The impact of patients' pre-treatment expectations on immunosuppressive treatment outcomes in myasthenia gravis: A pilot correlational study.

INTRODUCTION/AIMS: The impact of treatment expectations on active treatment outcomes has not been specifically investigated in neuromuscular disorders. We thus explored in myasthenia gravis (MG) the contribution of patients' pre-treatment expectations combined with an immunosuppressant drug on treatment outcomes. METHODS: This pilot correlational study involved 17 patients with generalized MG, scheduled to start immunosuppressant azathioprine. At baseline, a healthcare professional administered: (i) the Stanford Expectations of Treatment Scale; (ii) a structured checklist paper form asking patients which side-effects they expected to develop after starting azathioprine, coupled with a standardized framing of statements. Quantitative Myasthenia Gravis (QMG) score and daily dose of concomitant drugs were assessed by neurologists as clinical outcomes. Clinical outcomes and side-effects were re-assessed at 3 and 6 months, and clinical outcomes were monitored at 18 months. RESULTS: Clinically significant improvement in the QMG scores was achieved at 3 or 6 months. The level of state anxiety appeared to act as moderator of pre-treatment negative expectations (strong, positive, indicative correlation, rs = .733, p = .001). The latter were, in turn, associated with the fulfillment of side-effects that patients expected to develop with the new treatment (moderate, positive, indicative correlation, rs = .699, p = .002). No significant correlation emerged between positive and negative expectations. DISCUSSION: Our findings show a very quick clinical response and also suggest that patients' expectations and anxiety contributed to treatment outcomes, highlighting the importance of promoting safety messages and education strategies around newly introduced treatments. Future goals include evaluating a larger cohort that includes a matched control group.

Mind and body connection in expert meditators: a computational study based on central and peripheral nervous system.

A meditative 'technique' is conceived as a continuum of different affective states involving mind and body jointly. Meditative practices can involve cognitive effort (e.g., focused attention and open-minded techniques), as well as automatic and implicit practices (e.g., transcendental techniques). The NGALSO tantric self-healing meditation technique is a brief, comprehensive meditation technique relying on mind and body connection. In this study, we aimed to investigate the state and the trait neurophysiological correlates of NGALSO meditation practice. First, 19 EEG channels and a 3-lead ECG signal were recorded from 10 expert meditators (more than 7 years of daily meditation) and 10 healthy inexpert participants (controls) who underwent the same meditative procedure. The neuropsychological profiles of experts and controls were compared. Results showed that expert meditators had significantly higher power spectra on alpha, theta and beta, and a higher sympathetic tone with lower parasympathetic tone after meditation. Conversely, the control group had significantly less power spectra on alpha, theta and beta, and a higher parasympathetic tone with lower sympathetic tone after meditation. A machine learning approach also allowed us to classify experts vs. controls correctly by using only EEG Theta bands before or after meditation. ECG results allowed us to show a significantly higher effort by expert meditators vs. controls, thus suggesting that a higher effort is required for this meditation, in line with the principle 'no pain, no gain' in body and mind.

Are eco-sustainable dietary patterns associated with impulsiveness? An insight from Italy.

Impulsivity is known to influence food choices. We explored possible differences in its expression between individuals with or without an eco-sustainable diet and its relationship with cognitions and behaviours about eco-sustainable foods. Participants were categorised as having or not having an eco-sustainable diet. Impulsivity traits and cognitions and behaviours about sustainable food products were measured. Among the 332 participants, 92.78% showed an eco-sustainable diet, whereas only 7.22% had an eco-sustainable diet. No difference between groups emerged about impulsive traits, whereas significant differences emerged in cognitions and behaviours about sustainable foods, with the only exceptions of subjective norms and past behaviour. Impulsive traits were linked to cognitions and behaviours differently within groups. Impulsivity traits may be related to actions towards eco-sustainable foods, with the perception of their availability playing a crucial role. Increasing contextual opportunities may be fundamental for having eco-sustainable consumers.

Modulation of Motor Awareness: A Transcranial Magnetic Stimulation Study in the Healthy Brain.

Previous studies on the mechanisms underlying willed actions reported that the premotor cortex may be involved in the construction of motor awareness. However, its exact role is still under investigation. Here, we investigated the role of the dorsal premotor cortex (PMd) in motor awareness by modulating its activity applying inhibitory rTMS to PMd, before a specific motor awareness task (under three conditions: without stimulation, after rTMS and after Sham stimulation). During the task, subjects had to trace straight lines to a given target, receiving visual feedback of the line trajectories on a computer screen. Crucially, in most trials, the trajectories on the screen were deviated, and to produce straight lines, subjects had to correct their movements towards the opposite direction. After each trial, participants were asked to judge whether the line seen on the computer screen corresponded to the line actually drawn. Results show that participants in the No Stimulation condition did not recognize the perturbation until 14 degrees of deviation. Importantly, active, but not Sham, rTMS significantly modulated motor awareness, decreasing the amplitude of the angle at which participants became aware of the trajectory correction. These results suggest that PMd plays a crucial role in action self-monitoring.

