International Journal of Environmental Research and Public Health, 2021
The SARS-CoV-2 pandemic, characterized by home confinement and other restrictive measures to redu... more 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...
Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under ... more Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications. Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach. Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7-69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9-8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017). Palermo et al. Placebo-Related Adverse Events in Schizophrenia Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects.
ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily ... more ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreove...
The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suf... more The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry. Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p=.04), monitoring resolution (p=.04) and control sensitivity (p=.04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task. We did not find any association with executive functions using the hypo-bradykinesia rating scale. Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.
Издательство «Фəн» Казань, Татарстан Главный редактор Член-корреспондент АН РТ Ф.Ш. Хузин Замести... more Издательство «Фəн» Казань, Татарстан Главный редактор Член-корреспондент АН РТ Ф.Ш. Хузин Заместители главного редактора: доктор исторических наук А.Г. Ситдиков доктор исторических наук Ю.А. Зеленеев Ответственный секретарь-кандидат ветеринарных наук Г.Ш. Асылгараева Редакционный совет: Р.С. Хакимоввице-президент АН РТ (Казань, Россия) (председатель) Х.А. Амирхановчлен-корреспондент РАН, доктор исторических наук, профессор (Махачкала, Россия) И. Бальдауфдоктор наук, профессор (Берлин, Германия) П. Георгиевдоктор наук, доцент (Шумен, Болгария) Е.П. Казаковдоктор исторических наук (Казань, Россия) Н.Н. Крадинчлен-корреспондент РАН, доктор исторических наук, профессор (Владивосток, Россия) А. Тюрк-PhD (Будапешт, Венгрия) И. Фодордоктор исторических наук, профессор (Будапешт, Венгрия) В.Л. Янинакадемик РАН, доктор исторических наук профессор (Москва, Россия) Редакционная коллегия: А.А. Выборнов-доктор исторических наук, профессор (Самара, Россия) М.Ш. Галимова-кандидат исторических наук (Казань, Россия) Р.Д. Голдина-доктор исторических наук, профессор (Ижевск, Россия) И.Л. Измайлов-кандидат исторических наук (Казань, Россия) С.В. Кузьминых-кандидат исторических наук (Москва, Россия) А.Е. Леонтьев-доктор исторических наук (Москва, Россия) Т.Б. Никитина-доктор исторических наук (Йошкар-Ола, Россия) Ответственный за выпуск: Б.Л. Хамидуллинкандидат исторических наук (Казань, Россия)
Awareness of deficits in patients with neurological disorders may be described as a theoretical u... more Awareness of deficits in patients with neurological disorders may be described as a theoretical unitary phenomenon, which has been analysed reaching interesting results in the last decades. Awareness of deficits manifests itself in a continuum ranging from full awareness to total absence. In line with a neurocognitive approach, a reduction in self-awareness could be explained considering executive dysfunction associated with prefrontal cortex anatomo-functional changes. Our mini-review will focus on reduced self-awareness in neurological disorders, such as Alzheimer's disease, behavioural Frontotemporal Dementia and Acquired Brain Injuries. Results achieved thanks to an explanatory investigative approach combined with a theoretical reference model will be presented. Data suggest the key role of executive functions in supporting adequate self-awareness towards patients' cognitive-behavioural profile and instrumental activity autonomy. The Cognitive Awareness Model seems to be one of the best theoretical model to better approach this phenomenon.
The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been... more The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been challenged. Alternative views now propose that the activity of the primary and secondary somatosensory cortices (SI, SII), the insula and cingulate cortex may be related to a basic defensive system through which significant potentially dangerous events for the body's integrity are detected. By reviewing the role of the SI, SII, the cingulate and the insular cortices in the perception of nociceptive and tactile stimuli, in attentional, emotional and reward tasks, and in interoception and memory, we found that all these task-related networks overlap in the dorsal anterior cingulate cortex, the anterior insula and the dorsal medial thalamus. A thorough analysis revealed that the 'pain-related' network shares important functional similarities with both somatomotor-somatosensory networks and emotional-interoceptive ones. We suggest that these shared areas constitute the central part of an adaptive control system involved in the processing and integration of salient information coming both from external and internal sources. These areas are activated in almost all fMRI tasks and have been indicated to play a pivotal role in switching between externally directed and internally directed brain networks.
