Placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease and healthy participants.

ABSTRACT: The role of placebo analgesia and nocebo hyperalgesia in patients with Alzheimer disease (AD) is largely unknown, with only few studies in the area. Therefore, this study aims to investigate to which extent placebo analgesia and nocebo hyperalgesia effects are present in patients experiencing mild-to-moderate AD. Twenty-one patients with AD (test population) and 26 healthy participants (HP; design validation) were exposed to thermal pain stimulation on 3 test days: Lidocaine condition (open/hidden lidocaine administration), capsaicin condition (open/hidden capsaicin administration), and natural history (no treatment), in a randomized, within-subject design. Open lidocaine and open capsaicin were accompanied by verbal suggestions for pain relief and pain increase, respectively. Expected pain and actual pain intensity were measured on a numerical rating scale (0-10). Placebo and nocebo effects were calculated as pain differences in open-hidden lidocaine and capsaicin, respectively, controlled for no treatment. Healthy participants obtained a placebo effect ( P = 0.01) and a trend for a nocebo effect ( P = 0.07). Patients with AD did not obtain a placebo effect ( P = 0.44) nor a significant nocebo effect ( P = 0.86). Healthy participants expected lower and higher pain with open vs hidden lidocaine and capsaicin, respectively ( P < 0.001). The same expectation effects were seen in patients with AD (open vs hidden lidocaine, P = 0.008; open vs hidden capsaicin, P < 0.001). With a well-controlled experimental setting, this study suggests that patients with AD may not experience placebo analgesia effects. Nocebo hyperalgesia effects in patients with AD needs further research. These findings may have implications for the conduction of clinical trials and the treatment of patients with AD in clinical practice.

A unique neuropsychophysiological approach to objectify emotion (dys)regulation in healthy older adults during the COVID-19 pandemic.

The response of older people to the COVID-19 pandemic has attracted much attention as they are at increased risk of adverse outcomes. A longitudinal study has shown that improvement in global cognitive, executive and language functioning in healthy older adults enrolled at the University of the Third Age appears to play a protective role against emotional dysregulation and mood changes during the pandemic. To date, no study has examined emotional dysregulation through COVID-19-related images using facial electromyographic recordings in healthy older adults. Therefore, we aimed to analyze the relationships between zygomaticus and corrugator reactivity, neuropsychological measures, and the affective dimensions of arousal, dominance, and valence. The results showed an unexpected association between higher zygomaticus activity and higher levels of apathy, depression, and anxiety. In contrast, increased contracture of the corrugator was associated with poorer performance on cognitive tests (global cognition, memory, executive functions) and physical status, i.e., walking speed. These results are consistent with the reappraisal of emotional stimuli in response to the challenges of the pandemic. Interestingly, COVID-19-related stimuli triggered the activation of bottom-up affectivity strategies associated with higher mood levels and interacted with top-down factors that play an important role in the dysregulation of cognitive control.

Exploring Biomarkers of Mental Flexibility in Healthy Aging: A Computational Psychometric Study.

Mental flexibility (MF) has long been defined as cognitive flexibility. Specifically, it has been mainly studied within the executive functions domain. However, there has recently been increased attention towards its affective and physiological aspects. As a result, MF has been described as an ecological and cross-subject skill consisting of responding variably and flexibly to environmental cognitive-affective demands. Cross-sectional studies have mainly focused on samples composed of healthy individual and of patients with chronic conditions such as Mild Cognitive Impairment and Parkinson's, emphasizing their behavioral rigidity. Our study is the first to consider a sample of healthy older subjects and to outline physiological and psychological markers typical of mental flexibility, to identify functional biomarkers associated with successful aging. Our results reveal that biomarkers (respiratory and heart rate variability assessments) distinguished between individuals high vs. low in mental flexibility more reliably than traditional neuropsychological tests. This unveiled the multifaceted nature of mental flexibility composed of both cognitive and affective aspects, which emerged only if non-linear multi-variate analytic approaches, such as Supervised Machine Learning, were used.

The neuropsychology of healthy aging: the positive context of the University of the Third Age during the COVID-19 pandemic.