Attempting to Separate Placebo Effects from Exercise in Chronic Pain: A Systematic Review and Meta-analysis.

BACKGROUND: Pain is the most disabling characteristic of musculoskeletal disorders, and while exercise is promoted as an important treatment modality for chronic musculoskeletal conditions, the relative contribution of the specific effects of exercise training, placebo effects and non-specific effects such as natural history are not clear. The aim of this systematic review and meta-analysis was to determine the relative contribution of these factors to better understand the true effect of exercise training for reducing pain in chronic primary musculoskeletal pain conditions. DESIGN: Systematic review with meta-analysis DATA SOURCES: MEDLINE, CINAHL, SPORTDiscus, EMBASE and CENTRAL from inception to February 2021. Reference lists of prior systematic reviews. ELIGIBILITY CRITERIA: Randomised controlled trials of interventions that used exercise training compared to placebo, true control or usual care in adults with chronic primary musculoskeletal pain. The review was registered prospectively with PROSPERO (CRD42019141096). RESULTS: We identified 79 eligible trials for quantitative analysis. Pairwise meta-analysis showed very low-quality evidence (GRADE criteria) that exercise training was not more effective than placebo (g [95% CI]: 0.94 [- 0.17, 2.06], P = 0.098, I2 = 92.46%, studies: n = 4). Exercise training was more effective than true, no intervention controls (g [95% CI]: 0.99 [0.66, 1.32], P < 0.001, I2 = 92.43%, studies: n = 42), usual care controls (g [95% CI]: 0.64 [0.44, 0.83], P < 0.001, I2 = 76.52%, studies: n = 33), and when all controls combined (g [95% CI]: 0.84 [0.64, 1.04], P < 0.001, I2 = 90.02%, studies: n = 79). CONCLUSIONS: There is very low-quality evidence that exercise training is not more effective than non-exercise placebo treatments in chronic pain. Exercise training and the associated clinical encounter are more effective than true control or standard medical care for reductions in pain for adults with chronic musculoskeletal pain, with very low quality of evidence based on GRADE criteria.

Pain expectation and avoidance in the social context: an electrophysiological study.

Contingent negative variation (CNV) is an informative electrophysiological measure of pain anticipation showing higher amplitudes when highly painful stimulation is expected while presenting lower amplitudes when low painful stimulation is expected. Two groups of participants were recruited: one group expected and received an electrical stimulation of different intensities while being alone in the room (i.e. without social context), while a second group performed the same experiment with an observer in the room (i.e. with social context). Lower pain ratings and slower reaction times were observed in the group with social context and these results were accompanied in this group by a lower amplitude in the early component of the CNV as well as a lower amplitude of the later component of the wave. These results show that CNV can be considered a precise measure of central elaboration of pain anticipation explaining both its perceptual and motor components.

The Effect of Temporal Information on Placebo Analgesia and Nocebo Hyperalgesia.

OBJECTIVE: Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information. METHODS: Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained. RESULTS: Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time. CONCLUSIONS: Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.

The placebo effect in breath holding: a preliminary behavioral investigation.

PURPOSE: This study seeks to evaluate effects of expectations and conditioning on dry breath holding. METHODS: Sixty healthy volunteers were subdivided into 3 groups and were tested across 4 breath holding trials. Participants of the Control group (C) did not undergo any manipulation. Participants of the placebo (P) and nocebo (N) groups were told that they would inhale O2 (actually sham O2) or CO2 (actually sham CO2) along with opposite information that this would enhance or worsen their breath holding time, respectively. Opposite conditioning paradigms based on false visual feedback were employed to reinforce participants' positive (placebo) and negative (nocebo) beliefs. RESULTS: The P group showed the greater increase in breath holding time from baseline to the last trial (p = 0.0001) and the longest breath holding time in the last trial compared to the C group (p = 0.02) and the N group (p = 0.0001). Additionally, in the last trial the P group showed a greater decrease in peripheral oxygen saturation (SpO2) as compared to the C group (p = 0.04) and the N group (p = 0.001). Heart rate (HR) was accelerated in the N group during breath holding (in comparison to the P group [p = 0.04] and C group [p = 0.04]). CONCLUSIONS: Psychological components can affect behavioral and physiological parameters in breath holding. This study may inform future research about the role of placebo and nocebo effects for conditions in which critical functions are at play.