Nocebo is the evil twin of placebo, in which expectation of a negative outcome may lead to the wo... more Nocebo is the evil twin of placebo, in which expectation of a negative outcome may lead to the worsening of a symptom. Although the study of nocebo is limited, owing to the ethical constraints of its stressful and anxiogenic procedure, some of the underlying psychological and neurobiological mechanisms have been unraveled over the past few years. Pain is the condition from which most of our knowledge comes, and a pain-facilitating mechanism has been identified from both a biochemical and an anatomical point of view.
It has been demonstrated that patients in the placebo arm of a clinical trial may experience adve... more It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments.
Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurol... more Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurological and neurodegenerative diseases. Many individuals with CI have substantial, sustained, and complex health care needs, which frequently include pain. However, individuals with CI can have difficulty communicating the features of their pain to others, which in turn presents a significant challenge for effective diagnosis and treatment of their pain. Herein, we review the literature on responsivity of individuals with CI to experimental pain stimuli. We discuss pain responding across a large number of neurological and neurodegenerative disorders in which CI is typically present. Overall, the existing data suggest that pain processing is altered in most individuals with CI compared with cognitively intact matched controls. The precise nature of these alterations varies with the type of CI (or associated clinical condition) and may also depend on the type of pain stimulation used and the type of pain responses assessed. Nevertheless, it is clear that regardless of the etiology of CI, patients do feel noxious stimuli, with more evidence for hypersensitivity than hyposensitivity to these stimuli compared with cognitively unimpaired individuals. Our current understanding of the neurobiological mechanisms underpinning these alterations is limited but may be enhanced through the use of animal models of CI, which also exhibit alterations in nociceptive responding. Further research using additional behavioural indices of pain is warranted. Increased understanding of altered experimental pain processing in CI will facilitate the development of improved diagnostic and therapeutic approaches for pain in individuals with CI.
The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suf... more The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to ass...
The placebo effect in randomized clinical trials appears to have increased thereby contributing t... more The placebo effect in randomized clinical trials appears to have increased thereby contributing to problems of demonstrating statistically reliable effects of treatments that directly target biological mechanisms. The shortcomings of randomized clinical trials are currently discussed along with potential improvements of trial designs. In this review we explain how utilizing knowledge from the placebo and nocebo mechanisms literature could improve the information that can be obtained from randomized clinical trials. We present three major challenges in randomized clinical trials: (i) increasing placebo effects, (ii) variability of the placebo effect, and (iii) risk of un-blinding. We then explain how recent placebo and nocebo studies of effects of verbal suggestion, expectancy, and emotions may improve understanding and discussion of increasing placebo effects, account/control for large parts of the variability of placebo effects, and suggest ways to improve blinding in future trials.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
We induced specific expectations of analgesia on four different parts of the body to understand h... more We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediat...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
We investigated the mechanisms underlying the activation of endogenous opioids in placebo analges... more We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive...
Although we are very happy to open a discussion with Brodsky and Mark [1] on the effectiveness of... more Although we are very happy to open a discussion with Brodsky and Mark [1] on the effectiveness of transcutaneous electrical nerve stimulation (TENS) in postoperative pain, we are sorry to realize that they did not read carefully our article on the use of TENS after ...
The concept of placebo response has evolved in the past few years from the clinical trial setting... more The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough.
International Journal of Environmental Research and Public Health, 2021
The SARS-CoV-2 pandemic, characterized by home confinement and other restrictive measures to redu... more 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...
Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under ... more Background: Antipsychotic clinical trials use to present adverse events (AEs) for the drug under evaluation to treat schizophrenia. Interestingly, patients who receive the placebo during antipsychotic trials often report several AEs, but little is known about the essence of these negative effects in patients with schizophrenia spectrum disorders (SCD). In the present meta-analysis, we evaluated the relationship between the level of psychiatric symptomatology expressed as Positive and Negative Syndrome Scale (PANSS) scores and the rates of AEs reported in the placebo arms of double-blind clinical trials, for commonly prescribed atypical antipsychotic medications. Methods: We selected 58 clinical trials describing AEs in SCD placebo groups, which compared atypical antipsychotic medications with placebo. A total of 6,301 placebo-treated patients were considered. AE profiles of the class were clusterized using MedDRA classification and analysed using a meta-regression approach. Results: In the placebo arms the proportions of patients with any AE was 66.3% (95% CI: 62.7-69.8%). The proportion of withdrawal of patients treated with placebo because of AEs was 7.2% (95% CI: 5.9-8.4%). Interestingly, the AEs in the placebo arms corresponded to those of the antipsychotic-atypical-medication-class against which the placebo was compared. Namely, using meta-regression analysis we found an association between the level of psychiatric symptomatology measured with PANSS scores and higher AEs reported as nervous system (p = 0.020) and gastrintestinal disorders (p = 0.004). Moreover, the level of a higher psychiatric symptomatology expressed with PANSS scores was also related with higher AEs associated with psychiatric symptoms (p = 0.017). Palermo et al. Placebo-Related Adverse Events in Schizophrenia Conclusion: These findings emphasise that the AEs in placebo arms of clinical trials of antipsychotic medications were substantial. Importantly, a higher level of psychiatric symptomatology makes SCD patients more prone to express AEs, thus contributing to possible drop-outs and to a lower adherence to treatments. These results are consistent with the expectation theory of placebo and nocebo effects.
ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily ... more ABSTRACTSince baseline executive dysfunction predicts worsening Instrumental Activities of Daily Living (i-ADL) over time and progression to Alzheimer's Disease (AD), we aimed to analyze the role of neuropsychological variables to outline which factors can contribute to functional impairment. Specific attention to executive functions (EFs) has been given.A total of 144 subjects complaining of different cognitive deficits - ranging from "MCI likely due to AD" to "mild AD patients" - underwent an overall neuropsychological assessment. The Behavioral Assessment of the Dysexecutive Syndrome was used to analyze EFs. We conducted multiple linear regression analyses to study whether the level of independent living skills - assessed with the Lawton-scale - could be associated with cognitive and behavioral measurements.We found a significant association between i-ADL and specific EFs measured by Rule Shift Cards (p = 0.04) and Modified Six Elements (p = 0.02). Moreove...
The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suf... more The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to assess the executive functions of the prefrontal-ventral-striatal circuitry. Data showed that a reduction of self-awareness using the Dyskinesia rating scale was associated with global monitoring (p=.04), monitoring resolution (p=.04) and control sensitivity (p=.04). Patients failed to perceive their performance, distinguish between correct and incorrect sorts, be confident in their choice and consequently decide to gamble during the task. We did not find any association with executive functions using the hypo-bradykinesia rating scale. Our findings indicate that when the comparator mechanism for monitoring attentive performance is compromised at a prefrontal striatal level, patients lose the ability to recognize their motor disturbances that do not achieve conscious awareness.
Издательство «Фəн» Казань, Татарстан Главный редактор Член-корреспондент АН РТ Ф.Ш. Хузин Замести... more Издательство «Фəн» Казань, Татарстан Главный редактор Член-корреспондент АН РТ Ф.Ш. Хузин Заместители главного редактора: доктор исторических наук А.Г. Ситдиков доктор исторических наук Ю.А. Зеленеев Ответственный секретарь-кандидат ветеринарных наук Г.Ш. Асылгараева Редакционный совет: Р.С. Хакимоввице-президент АН РТ (Казань, Россия) (председатель) Х.А. Амирхановчлен-корреспондент РАН, доктор исторических наук, профессор (Махачкала, Россия) И. Бальдауфдоктор наук, профессор (Берлин, Германия) П. Георгиевдоктор наук, доцент (Шумен, Болгария) Е.П. Казаковдоктор исторических наук (Казань, Россия) Н.Н. Крадинчлен-корреспондент РАН, доктор исторических наук, профессор (Владивосток, Россия) А. Тюрк-PhD (Будапешт, Венгрия) И. Фодордоктор исторических наук, профессор (Будапешт, Венгрия) В.Л. Янинакадемик РАН, доктор исторических наук профессор (Москва, Россия) Редакционная коллегия: А.А. Выборнов-доктор исторических наук, профессор (Самара, Россия) М.Ш. Галимова-кандидат исторических наук (Казань, Россия) Р.Д. Голдина-доктор исторических наук, профессор (Ижевск, Россия) И.Л. Измайлов-кандидат исторических наук (Казань, Россия) С.В. Кузьминых-кандидат исторических наук (Москва, Россия) А.Е. Леонтьев-доктор исторических наук (Москва, Россия) Т.Б. Никитина-доктор исторических наук (Йошкар-Ола, Россия) Ответственный за выпуск: Б.Л. Хамидуллинкандидат исторических наук (Казань, Россия)
Awareness of deficits in patients with neurological disorders may be described as a theoretical u... more Awareness of deficits in patients with neurological disorders may be described as a theoretical unitary phenomenon, which has been analysed reaching interesting results in the last decades. Awareness of deficits manifests itself in a continuum ranging from full awareness to total absence. In line with a neurocognitive approach, a reduction in self-awareness could be explained considering executive dysfunction associated with prefrontal cortex anatomo-functional changes. Our mini-review will focus on reduced self-awareness in neurological disorders, such as Alzheimer's disease, behavioural Frontotemporal Dementia and Acquired Brain Injuries. Results achieved thanks to an explanatory investigative approach combined with a theoretical reference model will be presented. Data suggest the key role of executive functions in supporting adequate self-awareness towards patients' cognitive-behavioural profile and instrumental activity autonomy. The Cognitive Awareness Model seems to be one of the best theoretical model to better approach this phenomenon.
