Elisa Frisaldi

Pain and the context

Pain is a sensory and emotional experience that is substantially modulated by psychological, social and contextual factors. Research now indicates that the influence of these factors is even more powerful than expected and involves the therapeutic response to analgesic drugs as well as the pain experience itself, which in some circumstances can even be a form of reward. Different experimental approaches and models, both in the laboratory and in the clinical setting, have been used to better characterize and understand the complex neurobiology of pain modulation. These approaches include placebo analgesia, nocebo hyperalgesia, hidden administration of analgesics, and the manipulation of the pain–reward relationship. Overall, these studies show that different neurochemical systems are activated in different positive and negative contexts. Moreover, pain can activate reward mechanisms when experienced within contexts that have special positive meaning. Because routine medical practice usually takes place in contexts that use different rituals, these neurobiological insights might have profound clinical implications.

Teaching neurons to respond to placebos

We analysed the placebo response at the single‐neuron level in the thalamus of Parkinson patients to see the differences between first‐time administration of placebo and administration after pharmacological pre‐conditioning. When the placebo was given for the first time, it induced neither clinical improvement, as assessed through muscle rigidity reduction at the wrist, nor neuronal changes in thalamic neurons. However, if placebo was given after two, three or four prior administrations of an anti‐Parkinson drug, apomorphine, it produced both clinical and neuronal responses. Both the magnitude and the duration of these placebo responses depended on the number of prior exposures to apomorphine, according to the rule: the greater the number of previous apomorphine administrations, the larger the magnitude and the longer the duration of the clinical and neuronal placebo responses. These findings show that learning plays a crucial role in the placebo response and suggest that placebo non‐responders can be turned into placebo responders, with important clinical implications.

Characterization of the thalamic-subthalamic circuit involved in the placebo response through single-neuron recording in Parkinson patients.

The placebo effect, or response, is a complex phenomenon whereby an inert treatment can induce a therapeutic benefit if the subject is made to believe that it is effective. One of the main mechanisms involved is represented by expectations of clinical improvement which, in turn, have been found to either reduce anxiety or activate reward mechanisms. Therefore, the study of the placebo effect allows us to understand how emotions may affect both behavior and therapeutic outcome. The high rate of placebo responders in clinical trials of Parkinsons disease provided the motivation to investigate the biological underpinnings of the placebo response in Parkinsonian patients. The placebo effect in Parkinsons disease is induced through the administration of an inert substance which the patient believes to improve motor performance. By using this approach, different behavioral and neuroimaging studies have documented objective improvements in motor performance and an increase of endogenous dopamine release in both the dorsal and ventral striatum. Recently, single-neuron recording from the subthalamic and thalamic regions during the implantation of electrodes for deep brain stimulation has been used to investigate the firing pattern of different neurons before and after placebo administration. The results show that the subthalamic nucleus, the substantia nigra pars reticulata, and the ventral anterior thalamus are all involved in the placebo response in Parkinson patients, thus making intraoperative recording an excellent model to characterize the neuronal circuit that is involved in the placebo response in Parkinsons disease as well as in other disorders of movement.

Role of explicit verbal information in conditioned analgesia.

The exact role of expectation in conditioned analgesia is still elusive as it is not clear whether conditioning is an automatic process or rather it is cognitively mediated. This study is aimed at understanding the role of explicit verbal information in conditioned analgesia.

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.

The placebo effect on bradykinesia in Parkinson's disease with and without prior drug conditioning

Background: Placebo effects represent a major drawback in clinical trials, and their magnitude hampers the development of new treatments. Previous research showed that prior exposure to active treatments increases the placebo response for muscle rigidity in Parkinsons disease.

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.

Why We should Assess Patients’ Expectations in Clinical Trials

Most of the analgesic clinical trials have failed to succeed over the past years because of the occurrence of large placebo responses. Patients’ expectations about the therapeutic benefit represent a major determinant of the placebo response. Therefore, assessing patients’ expectations should become the rule in any clinical trial. This would allow us to better interpret therapeutic outcomes when comparing placebo and verum groups.

Placebo response in pain, fatigue, and performance: possible implications for neuromuscular disorders

The placebo response in neuromuscular disorders is not well understood. The only available data regarding its underlying mechanisms are related to neuropathic pain. In this review, we describe the factors that contribute to improved outcomes in the placebo arm, with specific attention to pain and fatigue, as well as some of the most important psychobiological mechanisms that may explain such a response. This approach may also improve our insight into the symptomatology and therapeutic responses of other neuromuscular disorders. The fact that >90% of tested analgesics for neuropathic pain have failed in advanced phases of clinical trials should prompt a greater investment of effort and resources into understanding the mechanisms and impact of placebos in clinical research. Such an endeavor will help improve the design of clinical trials and will provide information that informs clinical neuromuscular practice. Muscle Nerve 56: 358–367, 2017

Nonlinear analysis of electroencephalogram in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) is a form of dementia characterized by a profound alteration in personality and social behavior and is associated with atrophy in the frontal and temporal brain regions. Despite recent advances, diagnosis of FTLD remains challenging. In the last decade, different studies have combined EEG analysis with mathematical models and theories that consider EEG signals as the result of nonlinear chaotic activity. The aim of the present study was to determine whether new nonlinear dynamic analysis can provide useful information on brain activity in FTLD patients. 19-lead EEG was recorded in patients with clinical diagnosis of FTLD and in healthy controls under two different conditions: closed eyes and open eyes. A nonlinear measure of complexity, correlation dimension (D2), was calculated. Our results show an increase in D2 in healthy individuals when the eyes are open, in keeping with an increase in information processing. Conversely, in FTLD patients, no increase in D2 occurred in the open eyes condition, and D2 was significantly lower than that observed in controls. Our results suggest that the dynamic processes underlying the EEG are less chaotic and complex in FTLD patients compared with normal individuals, thus providing important information on both brain functioning and possible clinical diagnostic applications.