A novel tDCS sham approach based on model-driven controlled shunting

BackgroundTranscranial 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.ObjectiveTo 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.MethodsA 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).ResultsParticipants perceived Multifocal-tDCS and ActiSham similarly in terms of both localization and intensity of scalp sensations, 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, with Sham tDCS inducing more widespread itching and burning sensations. 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.ConclusionsCompared 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.     

Placebo responses in the treatment of urge incontinence

The treatment options of patients with urge incontinence are behavioral therapy, drug therapy and surgery. The evaluation and reported efficacy of these treatments, with particular reference to the potential placebo response in treatment is discussed.     

Open, Double-Blind and Long-Term Study of Vigabatrin in Chronic Epilepsy

We performed an open, double-blind, and long-term study of vigabatrin (gamma-vinyl-GABA, GVG) in patients with treatment-resistant epilepsy who were receiving only one or at most two standard antiepileptic drugs (AEDs). The novel design included a parallel, double-blind, placebo-controlled phase that minimized the number of patients receiving placebo and allowed determination of the optimum dose of GVG for each patient before initiation of the double-blind phase. The study was divided into four phases. The first phase was a 6-week period of baseline observation. In the second phase, GVG was added openly to previous AEDs for 8 weeks. During the first 2 weeks of this phase, the dose of GVG was increased weekly and then, in the absence of adverse effects, was held constant for the next 6 weeks. At the end of this open phase, seizure frequency during the 6 weeks of constant treatment was compared with the baseline seizure frequency for each patient. Patients who experienced reduction greater than 50% in the frequency of any seizure type during the open phase were defined as responders. These responders were then entered into the third and double-blind phase, in which they were randomly allocated wither to continue active GVG treatment or placebo for 8 weeks. Thirty-three patients entered the study; 31 of 33 patients completed the initial open phase. Twenty patients achieved a reduction greater than or equal to 50% in the frequency of one or more seizure types and were eligible for the double-blind phase; 10 were randomized to continue GVG and 10 were randomized to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

A placebo controlled trial of remoxipride in the prevention of relapse in chronic schizophrenia

Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D₂)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150–300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively (P=0.015). Efficacy analyses using clinical global impression (P=0.04) and change in BPRS scores (P=0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients.     

Anxiety psychopathology predictive of outcome in patients with panic disorder and depression treated with imipramine, alprazolam and placebo

This study examines clinical predictors of outcome for patients with panic disorder and depression in a 16 week, placebo-controlled trial of alprazolam and imipramine (n = 126). Baseline global severity of illness and phobic avoidance were differentially predictive of acute response to treatment. Patients in the mild to moderate range of global distress experienced smaller degrees of improvement on alprazolam than on imipramine at week 4. At endpoint, the relative effectiveness of the active medication versus placebo was diminished in patients with higher levels of phobic avoidance. This relationship was not evident for completers, suggesting that the adverse effects of avoidance on outcome after sustained treatment was reduced.     