The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been... more The idea of a 'pain matrix' specifically devoted to the processing of nociceptive inputs has been challenged. Alternative views now propose that the activity of the primary and secondary somatosensory cortices (SI, SII), the insula and cingulate cortex may be related to a basic defensive system through which significant potentially dangerous events for the body's integrity are detected. By reviewing the role of the SI, SII, the cingulate and the insular cortices in the perception of nociceptive and tactile stimuli, in attentional, emotional and reward tasks, and in interoception and memory, we found that all these task-related networks overlap in the dorsal anterior cingulate cortex, the anterior insula and the dorsal medial thalamus. A thorough analysis revealed that the 'pain-related' network shares important functional similarities with both somatomotor-somatosensory networks and emotional-interoceptive ones. We suggest that these shared areas constitute the central part of an adaptive control system involved in the processing and integration of salient information coming both from external and internal sources. These areas are activated in almost all fMRI tasks and have been indicated to play a pivotal role in switching between externally directed and internally directed brain networks.
Nocebo is the evil twin of placebo, in which expectation of a negative outcome may lead to the wo... more Nocebo is the evil twin of placebo, in which expectation of a negative outcome may lead to the worsening of a symptom. Although the study of nocebo is limited, owing to the ethical constraints of its stressful and anxiogenic procedure, some of the underlying psychological and neurobiological mechanisms have been unraveled over the past few years. Pain is the condition from which most of our knowledge comes, and a pain-facilitating mechanism has been identified from both a biochemical and an anatomical point of view.
It has been demonstrated that patients in the placebo arm of a clinical trial may experience adve... more It has been demonstrated that patients in the placebo arm of a clinical trial may experience adverse events (AEs), which may lead to nonadherence and dropout. However, so far, it is unknown to which extent this phenomenon is observed consistently across different diseases such as pain and neurodegenerative disorders.The current review shows for the first time that different diseases share a common risk for patients in terms of a negative outcome: a large percentage of placebo-treated patients experience AEs in pain conditions (up to 59%) and neurodegenerative disorders (up to 66%). In addition, the rate of patients who discontinue because of AEs is up to 10% and 11% in pain conditions and neurodegenerative disorders, respectively.We highlight methodological shortcomings with the aim of suggesting how the detection and reporting of AEs can be improved in future trials. The insights from the current review should be taken into consideration when designing clinical trials to tailor individualized treatments.
Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurol... more Cognitive impairment (CI) can develop during the course of ageing and is a feature of many neurological and neurodegenerative diseases. Many individuals with CI have substantial, sustained, and complex health care needs, which frequently include pain. However, individuals with CI can have difficulty communicating the features of their pain to others, which in turn presents a significant challenge for effective diagnosis and treatment of their pain. Herein, we review the literature on responsivity of individuals with CI to experimental pain stimuli. We discuss pain responding across a large number of neurological and neurodegenerative disorders in which CI is typically present. Overall, the existing data suggest that pain processing is altered in most individuals with CI compared with cognitively intact matched controls. The precise nature of these alterations varies with the type of CI (or associated clinical condition) and may also depend on the type of pain stimulation used and the type of pain responses assessed. Nevertheless, it is clear that regardless of the etiology of CI, patients do feel noxious stimuli, with more evidence for hypersensitivity than hyposensitivity to these stimuli compared with cognitively unimpaired individuals. Our current understanding of the neurobiological mechanisms underpinning these alterations is limited but may be enhanced through the use of animal models of CI, which also exhibit alterations in nociceptive responding. Further research using additional behavioural indices of pain is warranted. Increased understanding of altered experimental pain processing in CI will facilitate the development of improved diagnostic and therapeutic approaches for pain in individuals with CI.
