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.

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.

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 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-induced decrease in fatigue: evidence for a central action on the preparatory phase of movement.

Placebos have been found to affect a number of pathological processes and physiological functions through expectations of clinical improvement. Recently, the study of the placebo effect has moved from the clinical to the physical performance setting, wherein placebos can boost performance by increasing muscle work and by decreasing perceived exertion. However, nothing is known about the neurobiological underpinnings of this phenomenon. Here we show for the first time that a placebo, which subjects believed to be endurance-increasing caffeine, reduces fatigue by acting at the central level on the preparatory phase of movement. In fact, we recorded the readiness potential, which is the expression of the preparatory phase of movement at the level of the supplementary motor area, during repeated flexions of the index finger in a control group that did not receive any treatment and in a placebo group that received placebo caffeine. In the control group, as the number of flexions increased, both fatigue and readiness potential amplitude increased. By contrast, in the placebo group, as the number of flexions increased we found a decrease in perceived exertion along with no increase in readiness potential amplitude. This placebo-induced modulation of the readiness potential suggests that placebos reduce fatigue by acting centrally during the anticipatory phase of movement, thus emphasizing the important role of the central nervous system in the generation of fatigue.

Placebo and nocebo effects: a complex interplay between psychological factors and neurochemical networks.

Placebo and nocebo effects have recently emerged as an interesting model to understand some of the intricate underpinnings of the mind-body interaction. A variety of psychological mechanisms, such as expectation, conditioning, anxiety modulation, and reward, have been identified, and a number of neurochemical networks have been characterized across different conditions, such as pain and motor disorders. What has emerged from the recent insights into the neurobiology of placebo and nocebo effects is that the psychosocial context around the patient and the therapy, which represents the ritual of the therapeutic act, may change the biochemistry and the neuronal circuitry of the patient's brain. Furthermore, the mechanisms activated by placebos and nocebos have been found to be the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Overall, these findings highlight the important role of therapeutic rituals in the overall therapeutic outcome, including hypnosis, which may have profound implications both in routine medical practice and in the clinical trials setting.

Drawing lines while imagining circles: Neural basis of the bimanual coupling effect during motor execution and motor imagery.

When people simultaneously draw lines with one hand and circles with the other hand, both trajectories tend to assume an oval shape, showing that hand motor programs interact (the so-called "bimanual coupling effect"). The aim of the present study was to investigate how motor parameters (drawing trajectories) and the related brain activity vary during bimanual movements both in real execution and in motor imagery tasks. In the 'Real' modality, subjects performed right hand movements (lines) and, simultaneously, Congruent (lines) or Non-congruent (circles) left hand movements. In the 'Imagery' modality, subjects performed only right hand movements (lines) and, simultaneously, imagined Congruent (lines) or Non-congruent (circles) left hand movements. Behavioral results showed a similar interference of both the real and the imagined circles on the actually executed lines, suggesting that the coupling effect also pertains to motor imagery. Neuroimaging results showed that a prefrontal-parietal network, mostly involving the pre-Supplementary Motor Area (pre-SMA) and the posterior parietal cortex (PPC), was significantly more active in Non-congruent than in Congruent conditions, irrespective of task (Real or Imagery). The data also confirmed specific roles of the right superior parietal lobe (SPL) in mediating spatial interference, and of the left PPC in motor imagery. Collectively, these findings suggest that real and imagined Non-congruent movements activate common circuits related to the intentional and predictive operation generating bimanual coupling, in which the pre-SMA and the PPC play a crucial role.

The effects of placebos and nocebos on physical performance.

In this chapter we present and discuss recent studies on the mechanisms underlying placebo and nocebo effects in physical performance, showing how expectations and both pharmacological and nonpharmacological preconditioning procedures can be very effective in inducing placebo responses, with important implications for sport competitions. Furthermore, we place these findings within the biological model of central governor of fatigue, whose main goal is to protect our body from damage. A crucial aspect of this emerging field of placebo studies is related to the limit beyond which these procedures can be called doping in all respects.

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.

Dissociations and similarities in motor intention and motor awareness: the case of anosognosia for hemiplegia and motor neglect.

OBJECTIVES: To confront motor awareness in anosognosia for hemiplegia (AHP), where paralyzed patients deny their motor impairment, and in motor neglect (MN), where non-paralyzed patients behave as if they were paretic. METHODS: Eight right-brain-damaged-patients, 4 hemiplegic (2 with and 2 without AHP) and 4 non-hemiplegic (2 with only perceptual-neglect and 2 with also MN) were evaluated with a bimanual motor battery, before and after examiner's reinforcement to use the contralesional limb. The requested bimanual movements could be either symmetric or asymmetric, either intransitive or transitive (with/without objects). We compared the examiner's evaluation of patients' performance with the patients' self-evaluation of their own motor capability (explicit knowledge). We also evaluated the presence/absence of compensatory unimanual strategies that, if present, suggests implicit knowledge of the motor deficit. RESULTS: We found significant differences between conditions only in MN patients, whose performance was better after the examiner's reinforcement than before it, during symmetric than asymmetric movements and during intransitive than transitive movements. As for motor awareness, we found a lack of explicit and implicit knowledge in both AHP and MN patients. CONCLUSION: Although different in terms of motor intention and motor planning, AHP and MN are both characterised by anosognosia for the motor impairment.

'Moving' a paralysed hand: bimanual coupling effect in patients with anosognosia for hemiplegia.

Selective neurological impairments can shed light on different aspects of motor cognition. Brain-damaged patients with anosognosia for hemiplegia deny their motor deficit and believe they can still move the paralysed limb. Here we study, for the first time, if the anomalous subjective experience that their affected hand can still move, may have objective consequences that constrain movement execution with the opposite, intact hand. Using a bimanual motor task, in which anosognosic patients were asked to simultaneously trace out lines with their unaffected hand and circles with their paralysed hand, we found that the trajectories of the intact hand were influenced by the requested movement of the paralysed hand, with the intact hand tending to assume an oval trajectory (bimanual coupling effect). This effect was comparable to that of a group of healthy subjects who actually moved both hands. By contrast, brain-damaged patients with motor neglect or actual hemiplegia but no anosognosia did not show this bimanual constraint. We suggest that anosognosic patients may have intact motor intentionality and planning for the plegic hand. Rather than being merely an inexplicable confabulation, anosognosia for the plegic hand can produce objective constraints on what the intact hand does.

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.

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 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.

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.