Left or right ear? A neuroimaging study using combined taVNS/fMRI to understand the interaction between ear stimulation target and lesion location in chronic stroke.

BACKGROUND: Implanted vagus nerve stimulation (VNS) and transcutaneous auricular VNS (taVNS) have been primarily administered clinically to the unilateral-left vagus nerve. This left-only convention has proved clinically beneficial in brain disorders. However, in stroke survivors, the presence of a lesion in the brain may complicate VNS-mediated signaling, and it is important to understand the laterality effects of VNS in stroke survivors to optimize the intervention. OBJECTIVE: To understand whether taVNS delivered to different ear targets relative to the lesion (ipsilesional vs contralesional vs bilateral vs sham) impacts blood oxygenation level dependent (BOLD) signal propagation in stroke survivors. METHODS: We enrolled 20 adults with a prior history of stroke. Each participant underwent a single visit, during which taVNS was delivered concurrently during functional magnetic resonance imaging (fMRI) acquisition. Each participant received three discrete active stimulation conditions (ipsilesional, contralesional, bilateral) and one sham condition in a randomized order. Stimulation-related BOLD signal changes in the active conditions were compared to sham conditions to understand the interaction taVNS and laterality effects. RESULTS: All active taVNS conditions deactivated the contralesional default mode network related regions compared to sham, however only ipsilesional taVNS enhanced the activations in the ipsilesional visuomotor and secondary visual cortex. Furthermore, we reveal an interaction in task activations between taVNS and cortical visuomotor areas, where ipsilesional taVNS significantly increased ipsilesional visuomotor activity and decreased contralesional visuomotor activity compared to sham. CONCLUSION: Laterality of taVNS relative to the lesion is a critical factor in optimizing taVNS in a stroke population, with ipsilesional stimulation providing largest direct brain activation and should be explored further when designing taVNS studies in neurorehabilitation.

Newly generated and increased bound phenolic in lychee pulp during heat-pump drying detected by UPLC-ESI-triple-TOF-MS/MS.

BACKGROUND: During the thermal processing of fruit, it has been observed for phenolic compounds to either degrade, polymerize, or transfer into macromolecules. In this study, the bound and free phenolic compound composition, content, and phenolic-related enzyme activity of lychee pulp were investigated to determine whether the free phenolic had converted to bound phenolic during heat-pump drying (HPD). RESULTS: It was found that after HPD, when compared with the fresh lychee pulp (control), the content of bound phenolics of dried lychee pulp had increased by 62.69%, whereas the content of free phenolics of dried lychee pulp decreased by 22.26%. It was also found that the antioxidant activity of bound phenolics had also increased after drying. With the use of high-performance liquid chromatography-tandem mass spectrometry, it was identified that (+)-gallocatechin, protocatechuic aldehyde, isorhamnetin-3-O-rutoside, 3,4-dihydroxybenzeneacetic acid, and 4-hydroxybenzoic acid were newly generated during HPD, when compared with the control sample. After drying, the contents of gallic acid, catechin, 4-hydroxybenzoic acid, vanillin, syringic acid, and quercetin in bound phenolics had also increased, and polyphenol oxidase and peroxidase still showed enzyme activity, which could be related to the conversion of free phenolics to bound phenolics. CONCLUSION: Overall, during the thermal processing of lychee pulp, the free phenolics weres found to be converted into bound phenolics, new substances were generated, and antioxidant activity was increased. Hence, it was concluded that HPD improved the bound phenolics content of lychee pulp, thus providing theoretical support for the lychee processing industry. © 2021 Society of Chemical Industry.

Subthalamic Nucleus Deep Brain Stimulation Modulates 2 Distinct Neurocircuits.

OBJECTIVE: Current understanding of the neuromodulatory effects of deep brain stimulation (DBS) on large-scale brain networks remains elusive, largely due to the lack of techniques that can reveal DBS-induced activity at the whole-brain level. Using a novel 3T magnetic resonance imaging (MRI)-compatible stimulator, we investigated whole-brain effects of subthalamic nucleus (STN) stimulation in patients with Parkinson disease. METHODS: Fourteen patients received STN-DBS treatment and participated in a block-design functional MRI (fMRI) experiment, wherein stimulations were delivered during "ON" blocks interleaved with "OFF" blocks. fMRI responses to low-frequency (60Hz) and high-frequency(130Hz) STN-DBS were measured 1, 3, 6, and 12 months postsurgery. To ensure reliability, multiple runs (48 minutes) of fMRI data were acquired at each postsurgical visit. Presurgical resting-state fMRI (30 minutes) data were also acquired. RESULTS: Two neurocircuits showed highly replicable, but distinct responses to STN-DBS. A circuit involving the globus pallidus internus (GPi), thalamus, and deep cerebellar nuclei was significantly activated, whereas another circuit involving the primary motor cortex (M1), putamen, and cerebellum showed DBS-induced deactivation. These 2 circuits were dissociable in terms of their DBS-induced responses and resting-state functional connectivity. The GPi circuit was frequency-dependent, selectively responding to high-frequency stimulation, whereas the M1 circuit was responsive in a time-dependent manner, showing enhanced deactivation over time. Finally, activation of the GPi circuit was associated with overall motor improvement, whereas M1 circuit deactivation was related to reduced bradykinesia. INTERPRETATION: Concurrent DBS-fMRI using 3T revealed 2 distinct circuits that responded differentially to STN-DBS and were related to divergent symptoms, a finding that may provide novel insights into the neural mechanisms underlying DBS. ANN NEUROL 2020;88:1178-1193.

