| [Background]Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder among old ages. It is associated with progressive neuronal loss of the substantia nigra and brain stem and other brain structures combined with the appearance of intracytoplasmic inclusions composed of α-synuclein aggregates known as Lewy bodies. It is characterized by remor, rigidity, akinesia and postural changes in the clinical motor syndromes and cognitive dysfunction, anxiety, depression, olfactory dysfunction and sleep disorders.Freezing of gait is described as a’brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk’,which the feet appear ’glued to the floor’in those patients. Typically, freezing of gait lasts a couple of seconds, but episodes can exceed 30 s. Freezing of gait can occur in various situations, such as hesitate to initiating gait, turning, near to destination and across the obstacle or narrow space. Some patients can occur freezing of gait in the square space. Freezing of gait is considered as an independent factor of Parkinson’s disease. Freezing of gait occurs about 50% in advanced Parkinson’s disease. It can be evaluated through Hoehn & Yahr and the new freezing of gait questionnaire.The pathophysiology mechanism of freezing of gait remain unclear. The freezing of gait occured in the Parkinson’s disease ’off’ levodopa treatment was effective to the levodopa, however, that occured in the Parkinson’s disease ’on’ levodopa treatment was no use to the levodopa or surgical treatment. These imply that there might be different mechanism between freezing of gait and other movement disorders in Parkinson’s disease. A growing neuroimaging studies have found that freezing of gait does correlate with cognitive decline, postural instability, and emotion dysfunction, particularly executive dysfunction. The patients with freezing of gait show delayed step initiation associated with repetitive anticipatory postural adjustments due to an inability to inhibit postural preparation and initiate stepping.Resting-state functional magnetic resonance imaging (fMRI) technique is used under a quiet situation with immobility, eyes closed and inactive thinking. Compared to the task-state functional magnetic resonance imaging, functional magnetic resonance imaging is easy and repeatable to operate. Therefore, it has been widely used in functional connectivity networks in the human brain.A growing neuroimaging studies have emphasized that freezing of gait might not be a single clinical phenomenon. Jahn et al found that when freezing of gait patients imaged the situations such as standing, walking and running, brain signals were delivered from frontal lobe and hippocampus, through basal ganglia to the locomotion initiating center of dorsal brainstem, then downstream to the supraspinal regions. The pedunculopontine nucleus play an important role in gait integration. Snijders et al found that when freezing of gait patients showed more activity in the mesencephalic locomotor region and decreased responses in mesial frontal regions during motor imagery of gait compared to those without freezing of gait. All theses imply that the function of cortex to the execution decline and the pedunculopontine nucleus play an important role of it. Tessitore et al using independent component analysis found that among these five networks, patients with freezing of gait have reduced resting-state functional connectivity within the’executive-attention’network of the right hemisphere (middle frontal and angular gyrus) compared with those without freezing of gait, and these two reduced networks were related to clinical severity.Regional homogeneity (ReHo) is a new method to analyze the blood-oxygen-level dependent (BOLD) signal of the brain using kendall’s coefficient of concordance (KCC), which is hypothesized that there would be similar or synchronous hemodynamic characteristics for the every voxel within a functional cluster. Regional homogeneity can reflect the temporal homogeneity of the regional BOLD signal by evaluated the similarity or synchronization between the time series of a given voxel and its nearest neighbors, thus explain which brain functions have changed.To date, there are few studies using Regional homogeneity approaches to analyze the fMRI in Parkinson’s disease patients with freezing of gait.[Objective]In the present study we used Resting-State-functional MRI (RS-fMRI) and regional homogeneity (ReHo) approaches to examine spontaneous neural activity in different frequency bands in participants with Parkinson’s disease with freezing of gait, without freezing of gait, and healthy age-matched controls. We aim to investigate the neural mechanisms in the brain causing freezing of gait and to examine whether freezing of gait PD-related neural changes of pathophysiology mechanism can be revealed.