The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suf... more The study analyzes the presence of dyskinesias-reduced-self-awareness in forty-eight patients suffering from Parkinson's disease (PD). As the association with executive dysfunction is a matter of debate and we hypothesize it plays an important role in dyskinesias self-unawareness, we analyzed the role of dopaminergic treatment on the medial-prefrontal-ventral-striatal circuitry using a neurocognitive approach. Special attention was given to metacognitive abilities related to action-monitoring that represent a novel explanation of the phenomenon. PD patients were assessed using different rating scales that we devised to measure movement awareness disorders. In order to ascertain whether each variable measured at a cognitive-clinical level contributes to predicting the scores of the movement-disorder-awareness-scales, we conducted multiple logistic regression models using the latter as binary dependent variables. We used the Wisconsin Card Sorting Test-metacognitive-version to ass...
The placebo effect in randomized clinical trials appears to have increased thereby contributing t... more The placebo effect in randomized clinical trials appears to have increased thereby contributing to problems of demonstrating statistically reliable effects of treatments that directly target biological mechanisms. The shortcomings of randomized clinical trials are currently discussed along with potential improvements of trial designs. In this review we explain how utilizing knowledge from the placebo and nocebo mechanisms literature could improve the information that can be obtained from randomized clinical trials. We present three major challenges in randomized clinical trials: (i) increasing placebo effects, (ii) variability of the placebo effect, and (iii) risk of un-blinding. We then explain how recent placebo and nocebo studies of effects of verbal suggestion, expectancy, and emotions may improve understanding and discussion of increasing placebo effects, account/control for large parts of the variability of placebo effects, and suggest ways to improve blinding in future trials.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
We induced specific expectations of analgesia on four different parts of the body to understand h... more We induced specific expectations of analgesia on four different parts of the body to understand how endogenous opioid systems are activated by expectancies. The left hand, right hand, left foot, and right foot were simultaneously stimulated by means of a subcutaneous injection of capsaicin, which produces a painful burning sensation. Specific expectations of analgesia were induced by applying a placebo cream on one of these body parts and by telling the subjects that it was a powerful local anesthetic. In such a way, expectancy of the anesthetic effect was directed only toward the part on which the placebo cream was applied. We found that a placebo analgesic response occurred only on the treated part, whereas no variation in pain sensitivity was found on the untreated parts. If the same experiment was performed after an intravenous infusion of the opioid antagonist naloxone, this highly spatial-specific placebo response was totally abolished, indicating that it was completely mediat...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1999
We investigated the mechanisms underlying the activation of endogenous opioids in placebo analges... more We investigated the mechanisms underlying the activation of endogenous opioids in placebo analgesia by using the model of human experimental ischemic arm pain. Different types of placebo analgesic responses were evoked by means of cognitive expectation cues, drug conditioning, or a combination of both. Drug conditioning was performed by means of either the opioid agonist morphine hydrochloride or the nonopioid ketorolac tromethamine. Expectation cues produced placebo responses that were completely blocked by the opioid antagonist naloxone. Expectation cues together with morphine conditioning produced placebo responses that were completely antagonized by naloxone. Morphine conditioning alone (without expectation cues) induced a naloxone-reversible placebo effect. By contrast, ketorolac conditioning together with expectation cues elicited a placebo effect that was blocked by naloxone only partially. Ketorolac conditioning alone produced placebo responses that were naloxone-insensitive...
Although we are very happy to open a discussion with Brodsky and Mark [1] on the effectiveness of... more Although we are very happy to open a discussion with Brodsky and Mark [1] on the effectiveness of transcutaneous electrical nerve stimulation (TENS) in postoperative pain, we are sorry to realize that they did not read carefully our article on the use of TENS after ...
The concept of placebo response has evolved in the past few years from the clinical trial setting... more The concept of placebo response has evolved in the past few years from the clinical trial setting and medical practice to a psychobiological model that gives us important information on how the patient's brain is modified by the psychosocial context around the therapy. In this review, some examples will be given where physiological or pathological conditions are altered following the administration of an inert substance along with verbal instructions tailored to induce expectation of a change, and explanations will be presented with details on neurotransmitter changes and neural pathways activated. Although nothing is known about the biological underpinnings of the placebo response in the respiratory system, this review may help extending the neurobiological investigation of placebos from conditions such as pain and Parkinson's disease to respiratory disorders and symptoms such as cough.
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Papers by M. Amanzio