Posts Tagged Placebo

[ARTICLE] A Novel tDCS Sham Approach Based on Model-Driven Controlled Shunting – Full Text

Abstract

Background

Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique able to transiently modulate brain activity, is surging as one of the most promising therapeutic solutions in many neurological and psychiatric disorders. However, profound limitations exist in current placebo (sham) protocols that limit single- and double-blinding, especially in non-naïve subjects.

Objective

/hypothesis: To ensure better blinding and strengthen reliability of tDCS studies and trials, we tested a new optimization algorithm aimed at creating an “active” sham tDCS condition (ActiSham hereafter) capable of inducing the same scalp sensations perceived during real stimulation, while preventing currents from reaching the cortex and cause changes in brain excitability.

Methods

A novel model-based multielectrode technique —optimizing the location and currents of a set of small electrodes placed on the scalp— was used to control the relative amount of current delivered transcranially in real and placebo multichannel tDCS conditions. The presence, intensity and localization of scalp sensations during tDCS was evaluated by means of a specifically designed questionnaire administered to the participants. We compared blinding ratings by directly addressing subjects’ ability to discriminate across conditions for both traditional (Bifocal-tDCS and -Sham, using sponge electrodes) and our novel multifocal approach (both real Multifocal-tDCS and ActiSham). Changes in corticospinal excitability were monitored based on Motor Evoked Potentials (MEPs) recorded via concurrent Transcranial Magnetic Stimulation (TMS) and electromyography (EMG).

Results

Subjects perceived Multifocal-tDCS and ActiSham similarly in terms of both scalp sensations and their localization on the scalp, whereas traditional Bifocal stimulation was rated as more painful and annoying compared to its Sham counterpart. Additionally, differences in scalp localization were reported for active/sham Bifocal-tDCS. As for MEPs amplitude, a main effect of stimulation was found when comparing Bifocal-Sham and ActiSham (F(1,13)= 6.67, p=.023), with higher MEPs amplitudes after the application of Bifocal-Sham.

Conclusions

Compared to traditional Bifocal-tDCS, ActiSham offers better participants’ blinding by inducing very similar scalp sensations to those of real Multifocal tDCS both in terms of intensity and localization, while not affecting corticospinal excitability.

Introduction

Non-invasive Brain Stimulation (NIBS) techniques are used to modulate brain activity in a safe and well-tolerated way [1]. In particular, Transcranial direct current stimulation (tDCS), uses low-intensity electrical currents to modulate cortical excitability in a polarity-specific manner [1]. Classical tDCS montages consist of two rectangular sponge electrodes with a contact area of ∼25-35 cm2, where electrical current between 0.5mA and 4mA flows from a positively charged electrode (anode) to a negative one (cathode)[2] passing through various tissue compartments including skin, muscle, bone, cerebrospinal fluid and brain. Due to its safety and relatively low-cost, tDCS experiments have been widely carried out to investigate human neurophysiology and to test its application as a new potential therapeutic solution for neurological and psychiatric conditions. To ensure adequate understanding of the observed effects, however, researchers need to rely on valid and approved control placebo conditions, a fundamental requirement in randomized controlled trials. Traditional standard sham protocols consist on an initial ramp up of the current, followed by a short stimulation period (usually for 5-60 seconds) and a final ramp down [[3][4][5]], (i.e., Fade In of current, brief real Stimulation, Fade-Out; commonly known as “FISSFO” protocol), an approach thought to cause sensory stimulation similar to real tDCS without affecting cortico-spinal excitability [6]. However, both these assumptions (i.e., adequate blinding and absence of effects on the brain) are still under examination. FISSFO sham has been considered effective in providing a proper blinding when compared with real tDCS at 1mA for 20 minutes [6], becoming the standard for sham tDCS [7]. The rationale stems from participants’ reports in which the cutaneous perceptions that generally cue subjects on tDCS being effectively delivered (i.e., tingling or itching sensation), have been mostly reported during the first 30-60 seconds of stimulation to then gradually decrease, possibly due to habituation [4]. However, a recent investigation has revealed that even naïve subjects (N=192) are capable of distinguishing classic sham stimulation (FISSFO) from active tDCS when delivered at 1 mA for 20 minutes over the left dorsolateral prefrontal cortex (DLPFC) [8]. Prior experiments had already suggested blinding inefficacy when real tDCS is applied at 1.5-2 mA, even for only 10 minutes [9,10]. Accordingly, non-naïve subjects seem more capable of distinguishing real from sham tDCS [11] and extreme individual variability has been reported with regard to sensibility to stimulation intensity and duration, with subjects being able to perceive tDCS even at very low intensity (i.e., 400 μA) [11].

