Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong.

Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using high-performance ion chromatography-tandem mass spectrometry (HPIC-MS/MS) to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In-vivo and in-vitro studies revealed that these effects of JMT were mainly attributed to the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.

Trait- and State-Dependent Changes in Cortical-Subcortical Functional Networks Across the Adult Lifespan.

BACKGROUND: How the functional interactions of the basal ganglia/thalamus with the cerebral cortex and the cerebellum change over the adult lifespan in movie-watching and resting-state is less clear. PURPOSE: To investigate the functional changes in the organization of the human cortical-subcortical functional networks over the adult lifespan using movie-watching and resting-state fMRI data. STUDY TYPE: Cohort. SUBJECTS: Healthy 467 adults (cross-sectional individuals aged 18-88 years) from the Cambridge Centre for Ageing and Neuroscience (www.cam-can.com). FIELD STRENGTH/SEQUENCE: fMRI using a gradient-echo echo-planar imaging (EPI) sequence at 3 T. ASSESSMENT: Functional connectivities (FCs) of the subcortical subregions (i.e. the basal ganglia and thalamus) with both the cerebral cortex and cerebellum were examined in fMRI data acquired during resting state and movie-watching. And, fluid intelligence scores were also assessed. STATISTICAL TESTS: Student's t-tests, false discovery rate (FDR) corrected. RESULTS: As age increased, FCs that mainly within the basal ganglia and thalamus, and between the basal ganglia/thalamus and cortical networks (including the dorsal attention, ventral attention, and limbic networks) were both increased/decreased during movie-watching and resting states. However, FCs showed a state-dependent component with advancing age. During the movie-watching state, the FCs between the basal ganglia/thalamus and cerebellum/frontoparietal control networks were mainly increased with age, and the FCs in the somatomotor network were decreased with age. During the resting state, the FCs between the basal ganglia/thalamus and default mode/visual networks were mainly increased with age, and the FCs in the cerebellum were mainly decreased with age. Moreover, inverse relationships between FCs and fluid intelligence were mainly found in these network regions. DATA CONCLUSION: Our study may suggest that changes in cortical-subcortical functional networks across the adult lifespan were both state-dependent and stable traits, and that aging fMRI studies should consider the effects of both physiological characteristics and individual situations. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 3.

Pallidal volume reduction and prefrontal-striatal-thalamic functional connectivity disruption in pediatric bipolar disorders.

BACKGROUND: As a crucial node of the corticolimbic model, the striatum has been demonstrated in modulating emotional cues in pediatric bipolar disorders (PBD), the striatal distinction in structure and function between PBD-I and PBD-II remains unclear. METHODS: MRI data of 36 patients in PBD-I, 22 patients in PBD-II and 19 age-gender matched healthy controls (HCs) were processed. Here, we investigated structural and functional alterations of 8 subregions of striatum (bilateral nucleus accumbens, caudate, putamen and globus pallidus) by analyzing MRI data. RESULTS: We found volume reduction of the right pallidum, the significant positive correlation between the number of episodes and the functional connectivity between left pallidum and right caudate in PBD-I patients, abrupted prefrontal-striatal-thalamic functional connectivity in PBD-I group and decreased functional connectivity in PBD-II relative to HCs and PBD-I. LIMITATIONS: Future studies should enroll more subjects and adopt a longitudinal perspective, which could help to discover striatum structural or functional alterations during subject-specific clinical progress in different states. CONCLUSIONS: Results of the present study confirmed that structural and functional abnormality of striatum may be helpful in identifying PBD clinical types as distinctive biomarkers. The interruptions of the prefrontal-striatal-thalamic circuits may provide advantageous evidence for expounding the role of striatum in bipolar disorders etiology. Thus, potential mechanisms of dysfunction striatum need to be formulated and reconceptualized with multimodal neuroimaging studies in future.

Shared and specific patterns of structural and functional thalamo-frontal disturbances in manic and euthymic pediatric bipolar disorder.

Bipolar disorder (BD) is clinically defined by alternating depressive and manic episodes with a separated period of euthymia. Thalamo-frontal loop plays vital role in psychotic symptoms, altered motor control and executive difficulties in BD. It remains unclear that structural and functional alterations of thalamo-frontal loop among the different mood states in BD, especially in pediatric BD(PBD).Twenty manic PBD (mPBD), 20 euthymic PBD (ePBD) and 19 healthy controls (HCs) were included in the study. By analyzing the T1 images and fMRI signals, thalamus volume and frontal grey matter cortical thickness were tested, and functional connectivity (FC) between bilateral thalamus and frontal cortex was calculated. Relationship between clinical indices and thalamo-frontal FC was also evaluated in mPBD and ePBD adolescents.Compared to HCs, the cortical thickness of left middle frontal gyrus (MFG), bilateral superior frontal gyrus (SFG) was significantly decreased in both mPBD and ePBD patients, and volume of left thalamus and cortical thickness of right MFG significantly decreased in mPBD patients. Compared to that of the HCs and ePBD subjects, thalamo-frontal hyperconnectivity with MFG was found in mPBD, and compared with that of HCs, thalamo-frontal hypoconnectivity with precentral gyrus/SFG was found in ePBD. In ePBD patients, episode times positively correlated with FC values between thalamus and precentral gyrus.The findings of the present study demonstrate detailed knowledge regarding shared and specific structural and functional disruption in thalamo-frontal loop in mPBD and ePBD subjects. Thalamo-frontal abnormalities reported in adult BD subjects were also observed in adolescent BD patients, and thalamo-frontal dysfunction may be a crucial treatment target in BD.