Fufang Zhenzhu Tiaozhi (FTZ) capsule ameliorates diabetes-accelerated atherosclerosis via suppressing YTHDF2-mediated m6A modification of SIRT3 mRNA.

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Zhenzhu TiaoZhi (FTZ), a Chinese medicinal decoction, has continuously been used to treat metabolic syndrome. Atherosclerosis is the main pathological basis of cardiovascular disease. The N6 methyladenosine (m6A) modification is a highly dynamic and reversible process involving a variety of important biological processes. AIM OF THE STUDY: Here, we investigated the therapeutic effects and mechanism of FTZ in diabetes-accelerated atherosclerosis. MATERIALS AND METHODS: Doppler ultrasonography was used to examine the carotid intima-media thickness and plaque area in diabetic atherosclerosis patients. HFD mice were injected with streptozotocin to induce diabetes. HE and Oil red O staining were used to assess the effect of FTZ on lipid deposition. HUVECs were induced with HG/ox-LDL as a model of diabetic atherosclerosis. Furthermore, application of m6A methylation level kit, qRT-PCR, Western blot, tunel staining, reactive oxygen species staining and mPTP staining were performed to analyze the detailed mechanism. RESULTS: Clinical trials of FTZ have shown obvious effect of lowering blood glucose and blood lipids. These effects were reversed after FTZ intervention. Compared with the control, lipid deposition decreased significantly after FTZ administration. FTZ reduced endothelial cell apoptosis. At the same time, we found that FTZ reversed the increase of methylation reader YTHDF2 caused by ox-LDL treatment. Subsequently, we discovered that YTHDF2 degraded SIRT3 mRNA, leading to endothelial cell apoptosis and oxidative stress. CONCLUSION: FTZ attenuated diabetes-accelerated atherosclerosis by decreasing blood glucose and serum lipids levels, and increased endothelial cell antioxidant capacity, inhibited endothelial cell apoptosis via inhibiting YTHDF2-mediated m6A modification of SIRT3 mRNA, which reduced mRNA degradation.

Fu Fang Zhen Zhu Tiao Zhi Capsules Protect against Myocardial Ischemia by Inhibiting Cardiomyocyte Pyroptosis.

Background: Fu Fang Zhen Zhu Tiao Zhi (FTZ) is a traditional Chinese herbal prescription widely used to treat dyslipidemia, metabolic diseases, and diabetic coronary disorders. Cardiomyocyte death and loss of regenerative ability cause cardiac dysfunction and heart failure. FTZ can effectively treat diabetic cardiomyopathy and macrovascular diseases; however, the mechanism behind the phenomenon is still unclear. Here, we determined the mechanism of action of FTZ in treating myocardial infarction. Methods: Male C57BL/6 mice were treated with 2.4 or 1.2 g/kg FTZ, or administered saline by oral gavage daily for four weeks, and a 24-hour ligation was administered to the artery. Echocardiography was used to evaluate cardiac function. Hematoxylin and eosin and Evans blue/triphenyltetrazolium chloride staining were carried out by staining the cardiac tissue, used to evaluate cardiac function and infarct size. Using western blotting and reverse transcriptase-polymerase chain reaction, we determined the relative levels of NOD-like receptor protein (NLRP) 3, ASC, cleaved caspase-l (C-Caspase-1), GSDMD, and GSDMD-N. TUNEL, immunohistochemical, and immunofluorescence staining were used to determine cell death and NLRP3 expression. An enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of interleukin (IL)-1ß and IL-18. Results: FTZ reduced ischemia-induced cardiomyocyte cell death in vivo and H2O2-induced cell death in vitro by maintaining cardiac architecture and restoring cardiac function. FTZ decreased the NLRP3 expression and inhibited pyroptosis-correlated genes, including NLRP3, ASC, GSDMD, C-Caspase-1, and GSDMD-N. NLRP3 overexpression impaired the efficacy of FTZ by inducing pyroptosis. Conclusion: FTZ could preserve cardiac function resulting from ischemic insult by inhibiting pyroptosis, which was partially reversed by NLRP3 overexpression, indicating that NLRP3 could be a potential target of FTZ in treating myocardial infarction.

Closed-Loop Deep Brain Stimulation for Essential Tremor Based on Thalamic Local Field Potentials.