[Materials and Methods]1.ParticipantsWith Institutional Review Board approval,22 Parkinson’s disease patients with freezing of gait (10 female and 12 male) and 23 Parkinson’s disease patients without freezing of gait (9 female and 14 male) were recruited through the department of Neurology in Guangdong General Hospital. All the Parkinson’s disease patients were diagnosed according to 1997 UK Brain Bank criteria. The movement function of patients with freezing of gait were met the 2007 Movement Disorders Society Task Force criteria. And unified Parkinson’s disease rating scale (UPDRS) and Hoehn& Yahr scale were also assessed in patients with freezing of gait and patients without freezing of gait (in the morning OFF medication, after 12h withdrawal from anti-parkinsonian medications). Patients with freezing of gait met the following criteria were enrolled:(a) diagnosed as Parkinson’s disease according to the UK Brain Bank criteria. (b) identified score>0 to item 3 of the Freezing of Gait Questionnaire [’Do you feel that your feet get glued to the floor while walking, making a turn or when trying to initiate walking (freezing)?’]. (c) observed by 2 experienced neurologists when patients performed a brief series of timed up-and-go trials where they were required to make tight 180 degree turns to the left and right and displayed episodes of foot movement cessation, (d) free of any neurologic, psychiatric illnesses, joint replacement, musculoskeletal or vestibular disorders.18 age and gender-matched healthy controls (8 female and 10 male) were recruited from near area in China. All subjects were right handed according to the Edinburgh Handedness Inventory.2. MR Imaging AcquisitionFunctional MRI data were collected in the morning OFF medication, after 12h withdrawal from anti-parkinsonian medications to mitigate the pharmacological effects on neural activity.Brain functional MRI was performed on 3.0T scanner (Signa Excite HD GE, USA) with a 8-channel head coil. The parameters on 3.0T were as followed:a gradient echo planer image (GRE-EPI) sequence were acquired with repetition time (TR)/echo time (TE)= 2000/30 ms, matrix= 64×64, field of view=240×240 mm, slice thickness= 4, NEX=1, voxel size= 3.75mm×3.75mm., time points=186,30 axial slices covering the whole brain for 5580 images. The axial scans were parallel to the anteroposterior commissure (AC-PC) line. High-resolution 3D T1-weighted, anatomical images were obtained for co-registration with functional data. A fast spoiled gradient recalled echo inversion recovery (FSPGRIR) sequence to acquire sagittal T1-weighted images were acquired with repetition time (TR)/echo time (TE) =8.4/3.3 ms, matrix=256×256, flip angle=13°, slice thickness=1, voxel size= 0.47mm×0.47mm.3. Data preprocessingThrough Matlab R2012a, the acquired resting state data were analyzed using software DPARSF(DPARSF_V2.0 Basic Edition, DPARSFA; http://www.restfmri.net) and software REST (resting-state fMRI data analysis Toolkit V1.8.REST V1.8). Preprocessing steps included (1) DICOM convert into NIFTI; (2) Slice timing correction; (3) Realign; (4) Normalize; (5) Smooth; (6) Detrend.Individual ReHo maps without smoothed were generated for each subject using the DPARSF software; Kendall’s coefficient of concordance (KCC) was calculated between 0 to 1. ReHo maps normalization was performed by the averaged KCC of the whole brain. The calibrated ReHo maps were further smoothed using an isotropic Gaussian kernel with a full-width at half maximum (FWNM) of 4 mm×4mm×4 mm.4. Statistical AnalysisThrough software SPSS 13.0 (Chicago, IL,USA), the clinical data between freezing of gait, Parkinson’disease, normal control were compared according to different type of data, including age, gender, education time, disease duration, UPDRS-Ⅲ score, MMSE score. P value less than 0.05 was considered significantly different. Age and gender were considered as covariates. The results were made corresponding to a corrected P value less than 0.05 as determined by AlphaSim correction.ANOVA test was performed for ReHo between freezing of gait, Parkinson’ disease, normal control groups. Voxels with a P value less than 0.05 and a cluster size greater than 85 voxels were considered significantly different, corresponding to a corrected P value less than 0.05 as determined by AlphaSim correction. Differences of ReHo between each two groups were compared by using two sample t test. And then the significant regions were showed by XjView software according to Montreal Neurological Institute(MNI) coordinates.