【作者】 章勇；

【导师】 张达颖；

【作者基本信息】 南昌大学 ， 临床医学（专业学位）， 2021， 博士

【摘要】 背景与目的:慢性腰痛是临床常见病,合并下肢疼痛使腰痛控制难度增加。中枢结构和功能的重塑在疼痛慢性化起着至关重要的作用。静息态功能磁共振(resting-state functional magnetic resonance imaging,rs-fMRI)是探索中枢功能重塑的重要方法。慢性非特异性腰痛脑功能与结构变化已在多项研究中证实。但对于特定情况,即腰椎间盘突出继发腰腿痛(Low back-related leg pain due to lumbar disc herniation,LBLP)研究较少。同时rs-fMRI研究主要基于特定的低频范围(通常定义为0.01-0.1 Hz,经典频段)内的振荡波,而相对高频段(内含大量生理噪音)未进行研究。近年来多项研究表明:相对高频频段的波动振幅改变对疼痛也具有重要的病理意义。本研究依据Buzsáki的框架将BOLD信号分为五个特定频段:slow-6(0–0.01Hz)、slow-5(0.01-0.027 Hz)、slow-4(0.027-0.073 Hz)、slow-3(0.073-0.198Hz)和slow-2(0.198-0.25 Hz),利用rs-fMRI分析方法,在经典频段及五个特定频段研究LBLP脑功能(局部或短距离的功能、半球间同步性)的变化及其病理意义,为探索LBLP可能的中枢机制提供有价值的线索。研究方法:本研究为前瞻研究,采用横向研究方案,以LBLP患者及性别、年龄相匹配的健康人(healthy control,HC)为研究对象,采集rs-fMRI数据,利用低频振幅(amplitude of low frequency fluctuation,ALFF)、局部一致性(regional homogeneity,Re Ho)、体素镜像同伦连接(voxel-mirrored homotopic connectivity,VMHC)方法进行研究。1.纳入符合条件25名LBLP患者和27名HC受试者的rs-fMRI数据,利用ALFF方法,比较LBLP组和HC组在五个特定频段的波动振幅(Amplitude of fluctuations,AF)差异,AF差异脑区进一步行全频段分析及其与临床指标相关性。2.纳入符合条件25名LBLP患者和26名HC受试者的rs-fMRI数据,利用KCC-Re Ho和Co He-Re Ho两种方法,分别比较经典频段和五个特定频段LBLP组和HC组Re Ho的差异及其与临床指标相关性。3.纳入符合条件25名LBLP患者和27名HC受试者的rs-fMRI数据,利用VMHC方法,分别比较经典频段和五个特定频段LBLP组和HC组VMHC的差异,并以VMHC改变显著区域为种子点,行全脑功能连接分析,及其与临床指标相关性。结果:1.与HC组相比,LBLP患者在五个特定频段AF改变的脑区存在差异。对AF异常改变的脑区(双侧颞中/下回、双侧楔前叶、右前岛叶/额盖、双侧顶下小叶/中央后回、右侧小脑后叶和双侧尾状核)行全频段分析,LBLP患者的右侧小脑后叶的AF从低频段到高频段增加的趋势,而双侧楔前叶、双侧尾状核和右侧顶下小叶/中央后回的AF从低频段到高频段减少的趋势。在双侧直回AF的改变,存在疾病与五个特定频段显著交互作用。特定脑区、特定频段(slow-4、slow-5)的AF的改变与视觉模拟评分法(visual analogue scale,VAS)、手足的两点触觉辨别觉(two-point tacticle discrimination,TPTD)有关。2.在经典频段、五个特定频段,LBLP患者较HC组的Re Ho存在显著差异脑区。无论是在经典频段,还是五个特定频段,KCC-Re Ho较Co He-Re Ho能够检测到更多的差异脑区,疾病与五个特定频段显著交互作用存在于右侧小脑后叶、脑干、内侧前额叶皮质、楔前叶和顶下小叶。经典频段Re Ho的改变与临床指标无关。特定分析方法、特定脑区、特定频段(slow-2、slow-4、slow-5、slow-6)的Re Ho改变与病程、VAS评分、Fugl-Meyer评分、手足的TPTD有关。3.与HC组相比,LBLP患者在经典频段、五个特定频段VMHC改变的脑区存在差异。五个特定频段出现VMHC降低的脑区,作为种子点,行全脑功能连接分析,显示其全脑的连通性也下降。疾病与五个特定频段显著交互作用存在于小脑前叶、颞中回和前扣带回。半球间同步性降低可以区分LBLP患者和HC,并具有高敏感性、特异性。经典频段特定脑区、特定频段(slow-2、slow-4)的VMHC的改变与病程、VAS评分、Fugl-Meyer评分、手足的TPTD有关。结论:LBLP患者脑自发性活动、局部连通性、半球间同步性存在广泛的异常改变,为LBLP脑功能重塑提供了证据。AF、Re Ho、VMHC的改变均具有频率依赖性,在特定脑区、特定频段(低频段、高频段)中AF、Re Ho、VMHC的变化与临床指标相关,具有一定的病理意义。在未来探索疼痛状态下脑的内在功能,应综合考虑频段(包含高频段)和分析方法。更多还原