I expect what you expect: An electrophysiological study on social expectation of pain.

Expectations and motor reactions related to pain are mainly acquired through personal experiences. Contingent negative variation (CNV) has been shown to be an informative electrophysiological measure of this pain anticipation. Expectations can also arise while observing others in painful conditions. However, it still remains unclear what are the neural correlates of this phenomenon and how the observation of others in pain can subsequently change our personal pain perception as well as our motor reaction to pain. Using CNV as a measure of expectation, this study aims to assess whether expectations formed through observation change the observer's own experience of pain and reaction to pain. A new cooperative task was designed where one participant, the model, received an electrical stimulation while another, the observer, watched the experiment and both were asked to stop the stimulation as fast as possible. Crucially, in a successive session, participants inverted their roles so that models became observers and vice versa. CNV was recorded in both participants simultaneously by means of two synchronized electroencephalograms. Results showed that CNV area did not differ between models and observers and reaction times were significantly faster in observers compared to models. Moreover, observers' pain perception was correlated to models' pain perception as well as to observers' empathy scores. These data show how expectations, perceptions as well as reactions related to pain are crucially affected not only by observation but by personal attitudes toward others and all these changes can be clearly described through CNV.

The neurobiological underpinnings of placebo and nocebo effects.

The placebo effect, once considered only a nuisance in clinical research, is today a target of scientific inquiry that allows us understand how words, rituals and, more in general, the whole psychosocial context around the patient, affect the response to a treatment and the course of a disease. Today we are in a good position to study all these complex psychological factors by using a physiological and neuroscientific approach that uses modern neurobiological tools to probe different brain functions. Since a placebo is represented by the whole ritual of the therapeutic act, the main concept that has emerged today is that words and rituals may modulate the same biochemical pathways that are modulated by drugs. Most of our knowledge about these mechanisms comes from the field of pain, and represents a biomedical, psychological and philosophical enterprise that is changing the way we approach and interpret medicine, psychology and human biology. If on the one hand we know some of the mechanisms of drug action in the central nervous system, on the other we can now understand how the clinician-patient interaction may affect different physiological functions. In fact, the placebo effect and the therapist-patient relationship can be approached by using the same biochemical, cellular and physiological tools of the materia medica. This represents an epochal transition, in which the distinction between drugs and words is progressively getting thinner, and which helps us overcome the old dichotomy between psychology and biology.

Verbal communication about drug dosage balances drug reduction in Parkinson's disease: Behavioral and electrophysiological evidences.

INTRODUCTION: Changing drug dosage is common in clinical practice. Recent evidence showed that psychological factors may affect the therapeutic outcome. The aim of this study is to test whether verbal communication about drug dosage changes motor performance and fatigue in Parkinson's Disease (PD) patients. METHODS: We performed clinical (Unified PD Rating Scale), motor (number of finger flexions and perceived fatigue), and electrophysiological measurements (readiness potential, RP) in PD patients during medication-off and medication-on conditions in three groups. The first group got a full dose of l-dopa and was told it was a full dose. The second group got half dose and was told it was half dose. The third group got half dose, but it was told it was a full standard dose. RESULTS: We found that overt half dose was less effective than the full dose for clinical improvement, motor performance, and readiness potential. However, if half dose was given along with verbal instructions that it was a full dose, clinical improvement, motor performance and readiness potential were not significantly different from the full dose. CONCLUSIONS: Our findings indicate that verbal communication about dose reduction is as effective as the 50% dose reduction itself, demonstrating that deceptive information about the dose may have an important impact on the therapeutic outcome. Moreover, the supplementary motor area, source of the RP, seems to be involved in this psychological effect.

Dissociation between executed and imagined bimanual movements in autism spectrum conditions.

