Preserving the placebo effect after disclosure: A new perspective on non-deceptive placebos.

The present study explores whether a particular style of placebo disclosure could serve as a tool to foster a renewed trust in one's own inherent resources and elicit a meaningful placebo effect. In a motor performance task, two placebo groups received inert transcutaneous electrical nerve stimulation (TENS) in each of four sessions along with information on its force-enhancing properties. Before the final session, one of the placebo groups was informed about the placebo, which was portrayed as a means to unleash an inherent potential. Along with force, we systematically monitored task-specific self-efficacy to test whether this variable would be differentially modulated in the two placebo groups. Compared to two control groups, placebo groups showed higher force and self-efficacy in the last session. No differences in self-efficacy were observed in the placebo groups even after revealing the placebo procedure, suggesting that the disclosure was effective in 'safeguarding' individuals' self-efficacy. These findings may have important implications, paving the way for the use of placebos that not only are ethically permissible but also support individuals' self-efficacy.

Placebo effect on gait: a way to reduce the dual-task cost in older adults.

The ability to perform two tasks simultaneously is essential for daily activities. In older adults, this ability is markedly reduced, as evidenced by the dual-task cost on gait. Preliminary evidences indicate that the dual-task cost can be influenced by different types of manipulations. Here, we explored the effectiveness of a new approach to reduce the dual-task cost, based on the placebo effect, a psychobiological phenomenon whereby a positive outcome follows the administration of an inert device thought to be effective. Thirty-five healthy older adults were asked to walk on a sensorized carpet (single-task condition) and to walk while counting backward (dual-task condition) in two sessions (pre-test and post-test). A placebo group, randomly selected, underwent sham transcranial direct current stimulation over the supraorbital areas between sessions, along with information about its positive effects on concentration and attention. A control group did not receive any intervention between sessions. The dual-task cost was significantly reduced in the placebo group at the post-test session compared to the pre-test for several gait parameters (Cohen's d > 1.43). At the post-test session, the dual-task cost was also lower in the placebo group than in the control group (d > 0.73). Cognitive (number of subtractions and number of errors) and subjective (perceived mental fatigability) variables remained stable across sessions. The reduced dual-task cost in the placebo group could indicate the ability to re-establish the allocation of attentional resources between tasks. These findings could contribute to the development of cognitive strategies that leverage positive expectations to boost motor control in older adults.

The placebo effect shortens movement time in goal-directed movements.

The placebo effect is a powerful psychobiological phenomenon whereby a positive outcome follows the administration of an inert treatment thought to be effective. Growing evidence shows that the placebo effect extends beyond the healing context, affecting also motor performance. Here we explored the placebo effect on the control of goal-directed movement, a fundamental function in many daily activities. Twenty-four healthy volunteers performed upper-limb movements toward a target at different indexes of difficulty in two conditions: in the placebo condition, an electrical device (inert) was applied to the right forearm together with verbal information about its positive effects in improving movement precision; in the control condition, the same device was applied along with verbal information about its neutral effects on performance. Interestingly, we found shorter movement time in the placebo compared to the control condition. Moreover, subjective perception of fatigability was reduced in the placebo compared to the control condition. These findings indicate that the placebo effect can improve the execution of goal-directed movements, thus adding new evidence to the placebo effect in the motor domain. This study could inspire future applications to improve upper-limb movements or in clinical settings for patients with motor deficits.

Functional neurological disorder and placebo and nocebo effects: shared mechanisms.

Functional neurological disorder (FND) is characterized by neurological symptoms that cannot be explained by a structural neurological cause. Among the different aetiological models that have been proposed for FND, of note is the Bayesian predictive coding model, which posits that perception relies on top-down cortical predictions (priors) to infer the source of incoming sensory information. This model can also apply to non-pathological experiences, such as placebo and nocebo effects, wherein sensory information is shaped by prior expectations and learning. To date, most studies of the relationship between placebo and nocebo effects and FND have focused on the use of placebos for diagnosis and treatment of FND. Here, we propose that this relationship might go beyond diagnosis and therapy. We develop a framework in which shared cognitive, personality and neuroanatomical factors justify the consideration of a deeper link between FND and placebo and nocebo effects. This new perspective might offer guidance for clarification of the pathogenesis of FND and for the identification of potential biomarkers and therapeutic targets.

