Multi-model Magnetic Resonance Imaging Study On The Neural Mechanism Of Freezing Of Gait In Parkinson’s Disease

BackgroundParkinson’s disease is a common and complex neurological disorder.The crucial pathological feature of Parkinson’s disease is loss of dopaminergic neurons within the substantia nigra（SN）.Freezing of gait（FOG）is one of the most common motor symptoms experienced by patients with Parkinson’s disease（PD）and is defined as a brief and sudden inability to initiate walking,despite the intention to step.FOG always reduces mobility,significantly increases the risk of tumbles and possibly causes devastating consequences.As the neural mechanisms of FOG currently remain mysterious,current treatments for this disabling symptom are not satisfactory.With the development of multi-modal magnetic resonance imaging（MRI）and novel analysis methods providing multi-dimension perspectives,such as structure,metabolism and functional network changes of the whole brain,we can investigate the pathogenesis mechanisms of FOG in depth.Objective1.The downregulation of monoamines,especially dopamine in SN and norepinephrine in locus coeruleus（LC）,may be responsible for the FOG pathological basis.Thus,in part one we investigate MRI features of the SN and LC in PD patients with FOG.2.The altered perfusion in the cortico-basal ganglia-thalamic network may be associated with FOG symptoms in PD patients.Therefore,in part two,we investigate the alterations of FOG related cerebral blood flow（CBF）by MRI perfusion.3.The thalamus is not only a key relay node of thalamocortical circuit but also a hub in the regulation of gait.In part 3,we investigate the static and dynamic functional connectivity of the individual thalamic nuclei with cerebrocortex in FOG patients of PD by functional MRI.Methods1.Sixty-four PD patients,including 32 Parkinson’s disease patients with freezing of gait（PD-FOG）and 32 Parkinson’s disease patients without freezing of gait（PD-NFOG）,and 32 healthy controls（HC）underwent neuromelanin MRI.The volume,surface area and contrast to noise ratio（CNR）of SN and LC were measured and compared between PD-FOG,PD-NFOG and HC.The correlation analyses were conducted between the measurements of SN with clinical PD symptoms and the measurements of LC with clinical FOG severity.We plotted the receiver operating characteristic（ROC）curve and determine the sensitivity and specificity of the CNR of SN and LC for discriminating the PD group from the HC group and the PD-FOG group from the PD-NFOG group.2.Sixty PD individuals,including 30 PD-FOG and 30 PD-NFOG,and 30 HC underwent arterial spin labelling perfusion weighted imaging.The CBF were voxelwise compared among the three groups and validated in a different cohort of PD-FOG and PD-NFOG.The correlation analyses were conducted between the CBF values with clinical FOG severity.3.Fifty PD patients,including 25 PD-FOG and 25 PD-NFOG,and 25 HC underwent resting-state functional MRI.Seed-voxel-wise static and dynamic functional connectivity were calculated between thalamic nuclei and other voxels across the brain using the 14 thalamic nuclei in both hemispheres as regions of interest.Associations between altered thalamic functional connectivity based on significant inter-group differences and severity of FOG symptoms were also examined in PD-FOG.Results1.Both PD-FOG and PD-NFOG showed decreased volume,surface area and CNR of SN compared with HC.The PD-FOG exhibited decreased volume and surface area of LC compared with both PD-NFOG and HC groups,and decreased CNR of LC compared with HC group.The volume,surface area and CNR of SN were negatively correlated with unified Parkinson’s disease rating scale part III scores of all PD patients.The illness durations in PD patients were negatively correlated with the volume,surface area of SN,while not the CNR.And the volume and surface area of LC were negatively correlated with new freezing of gait questionnaire（NFOGQ）scores in PD-FOG.ROC analyses indicated that the area under the curve was 0.865 and 0.713 in the CNR of SN and LC,respectively,in PD versus HC,whereas it was 0.494 and 0.637 respectively,in PD-FOG versus PD-NFOG.Among these,for discriminating the PD from the HC,the sensitivity and specificity in the CNR of the SN was 90.6%and 71.9%,respectively,when the cut-off value was set at 2.101;the sensitivity and specificity in the CNR of the LC was 90.6%and 50.0%,respectively,when the cut-off value for CNR was set at 1.411.2.Compared with PD-NFOG,PD-FOG had increased CBF in bilateral thalamus and the left caudate nucleus and decreased CBF in the left inferior parietal cortex.The intergroup differences of CBF between PD-FOG and PD-NFOG were confirmed in a different cohort of 15 PD-FOG and 15 PD-NFOG in the validation analysis.Moreover,the CBF value in left caudate nucleus was positively correlated with the NFOGQ score in PD-FOG（r=0.409,P=0.025）.3.Both PD-FOG and PD-NFOG showed lower static functional connectivity between the right lateral posterior thalamic nuclei and right inferior parietal lobule compared with HC.Altered functional connectivity dynamics between the thalamic nuclei and several cortical areas were identified in PD-FOG,as shown by temporal dynamic functional connectivity analyses.Specifically,relative to PD-NFOG or HC,PD-FOG showed greater fluctuations in functional connectivity between the left intralaminar（IL）nuclei and right inferior parietal lobule and between the left medial geniculate and left postcentral gyrus.Furthermore,the dynamics of functional connectivity between the left pulvinar anterior nuclei and left inferior frontal gyrus were upregulated in both PD-FOG and PD-NFOG.The dynamics of functional connectivity between the right ventral lateral nuclei and left paracentral lobule were elevated in PD-NFOG but were maintained in PD-FOG and HC.The quantitative variability of functional connectivity between the left IL nuclei and right inferior parietal lobule was positively correlated with NFOGQ scores in PD-FOG（r=0.414,P=0.040）.Conclusions1.The dopaminergic changes in the SN were found across both PD-FOG and PDNFOG,whilst LC noradrenergic neuron reduction was more evident in PD-FOG.2.Perfusion alterations in both cortical and subcortical regions in the cortico-basal ganglia-thalamic network were related to the development of FOG phenomenon in PD.3.Dynamic functional connectivity between the thalamic nuclei and relevant associative cortical areas involved in sensorimotor integration or cognitive function was disrupted in PD-FOG reflected by greater temporal fluctuations.Abnormal dynamic functional connectivity between the left IL nuclei of the thalamus and right inferior parietal lobule was related to the severity of FOG.In summary,with the help of multi-modal MRI techniques,we have explored the related neural mechanisms of FOG in PD,providing underlying clues and theoretical supports for the possible use of neuromodulation effects to improve the gait freezing of PD patients in the future.