Elisa Carlino

How placebos change the patient's brain.

Although placebos have long been considered a nuisance in clinical research, today they represent an active and productive field of research and, because of the involvement of many mechanisms, the study of the placebo effect can actually be viewed as a melting pot of concepts and ideas for neuroscience. Indeed, there exists not a single but many placebo effects, with different mechanisms and in different systems, medical conditions, and therapeutic interventions. For example, brain mechanisms of expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena, such as Pavlovian conditioning, cognitive, and social learning. There is also some experimental evidence of different genetic variants in placebo responsiveness. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinsons disease. In these medical conditions, the neural networks that are involved have been identified: that is, the opioidergic–cholecystokinergic–dopaminergic modulatory network in pain and part of the basal ganglia circuitry in Parkinsons disease. Important clinical implications emerge from these recent advances in placebo research. First, as the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and rituals of the therapeutic act, may change the chemistry and circuitry of the patients brain. Second, the mechanisms that are activated by placebos are the same as those activated by drugs, which suggests a cognitive/affective interference with drug action. Third, if prefrontal functioning is impaired, placebo responses are reduced or totally lacking, as occurs in dementia of the Alzheimers type.

The top‐down influence of ergogenic placebos on muscle work and fatigue

Placebos have been shown to induce powerful effects in a variety of medical conditions, such as pain and movement disorders, as well as to increase physical performance and endurance in healthy subjects. Here we investigated the effects of an ergogenic placebo on the performance of the quadriceps muscle, which is responsible for the extension of the leg relative to the thigh. In a first experiment, a placebo was administered along with the suggestion that it was caffeine at high dose. This resulted in a significant increase in mean muscle work across subjects, which, however, was not accompanied by a decrease of perceived muscle fatigue. In a second experiment, the placebo caffeine was administered twice in two different sessions. Each time, the weight to be lifted with the quadriceps was reduced surreptitiously so as to make the subjects believe that the ‘ergogenic agent’ was effective. After this conditioning procedure, the load was restored to the original weight, and both muscle work and perceived fatigue assessed after placebo administration. Compared with the first experiment, the placebo effect was larger, with a significant increase in muscle work and decrease in perceived muscle fatigue. Within the context of the role of peripheral and/or central mechanisms in muscle performance, the present findings suggest a central mechanism of top‐down modulation of muscle fatigue. In addition, the difference between the first and second experiment underscores the role of learning in increasing muscle performance with placebos.

Placebo mechanisms across different conditions: from the clinical setting to physical performance

Although the great increase in interest in the placebo phenomenon was spurred by the clinical implications of its use, the progressive elucidation of the neurobiological and pharmacological mechanisms underlying the placebo effect also helps cast new light on the relationship between mind (and brain) and body, a topic of foremost philosophical importance but also a major medical issue in light of the complex interactions between the brain on the one hand and body functions on the other. While the concept of placebo can be a general one, with a broad definition generally applicable to many different contexts, the description of the cerebral processes called into action in specific situations can vary widely. In this paper, examples will be given where physiological or pathological conditions are altered following the administration of an inert substance or verbal instructions tailored to induce expectation of a change, and explanations will be offered with details on neurotransmitter changes and neural pathways activated. As an instance of how placebo effects can extend beyond the clinical setting, data in the physical performance domain and implications for sport competitions will also be presented and discussed.

Hidden Administration of Drugs

In placebo‐controlled trials, the placebo component of treatments is usually assessed by simulating a therapy through the administration of a dummy treatment (placebo) in order to eliminate the specific effects of the therapy. Recently, a radically different approach to the analysis of placebo responses has been implemented in which placebo responses are assessed without placebo groups. To do this, the placebo (psychological) component is eliminated by conducting hidden (unexpected) administrations of the active treatment. Compelling experimental evidence now shows that when the psychological component is eliminated through the administration of therapies unbeknownst to the patient, the effects of a variety of treatments are significantly reduced. Overall, the experimental data show that the action of different pharmacological agents can be modulated by cognitive and affective factors that can increase or decrease the effects of drugs. This experimental approach is thus a window into the complex interactions between psychology and pharmacodynamics.

Pain perception and tolerance in patients with frontotemporal dementia

&NA; Pain management in elderly people with cognitive impairment poses special challenges, due to difficulties in pain assessment and specific neurodegenerative changes along pain pathways. Most studies have concentrated on Alzheimers disease (AD) patients, in whom some contrasting findings have been found. For example, while psychophysical data suggest a selective blunting of the affective dimension of pain, pain‐related fMRI signal increases have also been described. Few data have been reported in patients with frontotemporal dementia (FTD). By electrical stimulation, we have measured pain threshold and pain tolerance in clinically diagnosed FTD patients with SPECT cerebral hypoperfusion. We performed our analysis on two separate and overlapping subgroups selected on the basis of (1) neuropsychological scores below cut‐off values (2) a strictly localized frontal and/or temporal hypoperfusion. We observed increased pain threshold in the first group and increased pain threshold and pain tolerance in the second group. Our results suggest differences in pain processing changes in distinct types of dementia, while at the same time caution that pain perception assessment may depend on the criteria adopted for diagnosis.

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.

Increasing uncertainty in CNS clinical trials: the role of placebo, nocebo, and Hawthorne effects

As modern research continues to unravel the details of the placebo phenomenon in CNS disorders, uncertainty about therapeutic outcomes in trials of treatments for several neurological conditions is growing. Advances in understanding the mechanisms of different placebo effects have emphasised the substantial challenges inherent in interpreting the results of CNS clinical trials. In the past few years, new mechanisms and concepts have emerged in the study of placebo, nocebo, and Hawthorne effects in CNS clinical trials. For example, the mere step of recruitment in a trial or social interaction among trial participants can change the baseline conditions and therefore affect the interpretation of therapeutic outcomes. Moreover, different genotypes have been shown to respond differently to placebos-eg, in studies of social anxiety, depression, and pain. Increasing recognition of these factors in the general population raises the question of whether attempts should be made to reduce placebo responses in CNS clinical trials. Both clinical trial design and medical practice could benefit from further investigation of these effects across a range of neuropsychiatric disorders.

Placebo analgesia and beyond: a melting pot of concepts and ideas for neuroscience.

Purpose of review In the last two decades, some of the neuroanatomical and neurophysiological substrates of the placebo effect have been elucidated. What has emerged is the multifactorial nature of the placebo effect, such that there is not a single placebo effect but many. Here we report on recent advances in our understanding of this phenomenon, with particular emphasis on its use as an experimental model to better clarify different brain mechanisms. Recent findings One of the most interesting findings in the past few years is that the placebo effect is a learning phenomenon, which is powerfully influenced by the manipulation of different variables. The involvement of opioid mechanisms is supported by several studies on pain, but also by the exploration of new fields such as memory and cognition. Nonopioid mechanisms have been described as well, for example, in pain, Parkinsons disease and anxiety. Recent evidence confirms and extends previous findings on the key role of prefrontal regions in the placebo response. Summary The study of the placebo effect is paying dividends and bodes well for the future. Whereas in clinical practice it can increase the efficacy of a therapy, in the experimental setting it represents an excellent tool for neuroscience.

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.