Functional disruption in prefrontal-striatal network in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. While a cortico-striatal-limbic network has been implicated in the pathophysiology of OCD, the neural correlates of this network in OCD are not well understood. In this study, we examined resting state functional connectivity among regions within the cortico-striatal-limbic OCD neural network, including the rostral anterior cingulate cortex, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, orbitofrontal cortex, ventromedial prefrontal cortex, amygdala, thalamus and caudate, in 44 OCD and 43 healthy participants. We then examined relationships between OCD neural network connectivity and OCD symptom severity in OCD participants. OCD relative to healthy participants showed significantly greater connectivity between the left caudate and bilateral dorsolateral prefrontal cortex. We also found a positive correlation between left caudate-bilateral dorsolateral prefrontal cortex connectivity and depression scores in OCD participants, such that greater positive connectivity was associated with more severe symptoms. This study makes a significant contribution to our understanding of functional networks and their relationship with depression in OCD.

Citrus peel flavonoids improve lipid metabolism by inhibiting miR-33 and miR-122 expression in HepG2 cells.

Citrus plants are rich in flavonoids and beneficial for lipid metabolism. However, the mechanism has not been fully elucidated. Both citrus peel flavonoid extracts (CPFE) and a mixture of their primary flavonoid compounds, namely, nobiletin, tangeretin and hesperidin, citrus flavonoid purity mixture (CFPM), were found to have lipid-lowering effects on oleic acid-induced lipid accumulation in HepG2 cells. The carnitine palmitoyltransferase 1α (CPT1α) gene was markedly increased, while the fatty acid synthase (FAS) gene was significantly decreased by both CPFE and CFPM in oleic acid-treated HepG2 cells. Flavonoid compounds from citrus peel suppressed miR-122 and miR-33 expression, which were induced by oleic acid. Changes in miR-122 and miR-33 expression, which subsequently affect the expression of their target mRNAs FAS and CPT1α, are most likely the principal mechanisms leading to decreased lipid accumulation in HepG2 cells. Citrus flavonoids likely regulate lipid metabolism by modulating the expression levels of miR-122 and miR-33.

AMPK activation is involved in hypoglycemic and hypolipidemic activities of mogroside-rich extract from Siraitia grosvenorii (Swingle) fruits on high-fat diet/streptozotocin-induced diabetic mice.

Previous studies suggested the anti-diabetic effect of mogrosides in type 1 diabetes. To evaluate the potential effect of mogrosides in type 2 diabetes, we herein investigated the hypoglycemic and hypolipidemic effects and the underlying mechanism of mogroside-rich extract (MGE) using a high-fat diet in combination with streptozotocin (STZ)-induced diabetic model. MGE feeding for 5 weeks did not result in any obvious impact on the body weight and energy intake, but caused a moderate decrease of organ index in diabetic mice. MGE-supplemented diabetic mice showed a notable reduction of fasting blood glucose (FBG), glycated serum protein (GSP), serum insulin, homeostasis model assessment-insulin resistance (HOMA-IR), and serum atherogenic lipid profiles in a dose-dependent manner, whereas significant increases in the anti-atherogenic lipid profile, insulin sensitivity, glucose and insulin tolerance capacity with high dose (300 mg kg-1) MGE were observed (P < 0.01). Besides, hepatocyte polymorphism, lipid accumulation and steatosis were ameliorated and restored to near normal at the high dose. Furthermore, hepatic 5'AMP-activated protein kinase (AMPK) signaling was dose-dependently activated. Accordingly, the mRNA levels of hepatic gluconeogenic and lipogenic genes were downregulated and fat oxidation-associated genes were upregulated. These findings suggest that the hypoglycemic and hypolipidemic activities of MGE are probably attributed to the attenuation of insulin resistance and activation of hepatic AMPK signaling.

Antiglycation and antioxidant activities of mogroside extract from Siraitia grosvenorii (Swingle) fruits.