BACKGROUND: High-frequency thalamic stimulation is an effective therapy for essential tremor, which mainly affects voluntary movements and/or sustained postures. However, continuous stimulation may deliver unnecessary current to the brain due to the intermittent nature of the tremor. OBJECTIVE: We proposed to close the loop of thalamic stimulation by detecting tremor-provoking movement states using local field potentials recorded from the same electrodes implanted for stimulation, so that the stimulation is only delivered when necessary. METHODS: Eight patients with essential tremor participated in this study. Patient-specific support vector machine classifiers were first trained using data recorded while the patient performed tremor-provoking movements. Then, the trained models were applied in real-time to detect these movements and triggered the delivery of stimulation. RESULTS: Using the proposed method, stimulation was switched on for 80.37 ± 7.06% of the time when tremor-evoking movements were present. In comparison, the stimulation was switched on for 12.71 ± 7.06% of the time when the patients were at rest and tremor-free. Compared with continuous stimulation, a similar amount of tremor suppression was achieved while only delivering 36.62 ± 13.49% of the energy used in continuous stimulation. CONCLUSIONS: The results suggest that responsive thalamic stimulation for essential tremor based on tremor-provoking movement detection can be achieved without any requirement for external sensors or additional electrocorticography strips. Further research is required to investigate whether the decoding model is stable across time and generalizable to the variety of activities patients may engage with in everyday life. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Subthalamic beta-targeted neurofeedback speeds up movement initiation but increases tremor in Parkinsonian patients.

Previous studies have explored neurofeedback training for Parkinsonian patients to suppress beta oscillations in the subthalamic nucleus (STN). However, its impacts on movements and Parkinsonian tremor are unclear. We developed a neurofeedback paradigm targeting STN beta bursts and investigated whether neurofeedback training could improve motor initiation in Parkinson's disease compared to passive observation. Our task additionally allowed us to test which endogenous changes in oscillatory STN activities are associated with trial-to-trial motor performance. Neurofeedback training reduced beta synchrony and increased gamma activity within the STN, and reduced beta band coupling between the STN and motor cortex. These changes were accompanied by reduced reaction times in subsequently cued movements. However, in Parkinsonian patients with pre-existing symptoms of tremor, successful volitional beta suppression was associated with an amplification of tremor which correlated with theta band activity in STN local field potentials, suggesting an additional cross-frequency interaction between STN beta and theta activities.

Closed-loop DBS triggered by real-time movement and tremor decoding based on thalamic LFPs for essential tremor.

High frequency Deep Brain Stimulation (DBS) targeting the motor thalamus is an effective therapy for essential tremor (ET). However, since tremor mainly affects periods of voluntary movements and sustained postures in ET, conventional continuous stimulation may deliver unnecessary current to the brain. Here we tried to decode movement states based on local field potentials (LFPs) recorded from motor thalamus and zona incerta in real-time to trigger the switching on and off of DBS in three patients with ET. Patient-specific models were first identified using thalamic LFPs recorded while the patient performed movements that tended to trigger tremor in everyday life. During the real-time test, LFPs were continuously recorded to decode movements and tremor, and the detection triggered stimulation. Results show that voluntary movements can be detected with a mean sensitivity ranging from 76.8% to 88.6% and a false positive rate ranging from 16.0% to 23.1% Postural tremor was detected with similar accuracy. The closed-loop DBS triggered by tremor detection suppressed intention tremor by 90.5% with a false positive rate of 20.3%.Clinical Relevance- This is the first study on closed-loop DBS triggered by real-time movement and tremor decoding based solely on thalamic LFPs. The results suggest that responsive DBS based on movement and tremor detection can be achieved without any requirement for external sensors or additional electrocorticography strips.

Neurofeedback-Linked Suppression of Cortical ß Bursts Speeds Up Movement Initiation in Healthy Motor Control: A Double-Blind Sham-Controlled Study.

Abnormally increased ß bursts in cortical-basal ganglia-thalamic circuits are associated with rigidity and bradykinesia in patients with Parkinson's disease. Increased ß bursts detected in the motor cortex have also been associated with longer reaction times (RTs) in healthy participants. Here we further hypothesize that suppressing ß bursts through neurofeedback training can improve motor performance in healthy subjects. We conducted a double-blind sham-controlled study on 20 human volunteers (10 females) using a sequential neurofeedback-behavior task with the neurofeedback reflecting the occurrence of ß bursts over sensorimotor cortex quantified in real time. The results show that neurofeedback training helps healthy participants learn to volitionally suppress ß bursts in the sensorimotor cortex, with training being accompanied by reduced RT in subsequent cued movements. These changes were only significant in the real feedback group but not in the sham group, confirming the effect of neurofeedback training over simple motor imagery. In addition, RTs correlated with the rate and accumulated duration of ß bursts in the contralateral motor cortex before the go-cue, but not with averaged ß power. The reduced RTs induced by neurofeedback training positively correlated with reduced ß bursts across all tested hemispheres. These results strengthen the link between the occurrence of ß bursts in the sensorimotor cortex before the go-cue and slowed movement initiation in healthy motor control. The results also highlight the potential benefit of neurofeedback training in facilitating voluntary suppression of ß bursts to speed up movement initiation.SIGNIFICANCE STATEMENT This double-blind sham-controlled study suggested that neurofeedback training can facilitate volitional suppression of ß bursts in sensorimotor cortex in healthy motor control better than sham feedback. The training was accompanied by reduced reaction time (RT) in subsequent cued movements, and the reduced RT positively correlated with the level of reduction in cortical ß bursts before the go-cue, but not with average ß power. These results provide further evidence of a causal link between sensorimotor ß bursts and movement initiation and suggest that neurofeedback training could potentially be used to train participants to speed up movement initiation.

Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping.

Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies.

Subcortical evoked activity and motor enhancement in Parkinson's disease.

Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of 'paradoxical kinesis' in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus - a key component of the reticular activating system - provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an 'energizing' influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease.

Subthalamic nucleus activity optimizes maximal effort motor responses in Parkinson's disease.

The neural substrates that enable individuals to achieve their fastest and strongest motor responses have long been enigmatic. Importantly, characterization of such activities may inform novel therapeutic strategies for patients with hypokinetic disorders, such as Parkinson's disease. Here, we ask whether the basal ganglia may play an important role, not only in the attainment of maximal motor responses under standard conditions but also in the setting of the performance enhancements known to be engendered by delivery of intense stimuli. To this end, we recorded local field potentials from deep brain stimulation electrodes implanted bilaterally in the subthalamic nuclei of 10 patients with Parkinson's disease, as they executed their fastest and strongest handgrips in response to a visual cue, which was accompanied by a brief 96-dB auditory tone on random trials. We identified a striking correlation between both theta/alpha (5-12 Hz) and high-gamma/high-frequency (55-375 Hz) subthalamic nucleus activity and force measures, which explained close to 70% of interindividual variance in maximal motor responses to the visual cue alone, when patients were ON their usual dopaminergic medication. Loud auditory stimuli were found to enhance reaction time and peak rate of development of force still further, independent of whether patients were ON or OFF l-DOPA, and were associated with increases in subthalamic nucleus power over a broad gamma range. However, the contribution of this broad gamma activity to the performance enhancements observed was only modest (≤13%). The results implicate frequency-specific subthalamic nucleus activities as substantial factors in optimizing an individual's peak motor responses at maximal effort of will, but much less so in the performance increments engendered by intense auditory stimuli.

Improvements in rate of development and magnitude of force with intense auditory stimuli in patients with Parkinson's disease.

Patients with Parkinson's disease can show brief but dramatic normalization of motor activity in highly arousing situations, a phenomenon often termed paradoxical kinesis. We sought to mimic this in a controlled experimental environment. Nine patients with Parkinson's disease and nine age-matched healthy controls were asked to grip a force dynamometer as quickly and strongly as possible in response to a visual cue. A loud (96 dB) auditory stimulus was delivered at the same time as the visual cue in ~50% of randomly selected trials. In patients with Parkinson's disease, the experiment was conducted after overnight withdrawal of antiparkinsonian drugs and again 1 h after patients had taken their usual morning medication. Patients showed improvements in the peak rate of force development and the magnitude of force developed when loud auditory stimuli accompanied visual cues. Equally, they showed improvements in the times taken to reach the peak rate of force development and their maximal force. The paradoxical facilitatory effect of sound was similar whether patients were off or on their usual antiparkinsonian medication, and could be reproduced in age-matched healthy controls. We conclude that motor improvement induced by loud auditory stimuli in Parkinson's disease is related to a physiological phenomenon which survives both with and after withdrawal of antiparkinsonian medication. The potential independence of the mediating pathways from the dopaminergic system provides impetus for further investigation as it may yield a novel nondopaminergic target for therapeutic manipulation in Parkinson's disease.

Doing better than your best: loud auditory stimulation yields improvements in maximal voluntary force.

Could task performance be constrained by our ability to fully engage necessary neural processing through effort of will? The StartReact phenomenon suggests that this might be the case, as voluntary reaction times are substantially reduced by loud sounds. Here, we show that loud auditory stimulation can also be associated with an improvement in the force and speed of force development when 18 healthy subjects are repeatedly asked to make a maximal grip as fast and as strongly as possible. Peak grip force was increased by 7.2 ± 1.4% (SEM) (P < 0.0001), and the rate of force development was increased by 17.6 ± 2.0% (P < 0.00001), when imperative visual cues were accompanied by a loud auditory stimulus rather than delivered alone. This implies that loud auditory stimuli may allow motor pathways to be optimised beyond what can be achieved by effort of will alone.