Limits to clinical trials in surgical areas

Randomized clinical trials are considered to be the gold standard of evidence‐based medicine nowadays. However, it is important that we point out some limitations of randomized clinical trials relating to surgical interventions. There are limitations that affect the external and internal validity of many surgical study designs. Some limitations can be bypassed, but can make it more difficult for the study to be carried out. Other limitations cannot be bypassed. When it is intended to extrapolate the result of a randomized clinical trial, the premise is that the performed or to be performed intervention will be similar wherever applied and/or for every doctor using it. However, no matter how standardized the technique may be, the results are not similar for all surgeons, which implies a significant limitation to surgical randomized clinical trials concerning external validity. When considering the various limitations presented for performing surgical trials capable of generating scientific evidence within the patterns currently proposed in the evidence level classifications of medical publications, it is necessary to rethink whether those scientific evidence levels are similarly applicable to surgical works and to nonsurgical trials. We currently live in a time of supposed “inferiority” of surgical scientific works under the optics of the current quality criteria for a “suitable” clinical trial

Head-to-Head Comparison of Transcranial Random Noise Stimulation, Transcranial AC Stimulation, and Transcranial DC Stimulation for Tinnitus

Tinnitus is the perception of a sound in the absence of an external sound stimulus. This phantom sound has been related to plastic changes and hyperactivity in the auditory cortex. Different neuromodulation techniques such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS) have been used in an attempt to modify local and distant neuroplasticity as to reduce tinnitus symptoms. Recently, two techniques of pulsed electrical stimulation using weak electrical currents – transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) – have also shown significant neuromodulatory effects. In the present study we conducted the first head-to-head comparison of three different transcranial electrical stimulation (tES) techniques, namely tDCS, tACS, and tRNS in 111 tinnitus patients by placing the electrodes overlying the auditory cortex bilaterally. The results demonstrated that tRNS induced the larger transient suppressive effect on the tinnitus loudness and the tinnitus related distress as compared to tDCS and tACS. Both tDCS and tACS induced small and non-significant effects on tinnitus symptoms, supporting the superior effects of tRNS as a method for tinnitus suppression

Pharmacological and Combined Interventions for the Acute Depressive Episode: Focus on Efficacy and Tolerability

Background: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients. Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles. Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted

Pharmacological and combined interventions for the acute depressive episode: focus on efficacy and tolerability

Andre R Brunoni1, Renerio Fraguas Jr1, Felipe Fregni21Department and Institute of Psychiatry, University of Sao Paulo, Brazil; 2Laboratory of Neuromodulation, Spaulding Rehabilitation Center, Harvard Medical School and Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USABackground: Use of antidepressants is the gold standard therapy for major depression. However, despite the large number of commercially available antidepressant drugs there are several differences among them in efficacy, tolerability, and cost-effectiveness. In addition the optimal augmentation strategy is still not clear when dealing with treatment-resistant depression, a condition that affects 15% to 40% of depressed patients.Methods: We therefore reviewed the main characteristics of these drugs regarding their efficacy, tolerability, side effects and cost-effectiveness, by accessing all meta-analyses and systematic reviews published from 2004 to 2009. In addition, we reviewed the augmentation strategy of associated antidepressants with neurostimulation therapies (such as transcranial magnetic stimulation [TMS] and transcranial direct current stimulation [tDCS]). A search was undertaken in MEDLINE, Web of Science, Cochrane, and Scielo databases. We included: 21 meta-analyses of antidepressant trials, 15 neurostimulation clinical trials and 8 studies of pharmacoeconomics. We then performed a comprehensive review on these articles.Results and Conclusion: Although recent meta-analyses suggest sertraline and escitalopram might have increased efficacy/tolerability, other studies and large pragmatic trials have not found these to be superior to other antidepressant drugs. Also, we did not identify any superior drug in terms of cost-effectiveness due to the different designs observed among pharmacoecomics studies. Side effects such as sexual dysfunction, gastrointestinal problems and weight gain were common causes of discontinuation. Tolerability was an important issue for novel neurostimulation interventions, such as TMS and tDCS. These therapies might be interesting augmentation strategies, considering their benign profile of side effects, if proper safety parameters are adopted.Keywords: acute depressive episode, pharmacological interventions, combined intervention