On the other hand, additional sham protocols have been developed with modified durations of ramp up/down, or even delivering constant low intensity currents (0.016 or 0.034 mA) [7,12,13]. However, these approaches have not been properly tested on large sample of patients/subjects, with no data on the effects of such alternative sham protocols on the brain, while inconsistent results on many neurophysiological parameters have been documented when adopting such modified approaches [13].

Beyond the single or double blinding efficacy of FISSFO and related approaches [14], an element of interest is the question of whether tDCS effects are due to cortical interaction of the generated electric fields or from peripheral nervous system (PNS) stimulation. Since the ramp-up/ramp-down method for blinding decreases both cortical and peripheral stimulation, they cannot help disentangling cortical and peripheral effects. In addition, cortical effects of the brief period of real stimulation during sham protocols may not completely be excluded [15].

An additional challenge is the fact that the induced tDCS electric field is conditioned by the heterogeneity of cortical and non-cortical tissues, as well as by the complexity of cortical geometry [16]. In recent years, this has been addressed by the use of multichannel tDCS systems in combination with realistic finite element modeling of current propagation in the head derived from subject neuroimaging data (e.g. MRI, fMRI) [17,18]. The rationale for multifocal stimulation resides on both the need for more targeted stimulation of the cortex, as well as the notion that brain regions operate in networks and communicate with each other’s through modulatory interactions [[19][20][21]]. Realistic physical models provide a crucial element for better experimental understanding and control of the electric fields generated by tDCS.

In the present study, we investigate a novel approach to sham stimulation based on controlled shunting of currents via a model-based quantification of transcutaneous and transcranial effects. Specifically, the novel sham tDCS solution benefits from the use of an optimization algorithm allowing tDCS montages to be tailored in such a way that zero or very low magnitude electric fields are delivered on the brain, while medium to high intensity currents are maintained in at least some scalp electrodes, thus eliciting scalp sensations necessary for blinding. Notably, this allows to maintain the stimulation ON for the entire duration of sham tDCS, therefore inducing scalp sensations similar to real tDCS, while avoiding known limitations of the FISSFO protocol. We hypothesize that such montage (Active Sham, ActiSham hereafter) (i) will generate scalp sensations similar to a Multifocal (real) tDCS montage based on the same electrodes’ location and identical stimulation intensity/duration; and that (ii) ActiSham will not induce changes in cortico-spinal excitability (CSE), as assessed through Motor Evoked Potentials (MEPs) induced by Transcranial Magnetic Stimulation (TMS) as an index of corticospinal excitability. If successful, this and similar other approaches for improved sham stimulation could contribute to more efficient design of future tDCS research studies and clinical trials.

Methods

Study design

Fourteen subjects participated in 4 randomized tDCS stimulation visits, spaced 7±3 days to ensure no carryover effects. The tDCS conditions were: real Bifocal-tDCS, Bifocal-Sham, real Multifocal-tDCS and ActiSham. Each session lasted approximately 90 minutes during which participants seated in a comfortable chair with their eyes open. To measure changes in corticospinal excitability, single pulse TMS was applied over the left primary motor cortex (M1) at the beginning and the end of each stimulation session. Somatosensory sensations elicited by tDCS were addressed by means of ad-hoc questionnaires. See dedicated sections below for further details about tools and procedures.

Participants

Fourteen healthy right-handed naïve subjects (25.4 years ± 2.1; 5 males) were recruited at the University Campus of Siena, School of Medicine (Siena, Italy). Possible contraindications to either TMS or tDCS were assessed by means of a screening questionnaire [22]. Exclusion criteria included: history of seizures, head injury, pacemakers or other implanted medical devices, metallic objects in the head, hearing impairments, medications altering cortical excitability or other significant medical concerns. All participants gave written informed consent prior to participating to the study. The research proposal and associated methodologies were approved by the local ethical committee in accordance with the principles of the Declaration of Helsinki.

tDCS

tDCS sessions lasted 15 minutes, with electrode types, scalp montages and stimulation intensities customized for each tDCS protocol (Figure 1). Transcranial stimulation was delivered using a “Starstim 8” brain stimulator controlled via Bluetooth using a laptop computer (Neuroelectrics, Barcelona, Spain). For canonical Bifocal-tDCS (active or sham), stimulation was delivered through traditional 5×7 cm rectangular sponge electrodes, with a contact area of 35 cm2 (SPONSTIM, Neuroelectrics, Barcelona, Spain). Before current delivery, electrodes were soaked with 15 ml of sterile sodium chloride solution (0.9%). For Multichannel stimulation conditions (real and ActiSham), current was instead delivered using circular Ø 20 mm PISTIM electrodes (Neuroelectrics, Barcelona, Spain) with an Ag/AgCl core and a gel/skin contact area of 3.14 cm2. Electrodes were filled with a conductive gel before the tDCS intervention. To further improve current conductivity, the scalp was gently rubbed with an alcohol solution at the beginning of each session. Electrodes were inserted in a neoprene cap with available positions following the 10/20 EEG system.