Event-Related Potentials as Markers of Efficacy for Combined Working Memory Training and Transcranial Direct Current Stimulation Regimens: A Proof-of-Concept Study.

Our brains are often under pressure to process a continuous flow of information in a short time, therefore facing a constantly increasing demand for cognitive resources. Recent studies have highlighted that a lasting improvement of cognitive functions may be achieved by exploiting plasticity, i.e., the brain's ability to adapt to the ever-changing cognitive demands imposed by the environment. Transcranial direct current stimulation (tDCS), when combined with cognitive training, can promote plasticity, amplify training gains and their maintenance over time. The availability of low-cost wearable devices has made these approaches more feasible, albeit the effectiveness of combined training regimens is still unclear. To quantify the effectiveness of such protocols, many researchers have focused on behavioral measures such as accuracy or reaction time. These variables only return a global, non-specific picture of the underlying cognitive process. Electrophysiology instead has the finer grained resolution required to shed new light on the time course of the events underpinning processes critical to cognitive control, and if and how these processes are modulated by concurrent tDCS. To the best of our knowledge, research in this direction is still very limited. We investigate the electrophysiological correlates of combined 3-day working memory training and non-invasive brain stimulation in young adults. We focus on event-related potentials (ERPs), instead of other features such as oscillations or connectivity, because components can be measured on as little as one electrode. ERP components are, therefore, well suited for use with home devices, usually equipped with a limited number of recording channels. We consider short-, mid-, and long-latency components typically elicited by working memory tasks and assess if and how the amplitude of these components are modulated by the combined training regimen. We found no significant effects of tDCS either behaviorally or in brain activity, as measured by ERPs. We concluded that either tDCS was ineffective (because of the specific protocol or the sample under consideration, i.e., young adults) or brain-related changes, if present, were too subtle. Therefore, we suggest that other measures of brain activity may be more appropriate/sensitive to training- and/or tDCS-induced modulations, such as network connectivity, especially in young adults.

The Role of Expectation and Beliefs on the Effects of Non-Invasive Brain Stimulation.

Non-invasive brain stimulation (NIBS) techniques are used in clinical and cognitive neuroscience to induce a mild magnetic or electric field in the brain to modulate behavior and cortical activation. Despite the great body of literature demonstrating promising results, unexpected or even paradoxical outcomes are sometimes observed. This might be due either to technical and methodological issues (e.g., stimulation parameters, stimulated brain area), or to participants' expectations and beliefs before and during the stimulation sessions. In this narrative review, we present some studies showing that placebo and nocebo effects, associated with positive and negative expectations, respectively, could be present in NIBS trials, both in experimental and in clinical settings. The lack of systematic evaluation of subjective expectations and beliefs before and after stimulation could represent a caveat that overshadows the potential contribution of placebo and nocebo effects in the outcome of NIBS trials.

The effect of motor and cognitive placebos on the serial reaction time task.

Motor learning is a key component of human motor functions. Repeated practice is essential to gain proficiency over time but may induce fatigue. The aim of this study was to determine whether motor performance and motor learning (as assessed with the serial reaction time task, SRTT) and perceived fatigability (as assessed with subjective scales) are improved after two types of placebo interventions (motor and cognitive). A total of 90 healthy volunteers performed the SRTT with the right hand in three sessions (baseline, training and final). Before the training and the final session, one group underwent a motor-related placebo intervention in which inert electrical stimulation (TENS) was applied over the hand and accompanied by verbal suggestion that it improves movement execution (placebo-TENS). The other group underwent a cognitive-related placebo intervention in which sham transcranial direct current stimulation (tDCS) was delivered to the supraorbital area and accompanied by verbal suggestion that it increases attention (placebo-tDCS). A control group performed the same task without receiving treatment. Overall better performance on the SRTT (not ascribed to sequence-specific learning) was noted for the placebo-TENS group, which also reported less perceived fatigability at the physical level. The same was observed in a subgroup tested 24 hr later. The placebo-tDCS group reported less perceived fatigability, both at the mental and physical level. These findings indicate that motor- and cognitive-related placebo effects differently shape motor performance and perceived fatigability on a repeated motor task.

