Measuring expectation of pain: Contingent negative variation in placebo and nocebo effects.

BACKGROUND: Expectation is an important mechanism underlying placebo response. Here, we analysed expectation of placebo hypoalgesia and nocebo hyperalgesia by using, for the first time, the contingent negative variation (CNV), also known as expectancy wave. METHODS: Subjects were presented a green or red cue followed by a train of either non painful or painful electrical stimuli, and expected hypoalgesia after the green and hyperalgesia after the red cue. In experiment 1, expectation was reinforced using a conditioning procedure whereby the green and red cues were paired with non painful and painful stimuli, respectively (acquisition). In a second session (test) the intensity of the stimuli was kept constant, regardless of cue. In experiment 2 no conditioning was performed and participants expected an altered pain perception indicated by the visual cues. CNV mean amplitude, time necessary to stop the train of stimuli (reaction time) and pain ratings were measured. RESULTS: A difference in pain perception occurred when electrical stimuli followed the presentation of the green cue compared to the red in the test session, whereas reaction times showed no changes. The same difference occurred in the early CNV component, related to cognitive stimulus anticipation, whereas the late CNV component, related to motor preparation, did not change. Moreover, these differences in pain perception and CNV amplitude were less robust in the experiment 2. CONCLUSION: Placebo hypoalgesia and nocebo hyperalgesia differently affect sensory (pain perception) and motor components (pain avoidance) of pain. Furthermore, CNV is an electrophysiological objective measure capable of dissecting these components. SIGNIFICANCE: Dissection of placebo hypoalgesia, differentiating the sensory component (pain perception) from the motor component (pain avoidance). Study of these components using the contingent negative variation (CNV) as an electrophysiological objective measure.

Nature of the placebo and nocebo effect in relation to functional neurologic disorders.

Placebos have long been considered a nuisance in clinical research, for they have always been used as comparators for the validation of new treatments. By contrast, today they represent an active field of research, and, due to 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. There is not a single placebo effect, but many, with different mechanisms across different medical conditions and therapeutic interventions. Expectation, anxiety, and reward are all involved, as well as a variety of learning phenomena and genetic variants. The most productive models to better understand the neurobiology of the placebo effect are pain and Parkinson's disease. In these medical conditions, several neurotransmitters have been identified, such as endogenous opioids, cholecystokinin, dopamine, as well as lipidic mediators, for example, endocannabinoids and prostaglandins. Since the placebo effect is basically a psychosocial context effect, these data indicate that different social stimuli, such as words and therapeutic rituals, may change the chemistry of the patient's brain, and these effects are similar to those induced by drugs.

Bimanual non-congruent actions in motor neglect syndrome: a combined behavioral/fMRI study.

In Motor Neglect (MN) syndrome, a specific impairment in non-congruent bimanual movements has been described. In the present case-control study, we investigated the neuro-functional correlates of this behavioral deficit. Two right-brain-damaged (RBD) patients, one with (MN+) and one without (MN-) MN, were evaluated by means of functional Magnetic Resonance Imaging (fMRI) in a bimanual Circles-Lines (CL) paradigm. Patients were requested to perform right-hand movements (lines-drawing) and, simultaneously, congruent (lines-drawing) or non-congruent (circles-drawing) left-hand movements. In the behavioral task, MN- patient showed a bimanual-coupling-effect, while MN+ patient did not. The fMRI study showed that in MN-, a fronto-parietal network, mainly 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, as previously shown in healthy subjects. On the contrary, MN+ patient showed an opposite pattern of activation both in pre-SMA and in PPC. Within this fronto-parietal network, the pre-SMA is supposed to exert an inhibitory influence on the default coupling of homologous muscles, thus allowing the execution of non-congruent movements. In MN syndrome, the described abnormal pre-SMA activity supports the hypothesis that a failure to inhibit ipsilesional motor programs might determine a specific impairment of non-congruent movements.

Role of explicit verbal information in conditioned analgesia.

BACKGROUND: 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. METHODS: Two groups of healthy subjects received a conditioning procedure whereby two visual cues were paired with increase and decrease in stimulus intensity. In the 'conditioning/verbal information' group (VER), subjects were informed about the meaning of the cues, whereas no information was given to the second group (noVER). After two conditioning blocks, an evocation session was run in which the stimulus intensity was the same, irrespective of the cues. Pain perception was assessed according to a numerical rating scale from 0 (no pain) to 10 (maximal pain). The N2-P2 component of laser-evoked potentials (LEP) was used as an index of index of brain responses to nociceptive stimuli. RESULTS: In the evocation session, only the VER group reported a decrease in pain rating and LEP amplitude when the cues were presented, suggesting that the visual-analgesic association does not occur without explicit verbal information. CONCLUSIONS: In line with the cognitive theory of conditioning, our results indicate that just pairing a cue with different pain stimulus intensities is not sufficient, per se, to produce a learning process. What matters is the informational cognitive content of the cue, i.e. the meaning assigned to the cue itself. These findings may help understand the mechanisms of conditioned analgesia and more in general of learning.

Nipple reconstruction using the fleur-de-lis flap technique.

The authors propose a simple and reliable technique for nipple reconstruction characterized by minimal loss in vertical projection.

Cyclin D1 expression in pre-cancerous and cancerous lesions of the canine mammary gland.

Overexpression of cyclin D1, the regulatory subunit of cyclin-dependent kinases (cdk4 and cdk6) involved in cell cycle control, has often been found in breast cancer and other types of human cancer. Increased expression, or stability, of cyclin D1 molecules may cause sufficient cdk4 activation to produce retinoblastoma protein phosphorylation independently of mitogenic signals; this results in commitment of cells to the G1 phase at mitosis. In the present study, cyclin D1 expression was investigated in pre-cancerous and cancerous lesions of the canine mammary gland by a complex experimental approach, which included Western blot and immunohistochemical analysis of cyclin D1 and the related molecular system. Furthermore, to define relationships between cell growth and expression of cyclin D1, proliferative activity was studied by the AgNOR technique. The study provided the following information. Cyclin D1 overexpression was largely independent of the type of proliferative anomaly. Indeed, cyclin D1 was expressed in 60% of the pre-cancerous lesions and in 44% of cancerous lesions. Mitotic activity and cyclin D1 expression were related: mammary lesions that expressed cyclin D1 showed a high proliferative ratio, the opposite being true of cyclin D1-negative cell populations. This study may contribute to the establishment of an animal model for anti-cancer research based on cyclin D1 suppression or cdk inactivation, or both.

[Update on animal models for testing innovative antineoplastic strategies: the mammary tumor in dogs]. / Messa a punto di modelli animali per la sperimentazione di strategie antineoplastiche innovative: il tumore mammario canino.

In this study, the authors describe a new possible animal model to test new anticancer therapies. The selected animals are domestic animals such as dogs, which develop spontaneous tumours very similar in morphology and biology to human ones, also in relation to similar environmental oncogenic pressures. Cycline D1 overexpression, which has both a prognostic and pathogenetic value, is usually detected in human tumours. Thus, the use of cycline-dependent kinases inhibitors could be of value in anticancer therapy. We studied spontaneous canine mammary tumours in order to test the above hypothesis. Immunohistochemistry, AgNOR and western blotting analysis were performed, and the results revealed that cycline D1 is associated with metabolic, morphological and protein expression patterns typical of proliferating cells. The same protein expression pattern, the use of human antibodies for detecting canine proteins and the availability of neoplastic tissue make these spontaneous canine tumours a reliable model.