The altered right frontoparietal network functional connectivity in migraine and the modulation effect of treatment.

Aims This study aims to investigate the resting-state functional connectivity (rs-fc) of the right frontoparietal network (rFPN) between migraineurs and healthy controls (HCs) in order to determine how the rFPN rs-fc can be modulated by effective treatment. Methods One hundred patients and 46 matched HCs were recruited. Migraineurs were randomized to verum acupuncture, sham acupuncture, and waiting list groups. Resting-state functional magnetic resonance imaging data were collected before and after longitudinal treatments. Independent component analysis was applied in the data analysis. Results We found that migraineurs showed decreased rs-fc between the rFPN and bilateral precuneus compared with HCs. After treatments (real and sham), rFPN rs-fc with the precuneus was significantly reduced. This reduction was associated with headache intensity relief. In order to explore the role of the precuneus in acupuncture modulation, we performed a seed-based rs-fc analysis using the precuneus as a seed and found that the precuneus rs-fc with the bilateral rostral anterior cingulate cortex/medial prefrontal cortex, ventral striatum, and dorsolateral prefrontal cortex was significantly enhanced after treatment. Conclusion Our results suggest that migraineurs are associated with abnormal rFPN rs-fc. An effective treatment, such as acupuncture, may relieve symptoms by strengthening the cognitive adaptation/coping process. Elucidation of the adaptation/coping mechanisms may open up a new window for migraine management.

Assessing the oral bioavailability of difluorosialic acid prodrugs, potent viral neuraminidase inhibitors, using a snapshot PK screening assay.

Difluorosialic acids (DFSAs) are potent inhibitors of viral neuraminidase that demonstrate activity against oseltamivir- and zanamivir-resistant strains of influenza. Unfortunately, low oral bioavailability precludes their development as second generation neuraminidase inhibitors for treating influenza as this leaves them unsuitable for use in an oral formulation. Herein is described the preparation of a series of DFSA prodrugs designed to increase oral bioavailability. These prodrugs were evaluated using a snapshot PK screen and stability tests, with successful candidates being further assessed with a full pharmacokinetic workup. These new prodrugs increased oral bioavailability by up to three times that seen for the parent DFSAs.

Dose-dependent effects of high intensity focused ultrasound on compound action potentials in an ex vivo rodent peripheral nerve model: comparison to local anesthetics.

BACKGROUND: In animal models, focused ultrasound can reversibly or permanently inhibit nerve conduction, suggesting a potential role in managing pain. We hypothesized focused ultrasound's effects on action potential parameters may be similar to those of local anesthetics. METHODS: In an ex vivo rat sciatic nerve model, action potential amplitude, area under the curve, latency to 10% peak, latency to 100% peak, rate of rise, and half peak width changes were assessed after separately applying increasing focused ultrasound pressures or concentrations of bupivacaine and ropivacaine. Focused ultrasound's effects on nerve structure were examined histologically. RESULTS: Increasing focused ultrasound pressures decreased action potential amplitude, area under the curve, and rate of rise, increased latency to 10% peak, and did not change latency to 100% peak or half peak width. Increasing local anesthetic concentrations decreased action potential amplitude, area under the curve, and rate of rise and increased latency to 10% peak, latency to 100% peak, and half peak width. At the highest focused ultrasound pressures, nerve architecture was altered compared with controls. DISCUSSION: While some action potential parameters were altered comparably by focused ultrasound and local anesthetics, there were small but notable differences. It is not evident if these differences may lead to differences in clinical pain effects when focused ultrasound is applied in vivo or if focused ultrasound pressures that result in clinically relevant changes damage nerve structures. Given the potential advantages of a non-invasive technique for managing pain conditions, further investigation may be warranted in an in vivo pain model.

Ex Vivo Whole Nerve Electrophysiology Setup, Action Potential Recording, and Data Analyses in a Rodent Model.

Ex vivo rodent whole nerves provide a model for assessing the effects of interventions on nerve impulse transmission and consequent sensory and/or motor function. Nerve impulse transmission can be measured through sciatic nerve compound action potential (CAP) recordings. However, de novo development and implementation of an ex vivo whole nerve resection protocol and an electrophysiology setup that retains nerve viability, that produces low noise CAP signals, and that allows for data analysis is challenging. Additionally, some of the existing literature lacks detail and accuracy and may be out of date. This article describes detailed protocols for rodent ex vivo sciatic nerve dissection and handling; importance of an optimal physiologic solution; computer-aided designs for 3D printing of readily adaptable ex vivo rodent whole nerve electrophysiology chambers; construction of low-cost, effective suction electrodes; setup and use of nerve stimulators and amplifiers; acquisition of low noise, small voltage CAP data and digital conversion; use of software for data analyses of CAP components; and tips for troubleshooting. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Electrophysiology wiring and hardware setup Support Protocol 1: 3D printing an electrophysiology chamber Support Protocol 2: Building suction electrodes Basic Protocol 2: Sciatic nerve dissection and compound action potential recording Basic Protocol 3: Data export and analysis Support Protocol 3: Preparation of HEPES-buffered physiologic solution.

Tai Chi Chuan and Baduanjin practice modulates functional connectivity of the cognitive control network in older adults.

