A Randomized Clinical Trial of High-Dosage Coenzyme Q10 in Early Parkinson Disease No Evidence of Benefit The Parkinson Study Group QE3 Investigators IMPORTANCE Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE Coenzyme Q10 was safe and well tolerated in this population, bu...

Until recently, therapeutic development in psychiatry was targeted solely toward symptom reduction. While this is a worthwhile goal, it has yielded little progress in improved therapeutics in the last several decades in the field of mood disorders. Recent advancements in our understanding of pathophysiology suggests that an impairment of neuroplasticity may be a critical part of the development of neuropsychiatric disorders. Interventions that enhance or modulate neuroplasticity often reduce depressive symptoms when applied as stand-alone treatments. Unfortunately, when treatments are discontinued, the disease state often returns as patients relapse. However, treatments that enhance or modulate plasticity not only reduce symptom burden, but also may provide an opportune window wherein cognitive or behavioral interventions could be introduced to harness a state of enhanced neuroplasticity and lead to improved longer-term clinical outcomes. Here, we review the potential of synergistically combining plasticity-enhancing and behavioral therapies to develop novel translational treatment approaches for depression. After reviewing relevant neuroplasticity deficits in depression, we survey biological treatments that appear to reverse such deficits in humans, including N-methyl-D-aspartate receptor modulators (ketamine, Dcycloserine), electroconvulsive therapy, and transcranial brain stimulation. We then review

Background: Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache and various neurological symptoms. Migraine is typically treated by pharmacological or non-pharmacological therapies to relieve pain or prevent migraine attacks. Pharmacological therapies show limited efficacy in relieving headache and are often accompanied by adverse effects, while the benefits of acupuncture, a non-pharmacological therapy, have been well-documented in both the treatment and prevention of acute migraine attacks. However, the underlying mechanism of the effect of acupuncture on relieving migraine remains unclear. Recent advances in neuroimaging technology have offered new opportunities to explore the underlying neural mechanism of acupuncture in treating migraine. To pave the way for future research, this review provides an overview neuroimaging studies on the use of acupuncture for migraine in the last 10 years.Methods: Using search terms about acupuncture, neuroimaging and migraine, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure from January 2009 to June 2020 for neuroimaging studies that examined the effect of acupuncture in migraine. All published randomized and non-randomized controlled neuroimaging studies were included. We summarized the proposed neural mechanism underlying acupuncture analgesia in acute migraine, and the proposed neural mechanism underlying the sustained effect of acupuncture in migraine prophylaxis.Results: A total of 619 articles were retrieved. After removing reviews, meta-analyses, animal studies and etc., 15 articles were eligible and included in this review. The methods used were positron emission computed tomography (PET-CT; n = 2 studies), magnetic resonance spectroscopy (n = 1), and functional magnetic resonance imaging (fMRI; n = 12). The analyses used included the regional homogeneity (ReHo) method (n = 3), amplitude of low frequency (ALFF) method (n = 2), independent component analysis (ICA; n = 3), seed-based analysis (SBA; n = 1), both ICA and SBA (n = 1), Pearson's correlation to calculate functional connectivity (FC) between brain regions (n = 1), and a machine learning method (n = 1). Five studies focused on the instant effect of acupuncture, and the research objects were those with acute migraine (n = 2) and migraine in the interictal phase (n = 3). Ten studies focused on the lasting effect of acupuncture, and all the studies selected migraine patients in the interictal phase. This review included five task-based studies and 10 resting-state studies. None of the studies conducted a correlation analysis between functional brain changes and instant clinical efficacy. For studies that performed a correlation analysis between functional brain changes and sustained clinical efficacy, the prophylactic effect of acupuncture on migraine might be through regulation of the visual network, default mode network (DMN), sensory motor network, frontoparietal network (FPN), limbic system, and/or descending pain modulatory system (DPMS).Conclusion: The neural mechanism underlying the immediate effect of acupuncture analgesia remains unclear, and the neural mechanism of sustained acupuncture treatment for migraine might be related to the regulation of pain-related brain networks. The experimental design of neuroimaging studies that examined the effect of acupuncture in migraine also have some shortcomings, and it is necessary to standardize and optimize the experimental design. Multi-center neuroimaging studies are needed to provide a better insight into the neural mechanism underlying the effect of acupuncture on migraine. Multi-modality neuroimaging studies that integrate multiple data analysis methods are required for cross-validation of the neuroimaging results. In addition, applying machine learning methods in neuroimaging studies can help to predict acupuncture efficacy and screen for migraineurs for whom acupuncture treatment would be suitable.

