Altered Neurovascular Coupling for Multidisciplinary Intensive Rehabilitation in Parkinson's Disease

Abstract

Effective rehabilitation in Parkinson's disease (PD) is related to brain reorganization with restoration of cortico-subcortical networks and compensation of frontoparietal networks; however, further neural rehabilitation evidence from a multidimensional perspective is needed. To investigate how multidisciplinary intensive rehabilitation treatment affects neurovascular coupling, 31 PD patients (20 female) before and after treatment and 30 healthy controls (17 female) underwent blood oxygenation level-dependent functional magnetic resonance imaging and arterial spin labeling scans. Cerebral blood flow (CBF) was used to measure perfusion, and fractional amplitude of low-frequency fluctuation (fALFF) was used to measure neural activity. The global CBF-fALFF correlation and regional CBF/fALFF ratio were calculated as neurovascular coupling. Dynamic causal modeling (DCM) was used to evaluate treatment-related alterations in the strength and directionality of information flow. Treatment reduced CBF-fALFF correlations. The altered CBF/fALFF exhibited increases in the left angular gyrus and the right inferior parietal gyrus and decreases in the bilateral thalamus and the right superior frontal gyrus. The CBF/fALFF alteration in right superior frontal gyrus showed correlations with motor improvement. Further, DCM indicated increases in connectivity from the superior frontal gyrus and decreases from the thalamus to the inferior parietal gyrus. The benefits of rehabilitation were reflected in the dual mechanism, with restoration of executive control occurring in the initial phase of motor learning and compensation of information integration occurring in the latter phase. These findings may yield multimodal insights into the role of rehabilitation in disease modification and identify the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD.SIGNIFICANCE STATEMENT Although rehabilitation has been proposed as a promising supplemental treatment for PD as it results in brain reorganization, restoring cortico-subcortical networks and eliciting compensatory activation of frontoparietal networks, further multimodal evidence of the neural mechanisms underlying rehabilitation is needed. We measured the ratio of perfusion and neural activity derived from arterial spin labeling and blood oxygenation level-dependent fMRI data and found that benefits of rehabilitation seem to be related to the dual mechanism, restoring executive control in the initial phase of motor learning and compensating for information integration in the latter phase. We also identified the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD patients.

Keywords: Parkinson's disease; cerebral blood flow; dynamic causal modeling; functional magnetic resonance imaging; neurovascular coupling; rehabilitation.

Figure 1.

MIRT-induced motor improvement, global and regional neurovascular coupling distribution in PD patients before and after treatment and HCs. The threshold value for establishing significance was set at p < 0.05. A, Violin plots of the UPDRS-III scores before and after treatment. B, Top three rows, The spatial distributions of CBF and fALFF values and the CBF/fALFF ratios in the HCs and PD patients before and after treatment. The maps were averaged across subjects. Despite subtle differences, HCs and PD patients before and after treatment exhibited highly similar spatial distributions in the three measures. The results were mapped on cortical surfaces using BrainNet (https://www.nitrc.org/projects/bnv). Bottom, Scatter plot of the spatial correlations across voxels between CBF and fALFF values in an HC and a PD patient before and after treatment. C, Box plot distributions of global CBF-fALFF coupling in the HCs, PD patients before and after treatment. The solid lines represent the median, boxes represent lower and upper quartiles, and whiskers the minimum and maximum. Patients with PD who underwent treatment exhibited reduced CBF–fALFF coupling (p = 0.020). before, before treatment; after, after treatment; *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 2.

Significant alterations in the CBF, fALFF, and CBF/fALFF ratios before and after treatment (GRF corrected, voxel p value < 0.001, cluster p value < 0.05). A–C, Significant alterations in the CBF values, fALFF values, and CBF/fALFF ratios, respectively. Lingual_L, left lingual gyrus; Frontal_Sup_Medial_L, left superior frontal gyrus (medial); Frontal_Sup_L, left superior frontal gyrus (dorsolateral); Frontal_Sup_R, right superior frontal gyrus (dorsolateral); Calcarine_L, left calcarine fissure and surrounding cortex; Occipital_Sup_R, right superior occipital gyrus; Angular_L, left angular gyrus; Angular_R, right angular gyrus; Temporal_Sup_R, right superior temporal gyrus; Cingulum_Mid_R, right median cingulate and paracingulate gyri; Thalamus_L, left thalamus; Thalamus_R, right thalamus; Cingulum_Mid_L, left median cingulate and paracingulate gyri; Parietal_Inf_R, right inferior parietal with supramarginal and angular gyri; before, before treatment; after, after treatment.

Figure 3.

MIRT-induced alterations in the CBF/fALFF ratios across PD patients before and after treatment and HCs. A, B, The restoration of the normal pattern (A) in the right superior frontal gyrus (dorsolateral), the right superior temporal gyrus, and the right thalamus, as well as the compensatory effect (B) in the left angular gyrus. C, Treatment-related effects cannot be attributed to PD alone in the left thalamus, cingulate gyrus, or the right inferior parietal with supramarginal and angular gyri. The solid lines represent the median, boxes represent lower and upper quartiles, and whiskers the minimum and maximum. Frontal_Sup_R, right superior frontal gyrus (dorsolateral); Cingulum_Mid_L, left median cingulate and paracingulate gyri; Temporal_Sup_R, right superior temporal gyrus; Thalamus_L, left thalamus; Thalamus_R, right thalamus; Angular_L, left angular gyrus; Parietal_Inf_R, right inferior parietal with supramarginal and angular gyri; before, before treatment; after, after treatment; *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 4.

Correlation analysis between brain function and clinical variables. A, The percentage of change in the CBF/fALFF ratio in the right superior frontal gyrus (dorsolateral) was positively correlated with that of the UPDRS-III (r₍₂₅₎ = 0.39; p = 0.02; permutation test, uncorrected). B, C, No such correlation was found in the right superior frontal gyrus (dorsolateral) between the CBF and UPDRS-III (B) or between the fALFF and UPDRS-III (C). The translucent bands around the regression line represent the 95% confidence interval for the regression estimate. The contour lines show the kernel density estimations between brain function (CBF/fALFF ratio, CBF, fALFF) and clinical variables (UPDRS-III). Frontal_Sup_R, right superior frontal gyrus (dorsolateral); before, before treatment; after, after treatment.

Figure 5.

Effective connectivity of DCM analysis. We displayed the suprathreshold effective connectivity (posterior probability > 0.95) related to treatment. A, Regions shown to be involved in DCM analysis and the corresponding MNI coordinates in millimeters used for the DCM analysis. B, Connections showing a significant association with treatment (before vs after). Purple, before < after; green, before > after. C–E, Group mean effective connectivity in the HCs (C), PD patients before (D), and after treatment (E). Arrows have been weighted to indicate the relative size of the effects. Frontal_Sup_R, right superior frontal gyrus (dorsolateral); Angular_R, right angular gyrus; Parietal_Inf_R, right inferior parietal gyrus with supramarginal and angular gyri; Thalamus_L, left thalamus; Thalamus_R, right thalamus; before, before treatment; after, after treatment.