u003c/p\u003e\n \u003cp\u003eThe figure illustrates differences in FC among three groups, including cross-sectional and sagittal brain views. Weakened FC is depicted in blue, while enhanced FC values are represented in red. The lines connecting blue bars indicate T-values, with positive T-values shown in red and negative T-values in blue. (A): PD-GI group vs HC group; (B): PD-NGI group vs HC group; (C) \u0026amp; (D): PD-GI group vs PD-NGI group; (E): Weaker FC between Cerebelum_Crus2_R and the left middle frontal gyrus in the PD-GI group compared to the HC group; (F): Increased connectivity of Cerebelum_Crus2_R with the left paracentral lobule in the PD-NGI group compared with the HC group; (G): The PD-GI group exhibited significantly increased FC between Cerebelum_Crus2_R and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, compared with the PD-NGI group. FC: functional connectivity; HC: healthy control; PD-GI: PD patients with GI symptoms; PD-NGI: PD patients without GI symptoms.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003e4.5. Correlation between clinical data and different brain regions\u003c/h2\u003e\n \u003cp\u003eIn the structural MRI analysis, GMV in the right cerebellar hemisphere was negatively correlated with age and SCOP-AUT; besides, GMV in the left cerebellar hemisphere also showed negative correlations with age, disease duration, and SCOP-AUT. Additionally, negative correlations were observed between the left superior temporal gyrus and age, disease duration, LEDD, H-Y stage, UPDRSⅢ, and SCOP-AUT. Furthermore, in the functional MRI analysis, FC values between the right cerebellar hemisphere and the right median cingulate and paracingulate gyrus were positively correlated with LEDD and SCOP-AUT (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eThe colored band on the right indicates the correlation coefficient, with blue representing a positive correlation and red representing a negative correlation. CRBLCris2.R: Cerebellum_Crus2; CRBL6.L: Cerebellum_6; STG.L :the left superior temporal gyrus; DCG.R :the right median cingulate and paracingulate gyrus; MTG.L :the left Middle temporal gyrus.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e4.6 Independent risk factors and logistic regression model of GI symptoms\u003c/h2\u003e\n \u003cp\u003eBinary logistic regression analysis and receiver operating characteristic (ROC) curve were employed to assess independent risk factors in PD patients with GI symptoms. Results suggest that disease duration, H-Y stage, and NMSS may be independent risk factors for PD with GI symptoms. When combined with clinical characteristics such as disease duration, H-Y stage, and NMSS, along with VBM and FC data, the area under the curve (AUC) reached its maximum value. (Table 5, Fig. 5)\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBinary logistic regression\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eB\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eExp(B)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEXP(B)95%confidence interval of EXP༈B༉\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" rowspan=\"2\"\u003e\n \u003cp\u003eP\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003elower limit\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eupper limit\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.051\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.052\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.957\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.293\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge of onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.036\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.037\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.945\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.446\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDisease duration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.190\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.210\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.436\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.030*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLEDD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.303\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eH-Y stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.627\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.044\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.536\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.031*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUPDRSⅢ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.991\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.965\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.500\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNMSS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.042\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.004**\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMOCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.050\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.973\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.212\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAMD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.033\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.950\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHAMA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.047\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.558\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.093\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.911\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.237\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.506\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\"\u003e*: P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **: P\u0026thinsp;\u0026lt;\u0026thinsp;0.01\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eThe basic model includes clinical features such as disease duration, H-Y stage, and NMSS. The Basic\u0026thinsp;+\u0026thinsp;VBM model incorporates VBM data, including GMV of the right cerebellar hemisphere, left cerebellar hemisphere, and left superior temporal gyrus. The Basic\u0026thinsp;+\u0026thinsp;VBM\u0026thinsp;+\u0026thinsp;FC model adds functional connectivity (FC) data, including FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus, to the previous model. AUC: area under receiver operating curve; PD-GI: PD patients with GI symptoms; PD-NGI: PD patients without GI symptoms.