A Resting-state Functional MRI Study Based On Regional Homogeneity In Parkinson’s Disease

[Background]Parkinson’s disease (PD) is an aging-related progressive neurodegenerative disorder initially described in the 1800’s by James Parkinson as the’Shaking Palsy’. It is the most common serious movement disorder in the world, affecting about 1% of adults older than 60 years. In China, it is estimated that prevalence of Parkinson’s disease for adults older than 65 years is 1.7%, which is similar to that in developed countries. PD is a multifaceted disorder with a wide-range of clinical symptoms, which are viewed as motor and non-motor symptoms. The initial motor symptoms comprise the tremor, rigidity, akinesia and postural changes. The frequency of symptoms outside the motor phenomena of PD is substantial, collectively a range of symptoms including autonomic, behavioral (Neuropsychiatric-depression, psychosis), cognitive, olfactory, sensory and sleep disorders. The prevalence of dementia in PD is close to 30%, and its incidence is increased by 6 to 7 times over the general age-appropriate population. In general progression of these clinical problems may result in patients requiring care in a supervised environment. PD is one of the most main causes of disability in the elder.The cause of PD is enigmatic in most individuals. Pathologically, the degeneration of dopaminergic cells in the pars compacta of substantia nigra results in dopamine depletion in the striatum, then, the dysfunction of cortico-striatal-thalamic loops ensues. Dopamine depletion in PD leads to a remapping of cerebral connectivity that reduces the spatial segregation between different cortico-striatal loops. When dopamine depletion reaches 50-60% of normal in the contralateral striatum, the classic unilateral features of PD emerge. Subsequently, systematic pathological studies revealed that the pathology of PD is included regions outside the dopamine system. The disease is attributed in part to the presence of intracytoplasmic inclusions that contain the protein, alpha-synuclein. PD displays accumulations of alpha-synuclein, which aggregated forms (e.g., amyloid structures) are toxic. PD is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, which composed primarily of the protein a-synuclein.Clinically, dopamine replacement has become the main therapy in patients with PD. However, symptoms of Parkinson’s disease respond in varying degrees to drugs. Clinical syndromes are not fully treated by these therapies, nor be the natural history of this disorder motivating clinicians altered. Excessive dopamine may alter activity in other brain regions and be associated with cognitive dysfunction of patients with PD. surgery offers hope for patients no longer adequately controlled in dopamine replacement. The socioeconomic burden of PD is great. Given the oncoming wave of our aging population, as well as the relatively long disease duration and relentlessly progressive nature of this disease, these costs are predicted to increase greatly in the coming years.Resting-state functional magnetic resonance imaging (fMRI) technique, as a noninvasive and nonradiative means, has been widely used in functional connectivity networks in the human brain. In early PD patients as compared to healthy control, it was reported that cognitive decline may be associated with the abnormal spontaneous brain activity occured in occipital regions and associative cortical areas in patients with PD. Despite improvement in motor symptoms, the effect of dopaminergic medication on cognition in PD is less clear. In application to PD disease, fMRI study has demonstrated different functions mediated by the ventral and dorsal striatum, in consequence, dopamine replacement improves dorsal striatum-mediated motor symptoms but impairs ventral striatum function. There is no significant difference in the resting-state networks integrity between cognitively normal PD patients on dopaminergic medication and healthy people. The effect of dopamine in cognitive networks may be dose-dependent. The dopaminergic medication has changed the neural oscillation, which has in turn changed in cognitive performance.Recently, Zang et al have developed a new method, regional homogeneity (ReHo), to analyze the blood-oxygen-level dependent (BOLD) signal of the brain. It is hypothesized that there would be similar hemodynamic characteristics for the every voxel within a functional cluster. ReHo is suggested to reflect the temporal homogeneity of the regional BOLD signal by evaluated the similarity between the time series of a given voxel and its nearest neighbors. Different value of ReHo implies different hemodynamic response of the functional cluster. Based on data-driven approach, ReHo does not require the onset time of stimulus and have good test-retest reliability. Therefore, it is more useful for the study of resting-state fMRI. This method has been applied to explore the functional modulations in the resting state in the patients with Alzheimer’s disease (AD), patients with PD and patients with schizophrenia.