Older adults have been reported to have increased susceptibility to the adverse effects of SARS-CoV-2 infection, such as fatal outcomes, cognitive decline, and changes in physical and/or mental health. However, few studies have examined neuropsychological changes by comparing measurements before and during the pandemic in healthy older people. In addition, no longitudinal studies have examined whether older adults may have responded positively to the pandemic. We examined these issues through a 2-year neuropsychological study before and during the pandemic period. Results showed that scores before and during the pandemic were the same in memory and attention, whereas global cognitive, executive, and language functions improved. Participants also showed no longitudinal changes in depression, hypomania, and disinhibition, while apathy and, to a lesser extent, anxiety increased significantly. To examine possible signs of pandemic-related emotional (dys)regulation, subjects were shown images at follow-up that recalled the most dramatic lockdown phase while heart rate variability was recorded. Higher apathy was predicted by poorer global cognitive performance, increased anxiety, and emotional dysregulation as measured by a higher ratio of low-to-high frequency heart rate variability. Thus, preserved global cognition appears to play a protective role against the effects of pandemic-related anxiety and emotional dysregulation on apathy.

Electroencephalography-Based Brain-Machine Interfaces in Older Adults: A Literature Review.

The aging process is a multifaceted phenomenon that affects cognitive-affective and physical functioning as well as interactions with the environment. Although subjective cognitive decline may be part of normal aging, negative changes objectified as cognitive impairment are present in neurocognitive disorders and functional abilities are most impaired in patients with dementia. Electroencephalography-based brain-machine interfaces (BMI) are being used to assist older people in their daily activities and to improve their quality of life with neuro-rehabilitative applications. This paper provides an overview of BMI used to assist older adults. Both technical issues (detection of signals, extraction of features, classification) and application-related aspects with respect to the users' needs are considered.

Are Nocebo Effects in Adulthood Linked to Prenatal Maternal Cortisol Levels?

Objective: Placebo-induced adverse events, or nocebo effects, occur when doctor-patient communication anticipates the onset of negative symptoms. They have been found to correlate with the anxiety-related activity of the hypothalamic-pituitary-adrenal system. Here we try to determine if prenatal hyperactivity of this system, as assessed through plasma cortisol, may influence nocebo effects in adulthood. Method: We investigated the rate and magnitude of nocebo effects in 378 adults whose prenatal maternal plasma cortisol was measured during the first, second and third trimester of pregnancy. The healthy subjects underwent a nocebo oxygen challenge. This consisted of the inhalation of fake (placebo) oxygen and assessment of the following adverse events: headache, chest pain, abdominal pain, and cough. Plasma cortisol responses during the nocebo adverse events were also measured. Results: 41 out of 46 (89.1%) subjects who reported 3 adverse events, and 37 out of 37 (100%) subjects who reported 4 adverse events had prenatal maternal cortisol above normal levels. By contrast, only 10 out of 143 (7%) subjects who reported 0 adverse events showed prenatal maternal cortisol above the normal range. Moreover, whereas subjects who reported 3 and 4 adverse events showed a significant increase in plasma cortisol following the nocebo challenge, subjects who reported 0 adverse events showed no changes. Conclusions: These findings emphasize the importance of the doctor-patient communication in perceiving symptoms like pain, and suggest that those subjects with high prenatal maternal cortisol may be more sensitive to the effects of a negative communication in adulthood.

The nocebo phenomenon in the COVID-19 pandemic: a nocebodemic effect.

INTRODUCTION: The COVID-19 pandemic had remarkable effects on psychological distress. The main stressors were prolonged quarantine and social isolation, fear of infection and death, stigmatization, infodemic, financial difficulties, and job loss. These negative stressors, which affect mental and physical health, make people more vulnerable to nocebo-related risk behaviors. We aimed to summarize data on nocebo behaviors, such as the negative psychological consequences of the COVID-19 pandemic in terms of how people perceive and interpret medical services and treatments. AREAS COVERED: Limited data were found from randomized controlled trials with SARS-CoV-2 vaccines and from surveys on healthy people, healthcare workers, and patients with chronic pain disorders. EXPERT OPINION: Studies have shown nocebo effects among participants in SARS-CoV-2 vaccines trials, among patients with chronic pain, and among healthcare workers. These effects were widely amplified during the pandemic era, prefiguring a 'nocebodemic effect' to describe the massive negative interpretation of health services and medical treatments. Greater awareness of these findings could reduce the impact of the 'nocebodemic effect' and increase public trust in science.