Autism spectrum conditions (ASC) are characterized by social-communicative deficits and repetitive stereotyped behaviors. Altered motor coordination is also observed and a dysfunction of motor imagery has been recently reported on implicit tasks. However, no information on explicit motor imagery abilities is available in ASC. Here, we employed a spatial bimanual task to concurrently assess motor coordination and explicit motor imagery in autism. A secondary objective of the study was to evaluate these abilities across two populations of ASC, namely adolescents and adults with ASC. To this aim, we took advantage of the circles-lines task in which where participants were asked to continuously draw: right hand lines (unimanual condition); right hand lines and left hand circles (bimanual condition); right hand lines while imagining to draw left hand circles (imagery condition). For each participant, an Ovalization Index (OI) was calculated as a deviation of the right hand drawing trajectory from an absolute vertical axis. Results showed a significant and similar coupling effect in the bimanual condition (i.e., a significant increase of the OI values with respect to the unimanual condition) in both controls and ASC participants. On the contrary, in the imagery condition, a significant coupling effect was found only in controls. Furthermore, adult controls showed a significantly higher imagery coupling effect in comparison to all the other groups. These results demonstrate that atypical motor imagery processes in ASC are not limited to implicit tasks and suggest that development of neural structures involved in motor imagery are immature in ASC. Autism Res 2018, 11: 376-384. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism spectrum conditions (ASC) are characterized by social-communicative and motor coordination difficulties but in many cases also by an impaired capability to imagine movements. In this study we found that while two handed coordination in ASC can be developed as well as in typically developed persons, the development of motor imagery could still be immature in ASC, leading to difficulties in imagining, understanding as well as programming and coordinating complex movements.

The rehabilitative effects on written language of a combined language and parietal dual-tDCS treatment in a stroke case.

In this paper we report the effect of a combined transcranial direct current stimulation (tDCS) and speech language therapy on linguistic deficits following left brain damage in a stroke case. We show that simultaneous electrical excitatory stimulation to the left and inhibitory stimulation to the right parietal regions (dual-tDCS) affected writing and reading rehabilitation, enhancing speech therapy outcomes. The results of a comparison with healthy controls showed that application of dual-tDCS could improve, in particular, sub-lexical transcoding and, specifically, the reading of non-words with increasing length and complexity. Positive repercussions on patient's quality of functional communication were also ascertained. Significant changes were also found in other language and cognitive tasks not directly treated (comprehension and constructive apraxia).

Placebo effects: From pain to motor performance.

The placebo effect can be elicited by two main mechanisms: via classical conditioning and cognitive expectations. These two mechanisms have been traditionally investigated in one single domain. The aim of the present study is to investigate how a placebo effect obtained in one modality (pain tolerance) can be transferred to another modality (motor endurance) and which mechanisms (i.e. reinforced expectation/conditioning or expectations alone) are more responsible for this placebo transferability. Participants were tested in a pain tolerance task and in a motor task in two different experiments: after a conditioning procedure on pain tolerance in which they were made to believe in the effectiveness of an analgesic treatment procedure (experiment 1) or without a previous conditioning procedure (experiment 2). In both experiments, objective (pain tolerance and number of finger flexions) and subjective (pain and fatigue perception) measures were recorded. In experiment 1 subjects experienced an increase of pain tolerance and a reduction of pain perception as well as an increased number of flexions and a reduction of reported fatigue. Conversely, in experiment 2 subjects experienced only a reduction of pain and fatigue perception with no significant increase of objective measures. Our results point out that it is possible to transfer the positive effects observed on pain to a motor task but only if verbally induced expectations are reinforced by previous experiences. This result could represent an important step to apply placebo procedures in pathological conditions such as chronic fatigue or Parkinson's disease.

Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation.

The primary aim of this study was to evaluate and compare the effectiveness of two specific Non-Invasive Brain Stimulation (NIBS) paradigms, the repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial Direct Current Stimulation (tDCS), in the upper limb rehabilitation of patients with stroke. Short and long term outcomes (after 3 and 6 months, respectively) were evaluated. We measured, at multiple time points, the manual dexterity using a validated clinical scale (ARAT), electroencephalography auditory event related potentials, and neuropsychological performances in patients with chronic stroke of middle severity. Thirty four patients were enrolled and randomized. The intervention group was treated with a NIBS protocol longer than usual, applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS). We compared the results with a control group treated with sham stimulation. We split the data analysis into three studies. In this first study we examined if a cumulative effect was clinically visible. In the second study we compared the effects of the two techniques. In the third study we explored if patients with minor cognitive impairment have most benefit from the treatment and if cognitive and motor outcomes were correlated. We found that the impairment in some cognitive domains cannot be considered an exclusion criterion for rehabilitation with NIBS. ERP improved, related to cognitive and attentional processes after stimulation on the motor cortex, but transitorily. This effect could be linked to the restoration of hemispheric balance or by the effects of distant connections. In our study the effects of the two NIBS were comparable, with some advantages using tDCS vs. rTMS in stroke rehabilitation. Finally we found that more than one cycle (2-4 weeks), spaced out by washout periods, should be used, only in responder patients, to obtain clinical relevant results.