Bromazepam in generalized anxiety

Bromazepam was compared with placebo and with chlorprothixene in a randomized, double-blind group-comparative multicenter trial in general practice. Two hundred and forty-five patients with generalized anxiety disorder (DSM-III 1980) were treated for 2 weeks with two daily doses of bromazepam, 3 mg or chlorprothixene, 15 mg or placebo. Median reductions in Hamilton Anxiety rating were 12 (bromazepam), 10.3 (chlorprothixene) and 7.3 (placebo). The study revealed significant superiority of bromazepam over placebo (median differences 3.3, 95% confidence limits: 0.3 and 6.1) but not over chlorprothixene (median difference 1.4, 95% confidence limits –0.8 and +3.5). Significantly higher rates of tiredness, sedation and hypersomnia were found on bromazepam and chlorprothixene compared to placebo. Tolerance was rated as at least good in 85.6% on bromazepam, in 86% on chlorprothixene and in 87.8% on placebo. Neither previous psychopharmacological treatment nor presence of psychosocial stress were of perceptible influence. Bromazepam and chlorprothixene are both superior to placebo in generalized anxiety states treated in general practice, but spontaneous improvements/placebo effects are substantial.General practice The following general practitioners are gratefully acknowledged for their excellent co-operation: K. Andreasen (Grenaa), T. Andreasen (Helsingoer), C. Bjerre-Christensen (Viby J), J. Brix (Aabenraa), N.B. Caning (Stokkemarke), N. Christensen (Odense), P. Dehn-Jensen (Lyngby), J. Eggert (Langebaek), H. Fuglsang-Damgaard (Havndal), I. Fraemohs (Allingaabro), J. Gylling (Nykoebing Sjaelland), E. Halkjaer-Soerensen (Roedding), B. Hansson (Frederiksvaerk), C. Hauge (Espergaerde), S. Hede (Aalborg), G. Jensen (Copenhagen S), T. Knudsen (Arden), P. Kofod (Vejle), K. Kraen (Varde), V. Lade (Hjoerring), S. Mehlsen (Auning), J. Meyer-Christensen (Hobro), R. Michael (Langebaek), J. Munch (Oersted), L. Moeller-Hansen (Alleroed), U. Moeller (Graasten), K. Nielsen (Malling), S. Kjaerem Nielsen (Copenhagen), P.V. Nielsen (Odense), J. Peulicke (Espergaerde), O. Ravn (Roedding), C.U. Rosenberg (Aarhus), J. Rude (Goerlev), S. Spangsberg (Holbaek), H. Soegaard (Oelgod), O. Tang (Hoersholm)     

临床试验中使用安慰剂的伦理学问题

临床治疗研究采用随机双盲安慰剂对照试验日渐增多,安慰剂 伦理问题应值得重视。临床治疗试验首先应当遵循医学人体试验的医德原则即药物临床试验;其次应以世界医学会赫尔辛基宣言为准则,严格掌握安慰剂对照的适用指征,并分析了安慰剂效应的产生机制,对国内安慰剂对照例用情况及有关伦理学问题进行分析讨论。     

Is it possible to make cross-study comparisons of urinary continence rates in patients with overactive bladder?

ABSTRACT

Several antimuscarinic agents are available for the treatment of overactive bladder but there are few head-to-head studies to guide physicians in choosing one over another. Here we propose ways in which logical adjustments can be made to account for differences in disease severity and placebo effects when considering continence data to allow estimation of relative effectiveness across studies.     

Expectancy-Induced Placebo Analgesia in Children and the Role of Magical Thinking

Expectations and beliefs shape the experience of pain. This is most evident in context-induced, placebo analgesia, which has recently been shown to interact with the trait of magical thinking (MT) in adults. In children, placebo analgesia and the possible roles that MT and gender might play as modulators of placebo analgesia have remained unexplored. Using a paradigm in which heat pain stimuli were applied to both forearms, we investigated whether MT and gender can influence the magnitude of placebo analgesia in children. Participants were 49 right-handed children (aged 6–9 years) who were randomly assigned—stratified for MT and gender—to either an analgesia-expectation or a control-expectation condition. For both conditions, the placebo was a blue-colored hand disinfectant that was applied to the children's forearms. Independent of MT, the placebo treatment significantly increased both heat pain threshold and tolerance. The threshold placebo effect was more pronounced for girls than boys. In addition, independent of the expectation treatment, low-MT boys showed a lower tolerance increase on the left compared to the right side. Finally, MT specifically modulated tolerance on the right forearm side: Low-MT boys showed an increase, whereas high-MT boys showed a decrease in heat pain tolerance. This study documented a substantial expectation-induced placebo analgesia response in children (girls > boys) and demonstrated MT and gender-dependent laterality effects in pain perception. The findings may help improve individualized pain management for children.PerspectiveThe study documents the first experimental evidence for a substantial expectancy-induced placebo analgesia response in healthy children aged 6 to 9 years (girls > boys). Moreover, the effect was substantially higher than the placebo response typically found in adults. The findings may help improve individualized pain management for children.