The adjuvant activity of two urea derivatives on cytokinins: an example of serendipitous dual effect

The aim of this study was to investigate the action spectrum of two urea derivatives, the 1,3-di(benzo[d]oxazol-5-yl)urea (5-BDPU) and the 1,3-di(benzo[d]oxazol-6-yl)urea (6-BDPU). In order to evaluate a possible adjuvant activity on cytokinins the compounds alone or in the simultaneous presence of different cytokinins were assayed either on in vitro typical cytokinin-related bioassays, or on in planta interaction with cytokinin signal transduction pathway. The compounds ability to activate the cytokinin receptor CRE1/AHK4 was studied either by a heterologous bacterial assay or by a competitive binding assay and docking simulations were performed with the crystal structure of the same receptor. Then, owing to their chemical structure which resembles that of urea-type cytokinins, the ability of 5- and 6-BDPU to inhibit the activity of cytokinin oxidase/dehydrogenase of Zea mays (ZmCKX1) was investigated and docking simulations were performed as well. Accordingly to the experimental results, we speculate that BDPUs could show a dual activity: the blocking of the conformational re-adaption of CRE1/AHK4 receptor maintaining the cytokinin inside its binding pocket, thus possibly enhancing its kinase action; the inhibition of cytokinin oxidase/dehydrogenase activity thus possibly preventing its cleavage of natural cytokinins with isoprenoid side chain. Graphic abstract: [Figure not available: see fulltext.

Evidence-based umbrella review of cognitive effects of prefrontal tDCS

Abstract Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique, which has been increasingly used as an investigational tool in neuroscience. In social and affective neuroscience research, the prefrontal cortex has been primarily targeted, since this brain region is critically involved in complex psychobiological processes subserving both 'hot' and 'cold' domains. Although several studies have suggested that prefrontal tDCS can enhance neuropsychological outcomes, meta-analyses have reported conflicting results. Therefore, we aimed to assess the available evidence by performing an umbrella review of meta-analyses. We evaluated the effects of prefrontal active vs sham tDCS on different domains of cognition among healthy and neuropsychiatric individuals. A MeaSurement Tool to Assess Systematic Reviews 2 was employed to evaluate the quality of meta-analyses, and the GRADE system was employed to grade the quality of evidence of every comparison from each meta-analysis. PubMed/MEDLINE, PsycINFO and the Cochrane Database of Systematic Reviews were searched, and 11 meta-analyses were included resulting in 55 comparisons. Only 16 comparisons reported significant effects favoring tDCS, but 13 of them had either very low or low quality of evidence. Of the remaining 39 comparisons which reported non-significant effects, 38 had either very low or low quality of evidence. Meta-analyses were rated as having critically low and low quality. Among several reasons to explain these findings, the lack of consensus and reproducibility in tDCS research is discussed

Transcranial direct current stimulation as an add-on treatment to cognitive-behavior therapy in first episode drug-naive major depression patients: the ESAP study protocol

Background: Major Depressive Disorder (MDD) affects more than 264 million people worldwide. Current treatments include the use of psychotherapy and/or drugs, however similar to 30% of patients either do not respond to these treatments, or do not tolerate the side effects associated to the use of pharmacological interventions. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters. Several studies demonstrated that transcranial Direct Current Stimulation (tDCS) can be effective for symptoms relief in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other interventions.Methods/Design: This is a study protocol for a parallel, randomized, triple-blind, sham-controlled clinical trial in which a total of 90 drug-naive, first-episode MDD patients (45 per arm) will be randomized to one of two groups to receive a 6-weeks of CBT combined with either active or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). The primary outcome will depressive symptoms improvement as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) at 6-weeks. The secondary aim is to test whether CBT combined with tDCS can engage the proposed mechanistic target of restoring the prefrontal imbalance and connectivity through the bilateral modulation of the DLPFC, as assessed by changes over resting-state and emotional task eliciting EEG.Discussion: This study evaluates the synergetic clinical effects of CBT and tDCS in the first episode, drug-naive, patients with MDD. First episode MDD patients provide an interesting opportunity, as their brains were not changed by the pharmacological treatments, by the time course, or by the recurrence of MDD episodes (and other comorbidities).This work was partially supported by FEDER funds through the Programa Operacional Factores de Competitividade-COMPETE and by national funds through FCT-Fundacao para a Ciencia e a Tecnologia through the calls IF/00091/2015 and PTDC/PSI-ESP/29701/2017. The sponsors had no role in the study design, implementation, data analysis or publication

Transcranial direct current stimulation for the treatment of Major Depressive Disorder : a summary of preclinical, clinical and translational findings

Major depressive disorder (MDD) is a common psychiatric illness, with 6-12% lifetime prevalence. It is also among the five most disabling diseases worldwide. Current pharmacological treatments, although relatively effective, present important side effects that lead to treatment discontinuation. Therefore, novel treatment options for MDD are needed. Here, we discuss the recent advancements of one new neuromodulatory technique - transcranial direct current stimulation (tDCS) - that has undergone intensive research over the past decade with promising results. tDCS is based on the application of weak, direct electric current over the scalp, leading to cortical hypo- or hyper-polarization according to the specified parameters. Recent studies have shown that tDCS is able to induce potent changes in cortical excitability as well as to elicit long-lasting changes in brain activity. Moreover, tDCS is a technique with a low rate of reported side effects, relatively easy to apply and less expensive than other neuromodulatory techniques - appealing characteristics for clinical use. In the past years, 4 of 6 phase II clinical trials and one recent meta-analysis have shown positive results in ameliorating depression symptoms. tDCS has some interesting, unique aspects such as noninvasiveness and low rate of adverse effects, being a putative substitutive/augmentative agent for antidepressant drugs, and low-cost and portability, making it suitable for use in clinical practice. Still, further phase II and phase III trials are needed as to better clarify tDCS role in the therapeutic arsenal of MOD