[Objective]Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction. However, there is much pathophysiology remained unclear. Functional magnetic resonance imaging (fMRI) has been widely used on the research of PD. These studies have generally focused on task-related neural activity. However, the brain activity shown in fMRI studies is closely related to the "task" and "baseline resting" condition during movement performance. Therefore, we used resting-state functional MRI to examine human regional homogeneity in patients with PD and normal control (NC) subjects in order to investigate PD-related modulations of neural activity.[Materials and Methods]1.participantsThirty-five patients with Parkinson’s disease and 31 age- and gender-matched healthy controls were recruited. The patients with Parkinson’s disease were diagnosed by experienced neurologists according to the UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria. All patients were evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS), Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MOCA) and the Hoehn and Yahr scale in OFF medication state. The inclusion criteria for PD patients were (a) Hoehn and Yahr stages 1-2.5; (b) Hachinski Ischemic Score (HIS)< 4 points; (c) without any psychiatric or neurological disease history; (d) MRI scan revealed only cerebral atrophy and little T2WI high signal in deep white matter (maximum diameter<1 cm). The exclusion criteria were (a) acute cerebrovascular disease history in recent 3 months; (b) active epilepsy; (c) mental illness history such as delirium, depression or anxiety disorders; (d) patients diagnosed with Parkinsonism-Plus or secondary Parkinson syndrome; (e) severe claustrophobia, and contraindications to MRI (e.g. pacemaker, metallic foreign bodies). All healthy controls were assessed with MMSE and Hoehn and Yahr scale. The inclusion criteria for healthy controls were (a) neurological examination revealed no abnormality; (b) without any psychiatric or neurological disease history; (c) MRI examination revealed no abnormality except for cerebral atrophy and little T2WI high signal in deep white matter (maximum diameter < 1 cm); (d) Clinical Dementia Rating (CDR) was 0. All participants were right handed. Akinesia was the predominant symptom and was dominant on the right side in every patient. In the current study, all patients had an obvious delay in movement initiation, and had at most a mild tremor. Patients were assessed with the Unified Parkinson’s Disease Rating Scale (UPDRS; Lang and Fahn 1989), and the Hoehn and Yahr disability scale (Hoehn and Yahr,1967) while off their medications. Our study was approved by our institutional ethics committee. All participants signed a written informed consent prior to participation.2. MR Imaging AcquisitionAll participants underwent resting-state fMRI scan. fMRI data were collected from a 3T GE MRI scanner (Signa Excite II HD GE Healthcare, Milwaukee, WI). Before MRI scanning, every participant was instructed to keep eyes closed, not to think of anything in particular, and not to fall asleep. During the scanning, the subject was positioned supine in the gantry of the scanner with foam padding to limit head movement and ear plugs to reduce the impact of machine noise. For the functional resting state data, a gradient echo planer image (GRE-EPI) sequence was used to obtain axial images (repetition time/echo time (TR/TE)= 2000/30 ms, field of view (FOV)=240 mm×240 mm, matrix=64×64, flip angle (FLA)=80°, voxel size= 3.75 mm×3.75 mm, slice thickness=5mm, inter-slice space=0, slices=30). For the structural images, a fast spoiled gradient recalled echo inversion recovery (FSPGRIR) sequence was used to acquire sagittal T1-weighted images (TR=7.6 ms, TE=3.4ms, FOV=240 mm x 240 mm, matrix=256 x 256, FLA=20°, voxel size= 0.47 mm x 0.47 mm, slice thickness=1mm, inter-slice space=0, slices=146).3. Data preprocessingThe acquired resting state data were analyzed using software DPARSF (Data Processing Assistant for Resting-state fMRI, http://www.restfmri.net) which is based on SPM8 (Statistical Parametric Mapping, Version 8, Welcome Department of Cognitive