【Abstract】 Background and objective:Low back pain(LBP)is an common disorder,and treatment for it is often unsatisfactory.Structural and functional plasticity of the central nervous system plays critical role in pain chronification.Recently,brain changes such as abnormal function along with impaired structure in patients with nonspecific LBP have been confirmed in several studies by using resting-state functional magnetic resonance imaging(rs-fMRI),which is an essential way for identifying central plasticity.It currently remains unclear how central functional and structural alterations contributed to persisting low-back related leg pain(LBLP)due to lumbar disc herniation,a specific condition.In addition,past rs-fMRI studies were mainly based on oscillations within specific low-frequency ranges(typically defined as 0.01 – 0.1 Hz),while fluctuations in relatively high-frequency bands have been considered as simple physiological noises and thus unexplored.However,a growing evidence revealed that alterations in relatively high-frequency bands may be of physiological importance in pain.According to Buzsáki’s framework,oscillatory blood-oxygenation level-depen-dent(BOLD)waves can be divided into the following five specific frequency bands:slow-6(0–0.01 Hz),slow-5(0.01-0.027 Hz),slow-4(0.027-0.073 Hz),slow-3(0.073-0.198 Hz)and slow-2(0.198-0.25 Hz).In the present study,rs-fMRI was applied to reveal the change of brain function(i.e.,local or short-distance functional interactions,interhemispheric functional coordination)in five specific frequency bands and full-frequency bands in LBLP patients compared with healthy controls,and hence elucidate the central mechanisms underlying LBLP and provide theoretical foundation guiding precision treatment for LBLP in clinical practice.Participants and methods:Two groups of participants were recruited for this prospective study,including LBLP patients and age-,gender-,and education-matched healthy controls(HCs).After rs-fMRI scanning,methods such as amplitude of low frequency fluctuation(ALFF),regional homogeneity(Re Ho)and voxel-mirrored homotopic connectivity(VMHC)were applied to quantify features of brain intrinsic functional architecture.At first,a cohort of LBLP patients(n=25)and well-matched HCs(n=27)were recruited and underwent MRI scanning and a battery of clinical tests.Amplitude of fluctuations(AF)in five specific frequency bands and the full-frequency band were calculated and compared between the LBLP and HC groups using ALFF.Then,the associations between the AF in the five specific frequency bands and disease status were further assessed.Besides,this study adopted voxelwise Kendall’s coefficient of concordance(KCC)and coherence(Cohe)regional homogeneity(Re Ho)in the typical and five specific frequency bands to analyze individual whole-brain rs-fMRI scans in 25 LBLP patients and 26 HCs.Altered Re Ho was correlated with clinical metrics,which were assessed using partial correlational analysis.Finally,rs-fMRI data were obtained from 25 LBLP patients and 27 HCs,and symmetrical interhemispheric voxel’s time series in the two groups were further calculated as VMHC.In consideration of the frequency property,alterations of VMHC in the typical frequency band and five specific frequency bands were analyzed and compared using voxel-based analyses.Moreover,interactions between clinical metrics(as well as disease status)and the five specific frequency bands were demonstrated with full-factorial analysis.Results:Compared with healthy controls,LBLP patients exhibited a significantly altered AF in multiple brain regions at five specific frequencies.The regions with alterations in the five frequency bands were selected for full-frequency band analyses,including the right and left middle and inferior temporal gyri(MTG/ITG),bilateral precuneus(PCUN),right anterior insula/frontal operculum(a INS/f O),right or left inferior parietal lobule/postcentral gyrus(IPL/Po CG),posterior lobe of the right cerebellum(CPL)and bilateral caudate(CAU).the LBLP patients consistently exhibited a trend showing an increase in the AF in the right CPL and a decrease in the AF in the bilateral PCUN,CAU and right IPL/Po CG from the low-to high-frequency bands.A significant interaction was identified between the frequency bands and disease status in the bilateral rectal gyrus.Moreover,AF alterations in specific regions at specific frequency band were correlated with visual analogue scale(VAS)scores and two-point tactile discrimination(TPTD)performance.In addition,between-group differences demonstrated significant alterations in the Re Ho in LBLP patients in the typical and five specific frequency bands,respectively.KCC-Re Ho detected more regions than Cohe-Re Ho in both typical and five specific frequency bands.Further analyses showed significant interactions between disease status and the five specific frequency bands in the right CPL,brainstem,basal ganglia(BG),medial prefrontal cortex(m PFC),precuneus and IPL.However,no correlations were found between any of the clinical indices and altered Re Ho in the typical frequency bands.Moreover,there were pain-related alterations in Re Ho in the specific frequency bands(slow-2,slow-4,slow-5,slow-6)related to disease duration,VAS score,Fugl-Meyer assessment along with TPTD performance.Significantly altered VMHC values in the typical and five specific frequency bands were identified in patients with LBLP.Simultaneously,seed-based functional connectivity analysis revealed lower heterotopic connectivity patterns of the regions with reduced VMHC in LBLP patients.Besides,significant interactions between disease status and the five specific frequency bands were shown in several brain regions including the cerebellum anterior lobe(CAL),MTG and the anterior cingulate cortex(ACC).Change of the status of interhemispheric connectivity showed a great ability to distinguish the LBLP disease from HCs.Significant relationship was observed between the altered VMHC and the clinical metrics,such as the disease duration,VAS score,Fugl-Meyer assessment and TPPD performance,at typical frequency bands(slow-2,slow-4)in specific brain regions.Conclusion:Altered of spontaneous brain activity,disrupted multiscale frequency-related local connectivity and interhemispheric coordination implied in this study,provided novel evidence for understanding central plasticity responsible for LBLP.The pain-related changes in AF,Re Ho,and VMHC were frequency-dependent,and such alterations in specific region and frequency ranges were related to clinical indices with pathological importance.These findings suggest that the exact frequency band(including high-frequency band)and detailed analysis method should be considered for exploring pain-related intrinsic activity in future studies.更多还原