Enhancement of affective processing induced by bifrontal transcranial direct current stimulation in patients with major depression

ObjectiveOur aim was to evaluate whether one single section of transcranial direct current stimulation (tDCS), a neuromodulatory technique that noninvasively modifies cortical excitability, could induce acute changes in the negative attentional bias in patients with major depression. Subjects and MethodsRandomized, double-blind, sham-controlled, parallel design enrolling 24 age-, gender-matched, drug-free, depressed subjects. Anode and cathode were placed over the left and right dorsolateral prefrontal cortex. We performed a word Emotional Stroop Task collecting the response times (RTs) for positive-, negative-, and neutral-related words. The emotional Stroop effect for negative vs. neutral and vs. positive words was used as the measure of attentional bias. ResultsAt baseline, RTs were significantly slower for negative vs. positive words. We found that active but not sham tDCS significantly modified the negative attentional bias, abolishing slower RT for negative words. ConclusionActive but not sham tDCS significantly modified the negative attentional bias. These findings add evidence that a single tDCS session transiently induces potent changes in affective processing, which might be one of the mechanisms of tDCS underlying mood changes

Viewing Nature Scenes Positively Affects Recovery of Autonomic Function Following Acute-Mental Stress

A randomized crossover study explored whether viewing different scenes prior to a stressor altered autonomic function during the recovery from the stressor. The two scenes were (a) nature (composed of trees, grass, fields) or (b) built (composed of man-made, urban scenes lacking natural characteristics) environments. Autonomic function was assessed using noninvasive techniques of heart rate variability; in particular, time domain analyses evaluated parasympathetic activity, using root-mean-square of successive differences (RMSSD). During stress, secondary cardiovascular markers (heart rate, systolic and diastolic blood pressure) showed significant increases from baseline which did not differ between the two viewing conditions. Parasympathetic activity, however, was significantly higher in recovery following the stressor in the viewing scenes of nature condition compared to viewing scenes depicting built environments (RMSSD; 50.0 ± 31.3 vs 34.8 ± 14.8 ms). Thus, viewing nature scenes prior to a stressor alters autonomic activity in the recovery period. The secondary aim was to examine autonomic function during viewing of the two scenes. Standard deviation of R-R intervals (SDRR), as change from baseline, during the first 5 min of viewing nature scenes was greater than during built scenes. Overall, this suggests that nature can elicit improvements in the recovery process following a stressor. © 2013 American Chemical Society

Beyond the target area: an integrative view of tDCS-induced motor cortex modulation in patients and athletes

Transcranial Direct Current Stimulation (tDCS) is a non-invasive technique used to modulate neural tissue. Neuromodulation apparently improves cognitive functions in several neurologic diseases treatment and sports performance. In this study, we present a comprehensive, integrative review of tDCS for motor rehabilitation and motor learning in healthy individuals, athletes and multiple neurologic and neuropsychiatric conditions. We also report on neuromodulation mechanisms, main applications, current knowledge including areas such as language, embodied cognition, functional and social aspects, and future directions. We present the use and perspectives of new developments in tDCS technology, namely high-definition tDCS (HD-tDCS) which promises to overcome one of the main tDCS limitation (i.e., low focality) and its application for neurological disease, pain relief, and motor learning/rehabilitation. Finally, we provided information regarding the Transcutaneous Spinal Direct Current Stimulation (tsDCS) in clinical applications, Cerebellar tDCS (ctDCS) and its influence on motor learning, and TMS combined with electroencephalography (EEG) as a tool to evaluate tDCS effects on brain function

Regulatory considerations for the clinical and research use of transcranial Direct Current Stimulation (tDCS): Review and recommendations from an expert panel

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. Therefore, a group of research and clinician experts on tDCS were convened to review the research and clinical use of tDCS. This report reviews the regulatory status of tDCS and summarizes the results according to research, off-label, and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan, and the US. Research use, off label treatment, and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.F.F. is supported by a grant from National Institutes of Health (NIH) (Grant number 1R44NS08063201). A.R.B. is supported by the following grants: 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (Grant Number 20493), 2013 FAPESP Young Researcher from the São Paulo State Foundation (Grant Number 20911-5) and National Council for Scientific and Technological Development (CNPq, Grant Number 470904). J.B. is supported by the 2013 NARSAD Young Investigator from the Brain & Behavior Research Foundation (Grant Number 20988). H.E. is supported by grants from Tehran University of Medical Sciences. J.L. (SFRH/BPD/86027/2012) and S.C. (SFRH/BPD/86041/2012) are supported by grants from the Portuguese Foundation for Science and Technology (FCT). C.H.J. is supported by MOST (101-2811-H-008-014). G.V. is supported by as the Department of Science and Technology (Government of India) Research Grant (SR/CSI/158/2012) as well as Wellcome Trust / DBT India Alliance Senior Fellowship Research Award (500236/Z/11/Z). N.B. is supported by a F.A.R. grant from the University of Milano-Bicocca. M.B. is supported by NIH (NINDS, NIMH, NCI), Wallace H Coulter Foundation, Grove Foundation, DoD. W.C. is supported by National Council for Scientific and Technological Development-CNPq WC-301256/2013-6. The group is also grateful to the support from the Conselho Brasileiro de Neuromodulacao Clinica – Instituto Scala