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"5 Discussion","content":"\u003cp\u003eAnalysis of clinical data revealed that the PD-GI group exhibited more pronounced motor and non-motor symptoms compared with the PD-NGI group. This is consistent with previous findings suggesting that PD patients with GI symptoms tend to have a prolonged disease course, increased severity of both motor and non-motor symptoms, and a higher likelihood of experiencing cognitive impairment, anxiety, and depression \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe observed decreased GMV in the bilateral cerebellar hemispheres and left superior temporal gyrus in the PD-GI group. Subsequently, using the right cerebellum as the seed point for FC analysis, we identified significantly increased FC between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus, as well as the left middle temporal gyrus in the PD-GI group compared to the PD-NGI group. In fact, the cerebellum, cingulate gyrus, and temporal lobe are implicated in processing visceral emotion and nociceptive stimuli \u003csup\u003e[\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Several scholars have suggested that the cerebellum regulates visceral activity through the cerebellar-hypothalamic circuit, which may serve as a potential neuroanatomical basis for the connection between the cerebellum and GI symptoms \u003csup\u003e[\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. Neuroinflammation triggers injury and disease responses mediated by the anterior cingulate cortex (ACC), leading to autonomic nervous system activation, worsening immune dysfunction, and exacerbating gut damage \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Additionally, Soulier et al. demonstrated a significant correlation between the stimulation of brain regions such as the temporal pole and temporo-mesial structures and visceral emotional perception \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e. Thus, we speculated that the pathways involving the cerebellar-cingulate gyrus, cerebellar-temporal lobe, and cerebellar-hypothalamic may contribute to the pathophysiological mechanism of GI symptoms in PD patients.\u003c/p\u003e \u003cp\u003eHowever, there is a scarcity of imaging studies concerning GI symptoms in PD. Interestingly, Zheng et al. reported that PD patients with constipation exhibited significantly higher Amplitude of Low-Frequency Fluctuation (ALFF) in the right dorsal pons extending into the cerebellum and the right insula (INS), along with stronger functional connections between the superior temporal gyrus (STG) and cerebellum \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. This appears to be similar to our conclusion. Most previous studies of PD have focused on the basal ganglia region, often overlooking the cerebellum and temporal lobe. Nevertheless, the cerebellum influences both motor and non-motor symptoms in PD patients. Firstly, PD patients with dysphagia showed significantly increased FC between the cerebellum, frontal lobe, temporal lobe, anterior ACC, and INS \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.Secondly, abnormal diffusion in cerebellar white matter correlated with olfactory dysfunction in patients with PD \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Thirdly, positive FC between the cerebellar vermis Ⅷ and Ⅹ and relevant brain networks in PD patients with visuospatial disorders may serve as a compensatory mechanism \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Additionally, gray matter loss was found extensively in the cerebellum and corticolimbic network in non-demented patients with PD \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. Furthermore, the cerebellum has been implicated in other diseases featuring GI symptoms. Ding et al. reported that individuals with major depressive disorder (MDD) and GI symptoms exhibited higher connectivity within the cerebellar-anterior default mode network (DMN), with connectivity between the right Crus and right STG associated with the severity of both GI symptoms and depression in all MDD patients \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e. Increased Regional Homogeneity (ReHo) in the bilateral cerebellum Crus Ⅱ was also found in MDD patients with GI symptoms\u003csup\u003e[ 34]\u003c/sup\u003e. Additionally, the left cerebellum exhibited higher centrality in individuals with irritable bowel syndrome (IBS) and low somatization compared to those with high somatization and HCs \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. Patients with Crohn's disease (CD) showed decreased activity in the salience network (cerebellum, postcentral gyrus), DMN (parahippocampal gyrus, cerebellum), and cerebellar network (occipital fusiform gyrus, cerebellum) \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. However, functional MRI studies investigating temporal lobe changes in GI diseases remain limited, and the underlying mechanisms remain unclear. MDD patients with GI symptoms exhibited increased ReHo in the left superior temporal gyrus compared to those without GI symptoms \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e. Patients with IBS exhibited reduced ALFF values in the left superior frontal gyrus, right hippocampus, and right superior temporal pole \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. These findings suggest a potential correlation between the temporal lobe and GI symptoms. Our study also found that PD patients with GI symptoms exhibited more pronounced anxiety and depression, consistent with previous research linking the temporal lobe to mood disorders \u003csup\u003e[\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]\u003c/sup\u003e. However, the precise role of the pathways involving the cerebellar-cingulate gyrus and cerebellar-temporal lobe remains unknown, necessitating further research to validate our hypotheses.