[Results]Among 22 freezing of gait patients,2 freezing of gait patients were removed because of movement artifacts,2 freezing of gait patients were removed because of severe artifacts and frontal lobe deformation caused by frontal sinus,4 freezing of gait patients were removed because of large head motions (>2.5mm) in the z direction. Among 23 Parkinson’ disease patients without freezing of gait,2 freezing of gait patients were removed because of movement artifacts,1 freezing of gait patient was removed because of large head motions (>2.5mm) in the z direction. Therefore,14 Parkinson’ disease patients with freezing of gait (5 female and 9 male) and 20 Parkinson’ disease patients without freezing of gait (9 female and 11 male) and 18 healthy control (8 female and 10 male) were recruited. All subjects were right handed according to the Edinburgh Handedness Inventory.The average age of the remaining freezing of gait patients was (62.14±9.75 years), and the average age of the remaining Parkinson’ disease patients without freezing of gait was (62.70±8.40 years), and the average age of normal control was (63.67±10.21 years). The average education time of the remaining freezing of gait patients was (8.57±4.59 years), and the average education time of the remaining Parkinson’ disease patients without freezing of gait was (9.00±3.82 years), and the average education of normal control was (9.94±3.30 years). Differences of age and education time between those groups were compared by using ANOVA test, and gender between those groups were compared by using pearson χ2 test. No significant differences were found between those groups for age, gender and education time (P>0.05). The median of MMSE in freezing of gait patients was 26.5, the first quartile P25 and the second quartile P75 were 25.5 and 28, respectively; the median of MMSE in Parkinson’ disease patients without was 27, the first quartile P25 and the second quartile P75 were 26 and 29, respectively; the median of MMSE in normal control was 29, the first quartile P25 and the second quartile P75 were 28 and 30, respectively. Nonparametric test was employed to compare MMSE scores between those groups, and there was significant difference (P<0.001), among which there was no significant difference between freezing of gait and Parkinson’ disease patients without freezing of gait in MMSE (P>0.05) and there was significant difference (P<0.001), among which there was significant difference between freezing of gait and normal control in MMSE and between Parkinson’disease patients without freezing of gait and normal control in MMSE (P<0.05). The MMSE of freezing of gait and Parkinson’disease patients without freezing of gait were lower than that of normal control. The disease duration of freezing of gait was (7.93±6.75) years, the median of UPDRS-III was 35.5, the first quartile P25 and the second quartile P75 of UPDRS-III were 29 and 53.5; the median of Hoehn & Yahr (H-Y) was 3, the first quartile P25 and the second quartile P75 of Hoehn & Yahr were 3 and 4. The disease duration of Parkinson’disease patients without freezing of gait was (3.55±2.38) years, the median of UPDRS-III was 35.5, the first quartile P25 and the second quartile P75 of UPDRS-III were 25 and 42; the median of Hoehn & Yahr was 2, the first quartile P25 and the second quartile P75 of Hoehn & Yahr were 1 and 2.5. There were significant differences in disease duration and H-Y scales between freezing of gait and Parkinson’disease patients without freezing of gait (P<0.05), but no significant difference existed in the UPDRS-III of these two group (P>0.05).The ANOVA test revealed significant differences in the ReHo index in freezing of gait, Parkinson’disease patients without freezing of gait and normal control in the following regions:right putamen (Brodmann 48), left supplementary motor area (Brodmann 6) and left superior frontal region (Brodmann 9) (P<0.05; AlphaSim corrected). Differences of ReHo between each two groups were found as follows:left supplementary motor area (Brodmann 6) and left superior frontal region (Brodmann 9) were significant between freezing of gait and Parkinson’disease groups (P<0.05) but right putamen (Brodmann 48) (P>0.05); right putamen (Brodmann 48), left supplementary motor area (Brodmann 6) and left superior frontal region (Brodmann 9) (P<0.05) were both significant between freezing of gait and normal control groups; right putamen (Brodmann 48), left supplementary motor area (Brodmann 6) and left superior frontal region (Brodmann 9) were also significant between Parkinson’ disease and normal control groups (P<0.05).[Conclusion]In the present study we used Resting-State-functional MRI (RS-fMRI) and regional homogeneity (ReHo) approaches to examine spontaneous neural activity in different frequency bands in participants with Parkinson’s disease with freezing of gait, without freezing of gait, and healthy age-matched controls. We found that freezing of gait PD-related neural changes in the frontal lesions and supplementary motor area were associated with the freezing of gait, which could further explain pathophysiology mechanism of freezing of gait in Parkinson’s disease patients. This might help clinical doctors to make a better diagnosis, treatment strategy and preventive measure. |
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