Adverse events of active and placebo groups in SARS-CoV-2 vaccine randomized trials: A systematic review.

BACKGROUND: For safety assessment in clinical trials, adverse events (AEs) are reported for the drug under evaluation and compared with AEs in the placebo group. Little is known about the nature of the AEs associated with clinical trials of SARS-CoV-2 vaccines and the extent to which these can be traced to nocebo effects, where negative treatment-related expectations favor their occurrence. METHODS: In our systematic review, we compared the rates of solicited AEs in the active and placebo groups of SARS-CoV-2 vaccines approved by the Western pharmaceutical regulatory agencies.We implemented a search strategy to identify trial-III studies of SARS-CoV-2 vaccines through the PubMed database. We adopted the PRISMA Statement to perform the study selection and the data collection and identified three trial: two mRNA-based (38403 participants) and one adenovirus type (6736 participants). FINDINGS: Relative risks showed that the occurrence of AEs reported in the vaccine groups was higher compared with the placebo groups. The most frequently AEs in both groups were fatigue, headache, local pain, as injection site reactions, and myalgia. In particular, for first doses in placebo recipients, fatigue was reported in 29% and 27% in BNT162b2 and mRNA-1273 groups, respectively, and in 21% of Ad26.COV2.S participants. Headache was reported in 27% in both mRNA groups and in 24% of Ad26.COV2.S recipients. Myalgia was reported in 10% and 14% in mRNA groups (BNT162b2 and mRNA-1273, respectively) and in 13% of Ad26.COV2.S participants. Local pain was reported in 12% and 17% in mRNA groups (BNT162b2 and mRNA-1273, respectively), and in 17% of Ad26.COV2.S recipients. These AEs are more common in the younger population and in the first dose of placebo recipients of the mRNA vaccines. INTERPRETATION: Our results are in agreement with the expectancy theory of nocebo effects and suggest that the AEs associated with COVID-19 vaccines may be related to the nocebo effect. FUNDING: Fondazione CRT - Cassa di Risparmio di Torino, IT (grant number 66346, "GAIA-MENTE" 2019).

Are Sleep Problems Related to Psychological Distress in Healthy Aging during the COVID-19 Pandemic? A Review.

The SARS-CoV-2 pandemic, characterized by home confinement and other restrictive measures to reduce the spread of the infection, led to significant changes in people's habits and lifestyle. One of the most common problems is the worsening of sleep quality or quantity, which could have negative effects on psychological wellbeing, particularly in older adults. The purposes of the present literature review considering healthy aging subjects are (a) to examine the existing research on sleep alterations during the current pandemic and (b) to highlight possible relationships between sleep problems and psychological distress. A systematic search strategy was implemented according to PRISMA guidelines in the international literature online databases, up to 1 July 2021. After identification and screening phases, 11 articles were included in this review. The studies found possible associations between sleep problems and mood changes-particularly in terms of depression and anxiety. In addition, altered sleep patterns seemed to be related to changes in individual aspects, lifestyle, and attitudes adopted by older adults during the COVID-19 lockdown. Thus, the pandemic could affect the sleep and psychological wellbeing of the older population, even in healthy aging.

Nocebo-Prone Behavior Associated with SARS-CoV-2 Vaccine Hesitancy in Healthcare Workers.

Among healthcare workers (HCWs), SARS-CoV-2 vaccine hesitancy may be linked to a higher susceptibility to nocebo effects, i.e., adverse events (AEs) experienced after medical treatments due to negative expectations. To investigate this hypothesis a cross-sectional survey was performed with a self-completed questionnaire that included a tool (Q-No) for the identification of nocebo-prone individuals. A total of 1309 HCWs (67.2% women; 43.4% physicians; 28.4% nurses; 11.5% administrative staff; 16.6% other personnel) completed the questionnaires, among whom 237 (18.1%) had declined vaccination. Q-No scores were ≥15 in 325 participants (24.8%) suggesting nocebo-prone behavior. In a multivariate logistic regression model with Q-No score, age, gender, and occupation as independent variables, estimated odds ratios (ORs) of vaccination were 0.43 (i.e., less likely, p < 0.001) in participants with Q-No score ≥ 15 vs. Q-No score < 15, 0.58 in females vs. males (p = 0.013), and 4.7 (i.e., more likely) in physicians vs. other HCWs (p < 0.001), independent of age, which was not significantly associated with OR of vaccination. At least one adverse effect (AE) was reported by 67.5% of vaccinees, mostly local pain and flu-like symptoms. In a multivariate logistic regression model, with Q-No score, age, gender, and occupation as independent variables, estimated ORs of AE reporting were 2.0 in females vs. males (p < 0.001) and 1.47 in physicians vs. other HCWs (p = 0.017) independently of age and Q-No score, which were not significantly associated with OR of AE. These findings suggest that nocebo-prone behavior in HCWs is associated with SARS-CoV-2 vaccination hesitancy indicating a potential benefit of a campaign focused on nocebo-prone people.