Clinical research in pediatric organ transplantation

Solid organ transplantation has greatly improved survival in children with end-stage disease, becoming one of the main treatment options in this population. Nonetheless, there are significant challenges associated with validating and optimizing the effects of these interventions in clinical trials. Therefore, we reviewed the main issues related to conducting clinical transplantation research in children. We divided these challenges into three different categories: (i) challenges related to surgical techniques and anesthetic procedures, (ii) challenges related to post-transplant care and (iii) challenges specific to a particular population group and disease type. Some of the observed burdens for clinical research in this field are related to the limitations of conducting studies with a placebo or sham procedure, determining the standard of care for a control group, low prevalence of cases, ethical concerns related to use of a placebo control group and lack of generalizability from animal studies and clinical trials conducted in adult populations. To overcome some of these barriers, it is necessary to utilize alternative clinical trial designs, such as observational studies or non-inferiority trials, and to develop multicenter collaborations to increase the recruitment rate. In conclusion, the lack of robust data related to pediatric transplantation remains problematic, and further clinical trials are needed to develop more efficacious and safer treatments

Using non-invasive brain stimulation to augment motor training-induced plasticity

Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date

Simultaneous EEG Monitoring During Transcranial Direct Current Stimulation

Transcranial direct current stimulation (tDCS) is a technique that delivers weak electric currents through the scalp. This constant electric current induces shifts in neuronal membrane excitability, resulting in secondary changes in cortical activity. Although tDCS has most of its neuromodulatory effects on the underlying cortex, tDCS effects can also be observed in distant neural networks. Therefore, concomitant EEG monitoring of the effects of tDCS can provide valuable information on the mechanisms of tDCS. In addition, EEG findings can be an important surrogate marker for the effects of tDCS and thus can be used to optimize its parameters. This combined EEG-tDCS system can also be used for preventive treatment of neurological conditions characterized by abnormal peaks of cortical excitability, such as seizures. Such a system would be the basis of a non-invasive closed-loop device. In this article, we present a novel device that is capable of utilizing tDCS and EEG simultaneously. For that, we describe in a step-by-step fashion the main procedures of the application of this device using schematic figures, tables and video demonstrations. Additionally, we provide a literature review on clinical uses of tDCS and its cortical effects measured by EEG techniques

Applying Neuroscience Concepts to Enhance Learning in an Online Project-Based Learning Centered Course

This case study presents our findings regarding a Project-Based Learning Course, where we applied neuroscience concepts to make the learning experience more effective. The course, which followed a combination of project-based learning and flipped classroom approaches, was delivered during the first semester of 2020, to 20 graduate students of the Faculty of Education of the University of Sao Paulo, Brazil. We explain the course design, curriculum, and online components. We collected data from course questionnaires and analyzed them qualitatively. We found that the course fostered long-lasting learning, by allowing the students to connect theory and practice, by providing knowledge-sharing opportunities and by promoting the retrieval of the content learned. We also found that course design allowed continuous improvement of course, learning environment and activities, that also enhanced the learning experience. Our findings also suggested that the usage of flipped-classroom concepts improves the efficacy of the online meetings. Finally, comic strips' usage brought humor to class, helped the students fix content, and contributed to reducing the stress that the students were facing

A review of acute aerobic exercise and transcranial direct current stimulation effects on cognitive functions and their potential synergies

Today, several pharmaceutic and non-pharmaceutic approaches exist to treat psychiatric and neurological diseases. Because of the lack of treatment procedures that are medication free and the lack of severe side effects, transcranial direct current stimulation (tDCS) and aerobic exercise (AE) have been tested to explore the potential for initiating and modulating neuroplasticity in the human brain. Both tDCS and AE could support cognition and behavior in the clinical and non-clinical context to improve the recovery process within neurological or psychiatric conditions or to increase performance. As these techniques still lack meaningful effects, although they provide multiple beneficial opportunities within disease and health applications, there is emerging interest to find improved tDCS and AE protocols. Since multimodal approaches could provoke synergetic effects, several recent studies have begun to combine tDCS and AE within different settings such as in cognitive training in health or for treatment purposes within clinical settings, all of which show superior effects compared to single technique applications. The beneficial outcomes of both techniques depend on several parameters and the understanding of neural mechanisms that are not yet fully understood. Recent studies have begun to directly combine tDCS and AE within one session, although their interactions on the behavioral, neurophysiological and neurochemical levels are entirely unclear. Therefore, this review a) provides an overview of acute behavioral, neurophysiological, and neurochemical effects that both techniques provoke within only one single application in isolation; b) gives an overview regarding the mechanistic pathways; and c) discusses potential interactions and synergies between tDCS and AE that might be provoked when directly combining both techniques. From this literature review focusing primarily on the cognitive domain in term of specific executive functions (inhibition, updating, and switching), it is concluded that a direct combination of tDCS and AE provides multiple beneficial opportunities for synergistic effects. A combination could be useful within non-clinical settings in health and for treating several psychiatric and neurologic conditions. However, there is a lack of research and there are several possibly interacting moderating parameters that must be considered and more importantly must be systematically investigated in the future