Siraitia grosvenorii (Swingle) is one kind of medical and edible plants with various health-promoting properties. Recently, its hypoglycemic and antidiabetic activities have been reported, but the underlying mechanism remains to be explored. The current study was aimed to investigate the antioxidant and antiglycation activities of mogroside extract (MGE) from Siraitia grosvenorii (Swingle). The results showed that compared to glycated BSA, MGE at middle (125 µg/mL) and high dose (500 µg/mL) significantly inhibited BSA glycation evidenced by decreased fluorescent AGEs formation, protein carbonyls and Nε-(carboxymethyl) lysine (CML) level at 500 µg/mL by 58.5, 26.7 and 71.2%, respectively. Additionally, the antiglycative activity of MGE (500 µg/mL) was comparable to aminoguanidine (AG) at the equal concentration. However, the inhibitory effect of MGE on glycation-induced increase of fructosamine level and decrease of thiol level was not remarkable. MGE was a potent peroxide radicals scavenger (851.8 µmol TE/g), moderate DPPH and ABTS radicals scavenger with IC50 1118.1 and 1473.2 µg/mL, respectively, corresponding to positive controls ascorbic acid of IC50 9.6 µg/mL, and trolox of IC50 47.9 µg/mL, respectively, and mild reducing power. These findings suggest that MGE may serve as a new promising antiglycative agent against diabetic complications by inhibiting protein glycation and glycoxidation.

Brain-Gut Axis Modulation of Acupuncture in Functional Dyspepsia: A Preliminary Resting-State fcMRI Study.

Objective. To explore acupuncture effects on brain functional connectivity in patients with functional dyspepsia (FD). Methods. Eight patients in an acupuncture treatment group and ten healthy adults in the control group participated in the study. Acupuncture effectiveness was evaluated based on changes of the gastrointestinal symptoms, gastric motility measurements, and gastrin levels and comparisons with the control group when appropriate. To investigate functional connectivity changes related to FD and potential modulation after acupuncture, a set of regions of interest (ROIs) were selected according to previous fMRI reports of acupuncture. Results. Patients showed significant improvements of FD signs and symptoms after acupuncture treatments. For all of the ROIs, we identified subportions of the networks showing reduced connectivity in patients with FD. Connectivity between the ROIs and corresponding disease targets showed significant improvement after acupuncture treatment (P < 0.05) in all ROIs except for right medial temporal lobe-hippocampus and right inferior parietal lobule. Conclusion. Functional connectivity of the brain is changed in patients with FD but approximates that in healthy control after acupuncture treatment. The relief of gastrointestinal signs and symptoms by acupuncture is likely due to the normalization of brain-gut axis associated with FD.

Protective effect of flavonoid extract from Chinese bayberry (Myrica rubra Sieb. et Zucc.) fruit on alcoholic liver oxidative injury in mice.

To evaluate the beneficial effects of Chinese bayberry (Myrica rubra Sieb. et Zucc.) flavonoid extract (CBFE) on chronic alcohol-induced liver oxidative injury in mice, experimental mice were pretreated with different doses of CBFE (50-200 mg/kg) for 4 weeks by gavage feeding. Biochemical markers and enzymatic antioxidants from serum, liver tissue, mitochondria and microsomes were examined. Our results showed that the activities of TC, TG, L-DLC in serum, the activity of CYP2E1 in microsomes, and the levels of MDA in liver tissue and mitochondria, decreased significantly (P < 0.05) in the CBFE-treated group compared with the alcohol group. On the contrary, the activities of ALT, AST, and H-DLC in serum, enzymatic antioxidants GSH-Px, SOD and GST in liver tissue and mitochondria, and HO-1 in microsomes rose markedly (P < 0.05). Histopathological examination revealed that CBFE (200 mg/kg) pretreatment noticeably prevented alcohol-induced hepatocyte apoptosis and fatty degeneration. It was suggested that the hepatoprotective effects exhibited by CBFE on alcohol-induced liver oxidative injury may be due to its potent antioxidant properties.

Individual variability in functional connectivity architecture of the human brain.

The fact that people think or behave differently from one another is rooted in individual differences in brain anatomy and connectivity. Here, we used repeated-measurement resting-state functional MRI to explore intersubject variability in connectivity. Individual differences in functional connectivity were heterogeneous across the cortex, with significantly higher variability in heteromodal association cortex and lower variability in unimodal cortices. Intersubject variability in connectivity was significantly correlated with the degree of evolutionary cortical expansion, suggesting a potential evolutionary root of functional variability. The connectivity variability was also related to variability in sulcal depth but not cortical thickness, positively correlated with the degree of long-range connectivity but negatively correlated with local connectivity. A meta-analysis further revealed that regions predicting individual differences in cognitive domains are predominantly located in regions of high connectivity variability. Our findings have potential implications for understanding brain evolution and development, guiding intervention, and interpreting statistical maps in neuroimaging.