Hypothalamic-Pituitary-Adrenal Activity in Adverse Events Reporting After Placebo Administration.

Participants of clinical trials who receive a placebo treatment often report a variety of adverse events, sometimes called nocebo effects. The reason why these adverse events occur is not clear, and understanding the underlying mechanisms represents a challenge that is likely to improve the interpretation of clinical trials as well as medical practice. Here, we studied 192 healthy subjects who received placebo oxygen through a mask after reading (READ) or not reading (NO-READ) a list of possible adverse events of oxygen breathing: headache, chest pain, abdominal pain, and cough. The whole hypothalamus-pituitary-adrenal axis was assessed just before and right after placebo breathing by measuring the hypothalamic corticotropin-releasing hormone (CRH), pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol (COR). In addition, both state and trait anxiety were assessed. We found that 64.5% of the NO-READ group reported no adverse events, 30.2% had one, and only 5.2% had two adverse events. In contrast, only 20.8% of the READ group reported no adverse events, whereas 1, 2, 3, and 4 adverse events were reported with a frequency of 21.8%, 19.8%, 19.8%, and 17.7%, respectively. In addition, when the READ group reported three and four adverse events, CRH, ACTH, and COR were significantly increased compared to the NO-READ group, along with an increase in state anxiety scores. These data indicate that hypothalamic-pituitary-adrenal activity and state anxiety are increased in those subjects who report many adverse events after reading a list of adverse events, thus highlighting a possible neuroendocrine mechanism after placebo administration.

The Role of Neuropsychological Factors in Perceived Threat of SARS-CoV-2 in Healthy Ageing.

The COVID-19 pandemic is known to increase older adults' vulnerability to adverse outcomes. Alongside increased physical frailty, anxiety symptoms associated with the risk of SARS-CoV-2 contagion appear to represent its most prominent 'sequelae'. The attentional and linguistic resources required for decoding virus-related information may also influence the perceived threat of contagion. However, the possible role of neuropsychogeriatric factors on the latter dimension has never been assessed in a longitudinal study on the older population. To fill this gap, 50 healthy cognitively preserved older adults underwent a neuropsychological and physical frailty assessment before the pandemic (T0). Subsequently, they agreed to be interviewed and re-assessed during the lockdown (T1) and immediately after it (T2) through a longitudinal one-year study. Perceived threat of SARS-CoV-2 at T2 was predicted both by baseline anxiety and frailty scores, and by decreased performance in information processing speed and language comprehension tests. While confirming the joint role of frailty and anxiety, a moderation/interaction model showed that each of them was sufficient, at its highest level, to support the maximum degree of perceived threat of contagion. The contribution of neuropsychological factors to perceived threat of SARS-CoV-2 highlights their importance of tailoring information campaigns addressed to older people.

Lockdown Effects on Healthy Cognitive Aging During the COVID-19 Pandemic: A Longitudinal Study.