Figure 1

Figure 1Study design. (A) Active stimulation was delivered for 15 minutes, (30 seconds of ramp up and down). Corticospinal excitability was measured via TMS three times prior to stimulation (Pre-10, Pre-5 and Pre-0) and compared with post measurements collected up to 15 minutes after stimulation (Post-0, Post-5, Post-10, Post-15). Halfway through the protocol (i.e., at minute 7), subjects were asked to rate stimulation-related annoyance and pain levels. tDCS montages for Multifocal-tDCS (B), ActiSham (C), Bifocal-tDCS and Bifocal-Sham (D) are shown.

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Continue —-> A Novel tDCS Sham Approach Based on Model-Driven Controlled Shunting – ScienceDirect

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[Abstract] Sham tDCS: A hidden source of variability? Reflections for further blinded, controlled trials

Abstract

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS,tDCS most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies.

via Sham tDCS: A hidden source of variability? Reflections for further blinded, controlled trials – Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation

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[WEB SITE] Cannabidiol shows promise to reduce seizures for people with difficult-to-treat epilepsy

Taking cannabidiol may cut seizures in half for some children and adults with Lennox-Gastaut syndrome (LGS), a severe form of epilepsy, according to new information released today from a large scale controlled clinical study that will be presented at the American Academy of Neurology’s 69th Annual Meeting in Boston, April 22 to 28, 2017. Cannabidiol is a molecule from the cannabis plant that does not have the psychoactive properties that create a “high.”

Nearly 40 percent of people with LGS, which starts in childhood, had at least a 50 percent reduction in drop seizures when taking a liquid form of cannabidiol compared to 15 percent taking a placebo.

When someone has a drop seizure, their muscle tone changes, causing them to collapse. Children and adults with LGS have multiple kinds of seizures, including drop seizures and tonic-clonic seizures, which involve loss of consciousness and full-body convulsions. The seizures are hard to control and usually do not respond well to medications. Intellectual development is usually impaired in people with LGS.

Although the drop seizures of LGS are often very brief, they frequently lead to injury and trips to the hospital emergency room, so any reduction in drop seizure frequency is a benefit.

“Our study found that cannabidiol shows great promise in that it may reduce seizures that are otherwise difficult to control,” said study author Anup Patel, MD, of Nationwide Children’s Hospital and The Ohio State University College of Medicine in Columbus and a member of the American Academy of Neurology.

For the randomized, double-blind, placebo-controlled study, researchers followed 225 people with an average age of 16 for 14 weeks. The participants had an average of 85 drop seizures per month, had already tried an average of six epilepsy drugs that did not work for them and were taking an average of three epilepsy drugs during the study.

Participants were given either a higher dose of 20 mg/kg daily cannabidiol, a lower dose of 10 mg/kg daily cannabidiol or placebo as an add-on to their current medications for 14 weeks.

Those taking the higher dose had a 42 percent reduction in drop seizures overall, and for 40 percent, their seizures were reduced by half or more.

Those taking the lower dose had a 37 percent reduction in drop seizures overall, and for 36 percent, seizures were reduced by half or more.

Those taking the placebo had a 17 percent reduction in drop seizures, and for 15 percent, seizures were reduced by half or more.

There were side effects for 94 percent of those taking the higher dose, 84 percent of those taking the lower dose and 72 percent of those taking placebo, but most side effects were reported as mild to moderate. The two most common were decreased appetite and sleepiness.

Those receiving cannabidiol were up to 2.6 times more likely to say their overall condition had improved than those receiving the placebo, with up to 66 percent reporting improvement compared to 44 percent of those receiving the placebo.

“Our results suggest that cannabidiol may be effective for those with Lennox-Gastaut syndrome in treating drop seizures,” said Patel. “This is important because this kind of epilepsy is incredibly difficult to treat. While there were more side effects for those taking cannabidiol, they were mostly well-tolerated. I believe that it may become an important new treatment option for these patients.”

There is currently a plan to submit a New Drug Application to the FDA later this year.

Source: Cannabidiol shows promise to reduce seizures for people with difficult-to-treat epilepsy

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[Oral Presentation] Randomized, Placebo-Controlled, Phase III Study of Incobotulinumtoxina for Upper-Limb Post-Stroke Spasticity – Archives of Physical Medicine and Rehabilitation

To study efficacy and safety of incobotulinumtoxinA for upper-limb post-stroke spasticity.

Source: Randomized, Placebo-Controlled, Phase III Study of Incobotulinumtoxina for Upper-Limb Post-Stroke Spasticity – Archives of Physical Medicine and Rehabilitation

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