Neurology) implemented in Matlab R2008b. Preprocessing steps included (1) discarding the first 10 time points of fMRI data for each subject to eliminate the impact of magnetization equilibrium; (2) slice-time correction; (3) head motion correction by aligning to the first image of each session (participant’s head movements were limited to less than 1.5mm in translation and 1.5° in rotation; (4) spatial normalization to a Montreal Neurological Institute (MNI) standard space (EPI MNI-152 space); (5) removing linear drift; (6) temporarily low-pass filtering (0.01 0.08 HZ) to remove low-frequency drifts and physiological high-frequency noise.Individual ReHo maps were generated for each subject using the REST software; Kendall’s coefficient of concordance (KCC) was calculated at each voxel to establish similarities between the time series of each specific voxel and its 26 neighboring voxels. The KCC value was calculated to this voxel, and an individual KCC map was obtained for each subject. To reduce the influence of individual variations in the KCC value, ReHo maps normalization was performed by dividing the KCC among each voxel 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 mmx4mm×4mm.4. Statistical AnalysisDifferences of age between the two groups were compared by using Student t test, and Pearson χ2 test was applied to compare patient gender. Two independent-samples nonparametric test was employed to compare MMSE scores between PD and NC group.The one-sample t test was performed on the resting-state REST data for each group. Voxels with a P value less than 0.001 and a cluster size greater than 6 voxels were considered significantly different, corresponding to a corrected P value less than 0.05 as determined by AlphaSim correction in REST software. Subsequently, the regions that showed significant differences were extracted as a mask. A two-sample t test was performed on the resting-state REST data to identify the ReHo maps from the PD group and control group. Corresponding to a corrected P value less than 0.05 as determined by AlphaSim correction, a cluster size greater than 29 voxels was considered significantly different.[Results]Four PD patients and four healthy controls were removed because of large head motions (>1.5mm) in the z direction. Two PD patients and six healthy controls were discarded due to severe artifacts and frontal lobe deformation caused by frontal sinus. One healthy control was excluded because the subject cannot endure the whole fMRI scanning and the 3D structural data was not collected. The remaining 29 patients (59.79±10.39 years; 7 males,22 females) and 20 healthy controls (60.64±4.58 years; 13 males,15 females) were involved in further analysis. No significant differences were found between PD and control groups for age, male-to-female ratio. There was significant difference in MMSE scores between the two groups (P<0.02). The one-sample t test revealed significant differences in the ReHo index in the patients with PD in the following regions:right cerebellum anterior lobe, left middle occipital gyrus, left inferior frontal gyrus, left corpus callosum, right caudate, left middle frontal gyrus, right superior frontal gyrus, left brodmann, right middle frontal gyrus (P<0.001; AlphaSim corrected). Then, a two-sample two-tailed t-test was performed to determine differences in the ReHo value between the PD and NC group. Compared with the control group, the PD group showed increased regional activity in the right fusiform, right precuneus, left brodmann area, left paracentral lobule, left cerebellum posterior lobe; and the decreased regional activity in the left cerebellum posterior lobe, right lingual gyrus, right middle temporal gyrus, right inferior frontal gyrus, right middle temporal gyrus, left middle occipital gyrus, left middle occipital gyrus, right superior frontal gyrus, right precentral gyrus, left putamen (P<0.05; AlphaSim corrected).[Conclusion]In conclusion, the current results show that the pattern of neuronal activity is altered in the resting state in patients with PD. There were widespread differences in the ReHo values between the patients with PD and normal subjects within default mode network, supplementary motor area, premotor area, cerebellum. Dopamine depletion in patients with PD leads to a change of neuronal coherence that affects predominantly the sensorimotor circuit and integration. This change can be influenced by levodopa, which is closely associated with motor and non-motor symptoms. It is appropriate to use this noninvasive and simplistic method to measure the severity and monitor the progression of PD.