[Comparison of brain effects of electroacupuncture at Zusanli (ST 36) and Guanyuan (CV 4) shown by fMRI in 21 healthy volunteers].

OBJECTIVE: To observe different brain effects of electroacupuncture (EA) stimulation of Guanyuan (CV 4) and Zusanli (ST 36) in the normal subjects by using functional magnetic resonance image (fMRI). METHODS: Twenty-one healthy volunteers were recruited in the present study. fMRI was used to investigate brain responses [blood-oxygenation-level-dependent (BOLD) signals] to EA stimulation of CV 4 and ST 36. A filiform silver needle was inserted into CV 4 or the left ST 36 randomly in two consecutive fMRI tests, and then manipulated with uniform reducing-reinforcing methods to induce "Deqi". fMRI scan was performed before needling, during needle retention, during EA stimulation, and post-EA. Volunteer's subjective needling sensations were recorded after EA. Data of fMRI were analyzed by using software SPM 2 and fMRI was mapped by Degree Centrality Measure method for whole brain correlation. The activation, deactivation, short-distance and long-distance functional connectivity maps of cerebral regions were investigated. RESULTS: The fullness and numbness feelings of the subjects were stronger during EA at ST 36 than at CV 4. EA at ST 36 or CV 4 induced apparent similar deactivation effects in the anterior cingulate and medial prefrontal cortices. The default mode of the brain at rest state was modified by needle retention and EA stimulation, respectively. The functional brain network was significantly changed after EA. The instant post-acupuncture effects (enhancement of the shortdistance functional connectivity) were mainly found in the ventral medial prefrontal cortex (VMPF) and ventral anterior cingulate cortex (vACC) in the limbic-paralimbic-neocortical network, and there were a little bit stronger signals in ST 36 than in CV 4. CONCLUSION" EA stimulation of CV 4 and ST 36 induces a similar modulation effect in the limbic-medial prefrontal network in healthy subjects.

The Limbic-Prefrontal Network Modulated by Electroacupuncture at CV4 and CV12.

fMRI studies showed that acupuncture could induce hemodynamic changes in brain networks. Many of these studies focused on whether specific acupoints could activate specific brain regions and were often limited to manual acupuncture at acupoints on the limbs. In this fMRI study, we investigated acupuncture's modulation effects on brain functional networks by electroacupuncture (EA) at acupoints on the midline of abdomen. Acupoints Guanyuan (CV4) and Zhongwan (CV12) were stimulated in 21 healthy volunteers. The needling sensations, brain activation, and functional connectivity were studied. We found that the limbic-prefrontal functional network was deactivated by EA at CV4 and CV12. More importantly, the local functional connectivity was significantly changed during EA stimulation, and the change persisted during the period after the stimulation. Although minor differences existed, both acupoints similarly modulated the limbic-prefrontal functional network, which is overlapped with the functional circuits associated with emotional and cognitive regulation.

[Electroacupuncture at Guanyuan (CV 4) and Zhongwan (CV 12) modulates functional connectivity of the brain network in healthy volunteers].

OBJECTIVE: To observe the specific brain effects of electroacupuncture (EA) stimulation of Guanyuan (CV 4) and Zhongwan (CV 12). METHODS: Twenty-one healthy volunteers were recruited in the present study. Two silver filiform needles were separately inserted into Guanyuan (OV 4) or Zhongwan (CV 12), and manipulated with uniform reducing-reinforcing method to induce "Deqi". fMRI scan was performed before needling, during needle retention, EA stimulation, and post-EA. Data of fMRI was analyzed by using software SPM 2. The volunteer subjective needling sensations were recorded. The activation, deactivation, short-distance and long-distance functional connectivity maps of different cerebral regions were analyzed by using whole brain correlation analysis. RESULTS: Comparison between the two acupoints showed that fullness feeling was stronger in CV 4 than in CV 12. EA at CV 4 and CV 12 induced a similar stronger and prevalent deactivation in the ventral medial prefrontal cortex and the anterior cingulated cortex (ACO). The deactivation of the ACC was stronger in the CV 4 group than in the CV 12 group. The default BOLD mode of the brain at rest was modified by needle retention and EA, respectively. The short-distance functional connection brain network was significantly changed after EA. Interestingly, the ventral medial prefrontal cortex and anteroinferior portion of the anterior cingulate cortex in the limbic-paralimbic-neocortical network (LPNN) were involved in the instant post-effects of EA. Relatively smaller differences in the brain functional activity and short-distance functional connectivity were found between these two acupoints. CONCLUSION: EA of CV 4 and CV 12 can modulate short-distance functional connectivity of the LPNN, and have fewer differences in inducing needling sensation and deactivation of ACC, etc.