Pain expectation and avoidance in the social context: an electrophysiological study.

Contingent negative variation (CNV) is an informative electrophysiological measure of pain anticipation showing higher amplitudes when highly painful stimulation is expected while presenting lower amplitudes when low painful stimulation is expected. Two groups of participants were recruited: one group expected and received an electrical stimulation of different intensities while being alone in the room (i.e. without social context), while a second group performed the same experiment with an observer in the room (i.e. with social context). Lower pain ratings and slower reaction times were observed in the group with social context and these results were accompanied in this group by a lower amplitude in the early component of the CNV as well as a lower amplitude of the later component of the wave. These results show that CNV can be considered a precise measure of central elaboration of pain anticipation explaining both its perceptual and motor components.

The song of Anorexia Nervosa: a specific evoked potential response to musical stimuli in affected participants.

PURPOSE: Research applying electroencephalography (EEG) to Anorexia Nervosa (AN) is still limited, even though in other psychiatric disorders EEG has permitted to find out the hallmarks of the disorder. The aim of the study was to explore whether EEG basal activity and reactivity to musical stimulation differ in participants with AN as compared to healthy subjects (HS). METHODS: Twenty female participants (respectively 10 with AN and 10 healthy controls) were administered a battery of psychometric tests and underwent EEG under three different conditions: (1) at baseline; (2) after a generic music stimulation; and (3) after a favorite musical stimulation. RESULTS: In participants with AN, basal EEG showed the higher absolute amplitude of cortical slow waves (theta) in the parieto-occipital and temporal derivations, with a deficit in the beta band. In AN, there was a higher N100 latency and a reduced P300 latency compared to HS. While the N100 and P300 latencies were sensitive to the musical stimulus in HS, there was no difference after music stimulation in AN. CONCLUSION: These data suggest that AN is accompanied by a state of brain hyperarousal with abnormal reactivity to environmental stimuli, similar to the state of HS after musical stimulation. If confirmed, this finding may have treatment implications. LEVEL OF EVIDENCE: III, Evidence obtained from well-designed cohort or case-control analytic studies.

Low frequency subthalamic stimulation and event-related potentials in Parkinson disease.

BACKGROUND: High frequency (130 Hz) subthalamic Deep-Brain-Stimulation (STN-DBS) optimally improves cardinal motor symptoms in Parkinson disease (PD). Low stimulation frequencies (60-80 Hz) improve axial symptoms in some patients and, according to preliminary evidences, may also have a beneficial effect on the cognitive component of motor planning. OBJECTIVE: To analyze the configuration of the P300 component of cortical event-related auditory potentials (ERPs), a reliable index of attentive cognitive functions, at different stimulation frequencies in STN-DBS in PD patients. METHODS: 12 PD patients underwent ERPs recordings using a standard oddball auditory paradigm with STN-DBS at 60 Hz, 80 Hz, 130 Hz, and OFF-stimulation, applied in a randomized double-blind sequence. ERPs analysis considered the peak amplitude and latency of the P300 components at midline electrode positions (Fz, Cz, Pz). RESULTS: P300 latency over Cz and Pz electrodes significantly increased with STN-DBS at 130 Hz compared to OFF-stimulation. P300 latency was also significantly increased, though to a lesser degree, over Pz electrode with stimulation at 80 Hz. No significant P300 latency modifications were detected at 60 Hz stimulation compared to OFF-stimulation condition. P300 amplitude did not change significantly for any of the stimulation conditions tested. CONCLUSIONS: Low frequency STN-DBS is associated with minor modifications of P300 latency compared to conventional stimulation at 130 Hz, possibly suggesting that 60 and 80 Hz may have less interference with attentive and cognitive processes in PD patients.

I expect what you expect: An electrophysiological study on social expectation of pain.

Expectations and motor reactions related to pain are mainly acquired through personal experiences. Contingent negative variation (CNV) has been shown to be an informative electrophysiological measure of this pain anticipation. Expectations can also arise while observing others in painful conditions. However, it still remains unclear what are the neural correlates of this phenomenon and how the observation of others in pain can subsequently change our personal pain perception as well as our motor reaction to pain. Using CNV as a measure of expectation, this study aims to assess whether expectations formed through observation change the observer's own experience of pain and reaction to pain. A new cooperative task was designed where one participant, the model, received an electrical stimulation while another, the observer, watched the experiment and both were asked to stop the stimulation as fast as possible. Crucially, in a successive session, participants inverted their roles so that models became observers and vice versa. CNV was recorded in both participants simultaneously by means of two synchronized electroencephalograms. Results showed that CNV area did not differ between models and observers and reaction times were significantly faster in observers compared to models. Moreover, observers' pain perception was correlated to models' pain perception as well as to observers' empathy scores. These data show how expectations, perceptions as well as reactions related to pain are crucially affected not only by observation but by personal attitudes toward others and all these changes can be clearly described through CNV.