The COVID-19 pandemic is a health issue leading older adults to an increased vulnerability to unfavorable outcomes. Indeed, the presence of physical frailty has recently led to higher mortality due to SARS-CoV-2 infection. However, no longitudinal studies have investigated the role of neuropsychogeriatric factors associated with lockdown fatigue in healthy cognitive aging. Eighty-one healthy older adults were evaluated for their neuropsychological characteristics, including physical frailty, before the pandemic (T0). Subsequently, 50 of them agreed to be interviewed and neuropsychologically re-assessed during the lockdown (T1) and immediately after it (T2). Moreover, during another home confinement, they performed a psychological screening (T3) to evaluate possible mood changes and fatigue. According to Fried's frailty criteria, at T0, 63% of the sample was robust, 34.5% pre-frail, and only 2.5% frail. Significantly, these subjects presented a decrease in handgrip strength and walking speed (29.6 and 6.1%, respectively). Results from Principal Component Analyses and multiple regression models highlighted the contribution of "cognitive" and "psychological" factors (i.e., attentive-executive performance and mood deflections) in explaining handgrip strength and gait speed. At T3, lockdown fatigue was explained by higher scores on the Beck Depression Inventory and lower scores on the Trail Making Test part A. Results from a moderated-mediation model showed that the effect of psychomotor speed on lockdown fatigue was mediated by depression, with a moderating effect of gait speed. Our findings highlight the complex interrelationship between cognitive, psychological, and physical factors in the emergence of pandemic fatigue in a carefully selected older population.

Investigating Neuroimaging Correlates of Early Frailty in Patients With Behavioral Variant Frontotemporal Dementia: A MRI and FDG-PET Study.

Frailty is a dynamic clinical condition characterized by the reduction of interconnections among different psychobiological domains, which leads to a homeostatic vulnerability. The association between physical frailty and cognitive dysfunctions is a possible predictor of poor prognosis in patients with neurodegenerative disorders. However, this construct has not been fully analyzed by a multidimensional neuropsychogeriatric assessment matched with multimodal neuroimaging methods in patients with behavioral variant frontotemporal dementia (bvFTD). We have investigated cognitive dysfunctions and frailty status, assessed by both a neuropsychological evaluation and the Multidimensional Prognostic Index (MPI), in a sample of 18 bvFTD patients and compared to matched healthy controls. Gray matter (GM) volume (as assessed by voxel-based morphometry) and metabolism (on 18fluorodeoxyglucose positron emission tomography) were first separately compared between groups, then voxelwise compared and correlated to each other within patients. Linear regression of the MPI was performed on those voxels presenting a significant correlation between altered GM volume and metabolism. The neuropsychological assessment reflected the diagnoses and the functional-anatomical alterations documented by neuroimaging analyses. In particular, the majority of patients presented significant executive dysfunction and mood changes in terms of apathy, depression, and anxiety. In the overall MPI score, the patients fell in the lower range (indicating an early frailty status). On imaging, they exhibited a bilateral decrease of GM density and hypometabolism involving the frontal pole, the anterior opercular region, and the anterior cingulate cortex. Greater atrophy than hypometabolism was observed in the bilateral orbitofrontal cortex, the triangular part of the inferior frontal gyrus, and the ventral striatum, whereas the contrary was detected in the bilateral dorsal anterior cingulate cortex and pre-supplementary motor area. MPI scores significantly correlated only with the co-occurrence of a decrease of GM density and hypometabolism in the right anterior insular cortex, but not with the separate pathological phenomena. Our results show a correlation between a specific pattern of co-occurring GM atrophy and hypometabolism with early frailty in bvFTD patients. These aspects, combined with executive dysfunction and mood changes, may lead to an increased risk of poor prognosis, highlighting a potentially critical and precocious role of the insula in the pathogenesis of frailty.

How do nocebo effects in placebo groups of randomized controlled trials provide a possible explicative framework for the COVID-19 pandemic?

Introduction: Randomized clinical trials (RCTs) are useful to study the role of individual and contextual factors in which therapies vs placebos are administered and to provide an important perspective for understanding the phenomenon of nocebo-related risks.Areas covered: The results of nocebo effects in RCT placebo groups, measured in terms of adverse events (AEs) and dropouts, will be presented as an explicative framework for the COVID-19 pandemic. Currently, SARS-CoV-2 vaccines are the only RCTs routinely conducted during the pandemic. Information about efficacy and safety of different vaccines represents a fertile ground for nocebo phenomena. Individual and contextual factors will be emphasized in order to understand the presence of a refusal of immunization associated with a specific vaccine considered less effective and safe. Critical aspects and some guidelines will be presented in order to counteract the nocebo effects and to improve adherence to drug treatments and the vaccination campaign.Expert opinion: The nocebo effect could explain the presence of strong resistance in European countries to immunization with a vaccine perceived as less effective, compared to others. Increased awareness of the nocebo effect would be relevant as it could lead to a greater participation in the vaccination campaign and in protecting individuals against SARS-CoV-2 infection.