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Key Points MRD response has value as a prognostic factor for blinatumomab treatment in R/R B-cell precursor ALL. MRD response was associated with better outcomes in terms of OS and RFS in blinatumomab-treated R/R ALL.

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BackgroundMigraine is a primary neurological disorder associated with complex brain activity. Recently, mounting evidence has suggested that migraine is underpinned by aberrant dynamic brain activity characterized by linear and non-linear changes across a variety of time scales. However, the abnormal dynamic brain activity at different time scales is still unknown in patients with migraine without aura (MWoA). This study aimed to assess the altered patterns of brain activity dynamics over different time scales and the potential pathophysiological mechanisms of alterations in patients with MWoA.MethodsMultiscale entropy in 50 patients and 20 healthy controls (HCs) was calculated to investigate the patterns and altered brain complexity (BC) across five different time scales. Spearman rank correlation analysis between BC in regions showing significant intergroup differences and clinical scores (i.e., frequency of migraine attacks, duration, headache impact test) was conducted in patients with MWoA.ResultsThe spatial distribution of BC varied across different time scales. At time scale1, BC was higher in the posterior default mode network (DMN) across participants. Compared with HCs, patients with MWoA had higher BC in the DMN and sensorimotor network. At time scale2, BC was mainly higher in the anterior DMN across participants. Patients with MWoA had higher BC in the sensorimotor network. At time scale3, BC was mainly higher in the frontoparietal network across participants. Patients with MWoA had increased BC in the parietal gyrus. At time scale4, BC is mainly higher in the sensorimotor network. Patients with MWoA had higher BC in the postcentral gyrus. At time scale5, BC was mainly higher in the DMN. Patients with MWoA had lower BC in the posterior DMN. In particular, BC values in the precuneus and paracentral lobule significantly correlated with clinical symptoms.ConclusionMigraine is associated with alterations in dynamic brain activity in the sensorimotor network and DMN over multiple time scales. Time-varying BC within these regions could be linked to instability in pain transmission and modulation. Our findings provide new evidence for the hypothesis of abnormal dynamic brain activity in migraine.

Background Migraine is a highly prevalent neurological disorder. It is the third most prevalent disorder and the seventh highest cause of disability worldwide. Acupuncture may be a viable prophylactic treatment option for frequent or uncontrolled migraine. Clinical studies comparing acupuncture and placebo acupuncture have not reached a consistent conclusion in confirming whether acupuncture is effective in migraine prophylaxis. The effect of acupuncture mainly depends on acupoints and needles operation. We found that the design of the placebo acupuncture in previous studies included shallow needling at sham acupoints, non-penetrating needling at sham acupoints, and needling at inactive acupuncture points to achieve the inert effect of control group, but the non-penetrating needling at true acupoints was ignored. This randomized controlled trial aims to use true acupoints for non-penetrating acupuncture as control to evaluate the efficacy of manual acupuncture for the prophylaxis of migraine without aura (MWoA). Methods/design This is a single-blinded, randomized, controlled, prospective, multi-center trial with two parallel treatment groups. A total of 198 eligible patients with MWoA will be randomly divided into two groups (1:1 allocation ratio). The intervention group will receive manual acupuncture and the control group will receive placebo acupuncture (non-penetrating). Patients will receive three acupuncture treatment sessions per week for 4 consecutive weeks. All patients will then receive a 12-week follow-up. Discussion In this study, we are evaluating the efficacy and safety of manual acupuncture in the prophylaxis of MWoA. The placebo control is using non-penetrating needling verum acupoints. It is essential to determine an appropriate control method to ensure the methodological quality of a randomized controlled trial. Trial registration The trial has been registered in the Chinese Clinical Trial Registry (approval no. ChiCTR2000032308) in April 2020.