A Single-Blinded Trial Using Resting-State Functional Magnetic Resonance Imaging of Brain Activity in Patients with Type 2 Diabetes and Painful Neuropathy

Qing Zhang, Peng Zhang, Rui Yan, Xianghong Xu, Cunnan Mao, Xiaomei Liu, Fengfei Li, Jianhua Ma, Lei Ye, Zhijian Yao, Jindan Wu, Qing Zhang, Peng Zhang, Rui Yan, Xianghong Xu, Cunnan Mao, Xiaomei Liu, Fengfei Li, Jianhua Ma, Lei Ye, Zhijian Yao, Jindan Wu

Abstract

About two-thirds of patients with painful diabetic neuropathy (PDN) suffer from anxiety and/or depression disorders. However, the pathogenesis of PDN is unclear, in particular with respect to the mechanism associated with the central nervous system. We used the neuroimaging techniques of fraction amplitude of low-frequency fluctuation (fALFF) and regional homogeneity of resting-state functional magnetic resonance imaging (fMRI) to explore the brain activity in patients with PDN. The symptoms, signs and mental conditions of 19 patients with PDN and of 18 patients with non-pain neuropathy were assessed separately and compared. Blood oxygenation level-dependent resting-state fMRI scans of the brain were performed in all 37 patients with neuropathy and in 15 gender- and age-matched healthy controls. Our data showed that patients with PDN had increased insulin resistance (p = 0.03), increased depression (p = 0.02) and increased anxiety (p < 0.001) compared with the controls and that all of these conditions were associated with abnormal spontaneous activities in several regions of the brain, including the somatosensory, cognitive and emotional regions. The duration of diabetes, level of glycated hemoglobin, homeostasis model assessment of insulin resistance and estimated glomerular filtration rate were significantly correlated to abnormal spontaneous activity in patients' brains. These results lead to the conclusion that patients with PDN have abnormal brain activity, indicating that the central nervous system may contribute to painful diabetic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03700502.

Keywords: Fraction amplitude of low-frequency fluctuation; Painful diabetic neuropathy; Regional homogeneity; Resting state functional MRI.

Figures

Fig. 1
Fig. 1
Images of the fraction amplitude of low-frequency fluctuation (fALFF) in the transverse plane (a), coronal plane (b) and sagittal plane (c) to show areas that had significantly different activity intensity among the three groups. The fALFF data were analyzed by analysis of variance (ANOVA). Red color indicates an area that has significant difference in activity intensity
Fig. 2
Fig. 2
Images of fALFF in the transverse plane (a), coronal plane (b), and sagittal plane (c) to show areas that had significantly different activity intensity between the Group-PDN and Group-N. Two-independent samples t test was performed. Red color indicates an area that has an increased activity intensity of the Group PDN, and blue indicates a decrease. (d) Quantification of peak region from the x, y and z coordinates. Peak region obtained using the automated anatomical labeling (AAL) function; x, y, z coordinates of primary peak locations in the Montreal Neurological Institute (MNI) space. K value represents the continuous voxel value; positive t value indicates the fALFF value increases; negative t value indicates the fALFF decreases
Fig. 3
Fig. 3
Images of regional homo- geneity (ReHo) in the transverse plane (a), coronal plane (b), and sagittal plane (c) to show areas that had significantly different activity synchronism among the three groups. The ReHo data was analyzed by analysis of variance (ANOVA). Red color indicates an area that has significant difference in activity synchronism
Fig. 4
Fig. 4
Images of ReHo in the Frontal_Mid_R (a), Heschl_L (b) and Parietal_Inf_L (c) sequences to show areas that had increased activity synchronism. Two-independent samples t test was performed between the Group PDN and Group N. Red color indicates an area that has increased activity synchronism in the Group PDN, and blue indicates a decrease. (d) Quantification of x, y and z coordinates of primary peak locations in the Montreal Neurological Institute (MNI) space. Peak region obtained from AAL; x, yz coordinates of primary peak locations in the MNI space. K value represented the continuous voxel value; positive t value indicates the ReHo value increases; negative t value indicates the ReHo value decreases
Fig. 5
Fig. 5
Correlations between fALFF and ReHo in abnormal brain regions and the clinical index of patients. a, b In Group-PDN, the fALFF of the the Frontal_Inf_Oper_L sequence was negatively related to eGRF value (a) and in Group-N, the fALFF of the Frontal_Inf_Oper_L sequence was positively related to estimated glomerular filtration (eGRF) level (b). c In Group-PDN, the fALFF of the Frontal_Inf_Oper_L sequence was negatively related to glycated hemoglobin (HbA1c) level. d In Group-N, the fALFF of the Parietal_Inf_L sequence was positively related to HbA1c value. e In Group-PDN, the fALFF of the Occipital_Mid_L sequence was negatively related to the homeostasis model assessment-insulin resistance (HOMA-IR) value. f In Group-N, the fALFF of the Postcentral_L sequence was negatively related to HOMA-IR. g In Group-PDN, the ReHo of the PDN in Frontal_Mid_R sequence was positively related to diabetes course

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