Cathodal Cerebellar tDCS Combined with Visual Feedback Improves Balance Control.

Balance control is essential to maintain a stable body position and to prevent falls. The aim of this study was to determine whether balance control could be improved by using cerebellar transcranial direct current stimulation (tDCS) and visual feedback in a combined approach. A total of 90 healthy volunteers were randomly assigned to six groups defined by the delivery of tDCS (cathodal or anodal or sham) and the provision or not of visual feedback on balance during the acquisition phase. tDCS was delivered over the cerebellar hemisphere ipsilateral to the dominant leg for 20 min at 2 mA during a unipedal stance task. Body sway (i.e., ankle angle and hip position) was measured as an overall maximal unit in anteroposterior and mediolateral direction, together with participant rating of perception of stability, before (baseline), during (acquisition), and after (final) the intervention. We found a reduction in body sway during the acquisition session when visual feedback alone was provided. When the visual feedback was removed (final session), however, body sway increased above baseline. Differently, the reduction in overall maximal body sway was maintained during the final session when the delivery of cathodal tDCS and visual feedback was combined. These findings suggest that cathodal tDCS may support the short-term maintenance of the positive effects of visual feedback on balance and provide the basis for a new approach to optimize balance control, with potential translational implications for the elderly and patients with impaired posture control.

Positive verbal suggestion optimizes postural control.

Balance is a very important function that allows maintaining a stable stance needed for many daily life activities and for preventing falls. We investigated whether balance control could be improved by a placebo procedure consisting of verbal suggestion. Thirty healthy volunteers were randomized in two groups (placebo and control) and asked to perform a single-leg stance task in which they had to stand as steadily as possible on the dominant leg. The task was repeated in three sessions (T0, T1, T2). At T1 and T2 an inert treatment was applied on the leg, by informing the placebo group that it was effective in improving balance. The control group was overtly told that treatment was inert. An accelerometer applied on participants' leg allowed to measure body sways in different directions. Subjective parameters, like perception of stability, were also collected. Results showed that the placebo group had less body sways than the control group at T2, both in the three-dimensional space and in the anterior-posterior direction. Furthermore, the placebo group perceived to be more stable than the control group. This study represents the first evidence that placebo effect optimizes posture, with a potential translational impact in patients with postural and gait disturbances.

The role of the dorsolateral prefrontal cortex in the motor placebo effect.

The neural correlates of the placebo effect in the motor domain are still unknown. The aim of this study was to tackle the role of a frontal cortical region, the dorsolateral prefrontal cortex (dlPFC). To this end, we stimulated the cortical site corresponding to the left dlPFC with transcranial direct current stimulation (tDCS) during a placebo procedure and measured any change in the motor placebo effect in all the participants and more specifically in placebo-responders. Three different experiments were conducted in which healthy volunteers performed a force motor task with the index finger. The placebo treatment consisted of transcutaneous electrical nerve stimulation (TENS). In Experiment 1 (expectation alone), participants were only verbally suggested about the positive effects of TENS. In Experiment 2 (expectation and conditioning), participants were verbally suggested about TENS and conditioned with a surreptitious increase in a visual feedback of force. In Experiment 3 (control procedure), participants were told that TENS was inefficient. Each participant was tested in three different days with anodal, cathodal and sham tDCS over the dlPFC. Results showed that in Experiment 1 and 2 force increased after the procedure, independently of tDCS. By focusing on placebo-responders, we found that in Experiment 1 force remained stable after active tDCS, whereas it increased after inactive tDCS. These findings bring new evidence on the neural underpinnings of the motor placebo effect, by showing that independently of the polarity, active tDCS over the left dlPFC may undermine the expectation-induced enhancement of force in placebo-responders.