\u003c/p\u003e \u003cp\u003eFurthermore, our findings suggest that the course of the disease, H-Y stage, and NMSS may be independent risk factors for PD patients with GI symptoms. When integrated with clinical features and imaging results, this combined approach demonstrates strong predictive capability for identifying GI symptoms in PD. This underscored the importance of heightened awareness and consideration of GI symptoms in the clinical diagnosis and management of PD, particularly in patients with longer disease duration, higher H-Y stage, and more severe non-motor symptoms.\u003c/p\u003e \u003cp\u003eOur study has certain novel highlights; However, it also has its limitations. Firstly, considering that the PD-GI group exhibited more pronounced anxiety and depression symptoms, we cannot completely disregard the potential influence of emotional factors on the imaging results. However, we addressed this concern by making necessary adjustments during regression analysis and confirmed through correlation analysis that structural and functional brain regions were not significantly associated with anxiety and depression. Secondly, the demographic factors were not fully matched between groups. Although we minimized the impact of age on imaging results by including it as a covariate in MRI analysis, this limitation should be acknowledged. Additionally, due to the limited number of cases, we did not assess the impact of disease severity on imaging results in the PD-GI group through further subgrouping based on H-Y stage.\u003c/p\u003e \u003cp\u003eDespite these limitations, our study sheds light on the role of abnormalities in the structure and function of the cerebellum, cingulate gyrus, and temporal lobe in contributing to the manifestation of GI symptoms in PD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eDeclaration of Competing Interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eFinding\u003c/h2\u003e \u003cp\u003eThis research was supported by Applied Basic Research Foundation of Yunnan Province[grant numbers:202301AS070045,202101AY070001-115],National Natural Science Foundation of China [grant numbers: 81960242],Yunnan Province Clinical Research Center for Geriatric Disease [grant number: 202102AA310069],The Innovative Team of Yunnan Province (202305AS350019).\u003c/p\u003e \u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eFasano A, Visanji N P, Liu L W, Lang A E, Pfeiffer R F. 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Hum Brain Mapp, 2019, 40(18): 5382-5396.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Parkinson’s disease, gastrointestinal symptoms, voxel-based morphometry, functional connectivity","lastPublishedDoi":"10.21203/rs.3.rs-4575490/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4575490/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective: \u003c/strong\u003eGastrointestinal symptoms are one of the most common non-motor symptoms in Parkinson’s disease. This study aimed to investigate the neuroimaging mechanisms underlying gastrointestinal symptoms associated with Parkinson’s disease using functional connectivity and voxel-based morphometry.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: The study included 50 healthy controls, 71 Parkinson’s disease patients without gastrointestinal symptoms and 84 patients with gastrointestinal symptoms. Differences in gray matter volume among the three groups were assessed. Given a significant decrease in gray matter volume in the right cerebellar hemisphere, it was selected as the seed region for functional connectivity analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe Parkinson’s disease patients with gastrointestinal symptoms showed significant differences in disease duration, levodopa equivalents daily dose, Hoehn and Yahr stage, unified Parkinson's disease rating scale part Ⅲ, Hamilton anxiety scale, Scales for Outcomes in Parkinson’s disease-Autonomic, non-motor symptom scale, Montreal cognitive assessment, and orthostatic hypotension compared to the patients without gastrointestinal symptoms (p\u0026lt;0.05). Lower gray matter volume was observed in the group with gastrointestinal symptoms, particularly in the bilateral cerebellum hemisphere and the left superior temporal gyrus. Compared to the group without gastrointestinal symptoms, functional connectivity between the right cerebellar hemisphere and the right medial and lateral cingulate gyrus and left middle temporal lobe was significantly increased.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eParkinson’s disease patients with gastrointestinal symptoms present with a prolonged disease course and increased severity of both motor and non-motor symptoms. The gastrointestinal symptoms in Parkinson’s disease patients may be associated with structural and functional brain alterations.\u003c/p\u003e","manuscriptTitle":"Analysis of Parkinson’s disease patients with gastrointestinal symptoms using structural and functional magnetic resonance imaging","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-04 21:44:58","doi":"10.21203/rs.3.rs-4575490/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-08-15T15:05:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-31T16:44:31+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-22T04:48:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2024-07-21T03:07:14+00:00","index":"","fulltext":""},{"type":"decision","content":"Revise and Resubmit as Letter","date":"2024-07-03T12:37:21+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"32050752-f365-43be-939c-50ac8c17b312","owner":[],"postedDate":"September 4th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T06:38:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-04 21:44:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4575490","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4575490","identity":"rs-4575490","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}