Cognitive impairment is one of the most common problem saffecting older adults. In this study, we investigated whether Tai Chi Chuan and Baduanjin practice can modulate mental control functionand the resting state functional connectivity (rsFC) of the cognitive control network in older adults. Participants in the two exercise groups practiced either Tai Chi Chuan or Baduanjin for 12 weeks, and those in the control group received basic health education. Memory tests and fMRI scans were conducted at baseline and at the end of the study. Seed-based (bilateral dorsolateral prefrontal cortex, DLPFC) rsFC analysis was performed. We found that compared to the controls, 1) both Tai Chi Chuan and Baduanjin groups demonstrated significant improvements in mental control function; 2) the Tai Chi Chuan group showed a significant decrease in rsFC between the DLPFC and the left superior frontal gyrus (SFG) and anterior cingulate cortex; and 3) the Baduanjin group showed a significant decrease in rsFC between the DLPFC and the left putamen and insula. Mental control improvement was negatively associated with rsFC DLPFC-putamen changes across all subjects. These findings demonstrate the potential of Tai Chi Chuan and Baduanjin exercises in preventing cognitive decline.

Tai Chi Chuan and Baduanjin Increase Grey Matter Volume in Older Adults: A Brain Imaging Study.

The aim of this study is to investigate and compare how 12-weeks of Tai Chi Chuan and Baduanjin exercise can modulate brain structure and memory function in older adults. Magnetic resonance imaging and memory function measurements (Wechsler Memory Scale-Chinese revised, WMS-CR) were applied at both the beginning and end of the study. Results showed that both Tai Chi Chuan and Baduanjin could significantly increase grey matter volume (GMV) in the insula, medial temporal lobe, and putamen after 12-weeks of exercise. No significant differences were observed in GMV between the Tai Chi Chuan and Baduanjin groups. We also found that compared to healthy controls, Tai Chi Chuan and Baduanjin significantly improved visual reproduction subscores on the WMS-CR. Baduanjin also improved mental control, recognition, touch, and comprehension memory subscores of the WMS-CR compared to the control group. Memory quotient and visual reproduction subscores were both associated with GMV increases in the putamen and hippocampus. Our results demonstrate the potential of Tai Chi Chuan and Baduanjin exercise for the prevention of memory deficits in older adults.

Increased Hippocampus-Medial Prefrontal Cortex Resting-State Functional Connectivity and Memory Function after Tai Chi Chuan Practice in Elder Adults.

Previous studies provide evidence that aging is associated with the decline of memory function and alterations in the hippocampal (HPC) function, including functional connectivity to the medial prefrontal cortex (mPFC). In this study, we investigated if longitudinal (12-week) Tai Chi Chuan and Baduanjin practice can improve memory function and modulate HPC resting-state functional connectivity (rs-FC). Memory function measurements and resting-state functional magnetic resonance imaging (rs-fMRI) were applied at the beginning and the end of the experiment. The results showed that (1) the memory quotient (MQ) measured by the Wechsler Memory Scale-Chinese Revision significantly increased after Tai Chi Chuan and Baduanjin practice as compared with the control group, and no significant difference was observed in MQ between the Tai Chi Chuan and Baduanjin groups; (2) rs-FC between the bilateral hippocampus and mPFC significantly increased in the Tai Chi Chuan group compared to the control group (also in the Baduanjin group compared to the control group, albeit at a lower threshold), and no significant difference between the Tai Chi Chuan and Baduanjin groups was observed; (3) rs-FC increases between the bilateral hippocampus and mPFC were significantly associated with corresponding memory function improvement across all subjects. Similar results were observed using the left or right hippocampus as seeds. Our results suggest that both Tai Chi Chuan and Baduanjin may be effective exercises to prevent memory decline during aging.

Novel spirothiazamenthane inhibitors of the influenza A M2 proton channel.

The development of treatments for influenza that inhibit the M2 proton channel without being susceptible to the widespread resistance mechanisms associated with the adamantanes is an ongoing challenge. Using a yeast high-throughput yeast growth restoration assay designed to identify M2 channel inhibitors, a single screening hit was uncovered. This compound (3), whose structure was incorrectly identified in the literature, is an inhibitor with similar potency to amantadine against WT M2. A library of derivatives of 3 was prepared and activity against WT M2 and the two principal mutant strains (V27A and S31N) was assessed in the yeast assay. The best compounds were further evaluated in an antiviral plaque reduction assay using engineered WT, V27A and S31N M2 influenza A strains with otherwise identical genetic background. Compound 63 was found to inhibit all three virus strains in this cell based antiviral assay at micromolar concentrations, possibly through a mechanism other than M2 inhibition.

Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study.

BACKGROUND: Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD. METHODS: This is a nonrandomized, controlled study. The first cohort of patients (n=91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n=69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing (1) real and sham taVNS groups at week 4; (2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and (3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham). RESULTS: After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than patients in the sham taVNS group as indicated by Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS. LIMITATIONS: Patients were not randomized in this study. CONCLUSIONS: Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD.

Selecting pre-screening items for early intervention trials of dementia--a case study.

Our goal was to review and extend statistical methods for discriminating between normal subjects and those with dementia or cognitive impairment. We compared six different methods to one constructed by expert opinion, in their brevity and predictive power. The methods include logistic regression and neural networks, with standard and least absolute shrinkage and selection operator (LASSO) variable selection, as well as decision trees with and without boosting. These methods were applied to the baseline data of a subgroup of subjects in a dementia study, using their screening interview items to predict their clinical diagnosis of normal or non-normal (cognitively impaired or demented). The derived models were then validated on a different subgroup of subjects in the same study who had the screening and clinical diagnosis two to five years later. Performance of different models was compared based on their sensitivity and specificity in the validation sample. Generally, the six statistical methods performed slightly to moderately better than the expert-opinion model. Neural networks generally performed better than the logistic and decision tree models. LASSO improved the performance of logistic and neural network models, but it eliminated few input variables in the neural network. The single decision tree performed at least as well as the standard logistic model, and with fewer items, making it an attractive pre-screening tool. Using the boosting option for decision trees did not substantially improve the performance. We recommend that for each situation, different methods of classification should be attempted to obtain optimal results for a given purpose.