Verbal communication about drug dosage balances drug reduction in Parkinson's disease: Behavioral and electrophysiological evidences.

INTRODUCTION: Changing drug dosage is common in clinical practice. Recent evidence showed that psychological factors may affect the therapeutic outcome. The aim of this study is to test whether verbal communication about drug dosage changes motor performance and fatigue in Parkinson's Disease (PD) patients. METHODS: We performed clinical (Unified PD Rating Scale), motor (number of finger flexions and perceived fatigue), and electrophysiological measurements (readiness potential, RP) in PD patients during medication-off and medication-on conditions in three groups. The first group got a full dose of l-dopa and was told it was a full dose. The second group got half dose and was told it was half dose. The third group got half dose, but it was told it was a full standard dose. RESULTS: We found that overt half dose was less effective than the full dose for clinical improvement, motor performance, and readiness potential. However, if half dose was given along with verbal instructions that it was a full dose, clinical improvement, motor performance and readiness potential were not significantly different from the full dose. CONCLUSIONS: Our findings indicate that verbal communication about dose reduction is as effective as the 50% dose reduction itself, demonstrating that deceptive information about the dose may have an important impact on the therapeutic outcome. Moreover, the supplementary motor area, source of the RP, seems to be involved in this psychological effect.

The rehabilitative effects on written language of a combined language and parietal dual-tDCS treatment in a stroke case.

In this paper we report the effect of a combined transcranial direct current stimulation (tDCS) and speech language therapy on linguistic deficits following left brain damage in a stroke case. We show that simultaneous electrical excitatory stimulation to the left and inhibitory stimulation to the right parietal regions (dual-tDCS) affected writing and reading rehabilitation, enhancing speech therapy outcomes. The results of a comparison with healthy controls showed that application of dual-tDCS could improve, in particular, sub-lexical transcoding and, specifically, the reading of non-words with increasing length and complexity. Positive repercussions on patient's quality of functional communication were also ascertained. Significant changes were also found in other language and cognitive tasks not directly treated (comprehension and constructive apraxia).

Cognitive and Neurophysiological Effects of Non-invasive Brain Stimulation in Stroke Patients after Motor Rehabilitation.

The primary aim of this study was to evaluate and compare the effectiveness of two specific Non-Invasive Brain Stimulation (NIBS) paradigms, the repetitive Transcranial Magnetic Stimulation (rTMS), and transcranial Direct Current Stimulation (tDCS), in the upper limb rehabilitation of patients with stroke. Short and long term outcomes (after 3 and 6 months, respectively) were evaluated. We measured, at multiple time points, the manual dexterity using a validated clinical scale (ARAT), electroencephalography auditory event related potentials, and neuropsychological performances in patients with chronic stroke of middle severity. Thirty four patients were enrolled and randomized. The intervention group was treated with a NIBS protocol longer than usual, applying a second cycle of stimulation, after a washout period, using different techniques in the two cycles (rTMS/tDCS). We compared the results with a control group treated with sham stimulation. We split the data analysis into three studies. In this first study we examined if a cumulative effect was clinically visible. In the second study we compared the effects of the two techniques. In the third study we explored if patients with minor cognitive impairment have most benefit from the treatment and if cognitive and motor outcomes were correlated. We found that the impairment in some cognitive domains cannot be considered an exclusion criterion for rehabilitation with NIBS. ERP improved, related to cognitive and attentional processes after stimulation on the motor cortex, but transitorily. This effect could be linked to the restoration of hemispheric balance or by the effects of distant connections. In our study the effects of the two NIBS were comparable, with some advantages using tDCS vs. rTMS in stroke rehabilitation. Finally we found that more than one cycle (2-4 weeks), spaced out by washout periods, should be used, only in responder patients, to obtain clinical relevant results.

Electroencephalographic connectivity analysis in schizophrenia.

The aim of the present study was to further investigate the electroencephalogram (EEG) connectivity in schizophrenic patients by means of mutual information (MI), an analysis capable of detecting both the linear and nonlinear components of EEG. 19-lead EEGs were recorded in stable schizophrenic patients (N=17) and healthy controls (N=17) in two different conditions: closed eyes (CE) and open eyes (OE). In patients, higher MI values were observed in temporal-parietal-occipital regions compared with controls. In controls, an increase in brain connectivity in frontal regions was observed in the CE condition. This increase was not present in patients. Our results suggest that patients with schizophrenia present changes of brain connectivity that can be detected through MI analysis.

High-altitude headache: the effects of real vs sham oxygen administration.

High-altitude, or hypobaric hypoxia, headache has recently emerged as an interesting model to study placebo and nocebo responses, and particularly their peripheral mechanisms. In this study, we analyze the response of this type of headache to either real or sham (placebo) oxygen (O(2)) administration at an altitude of 3500 m, where blood oxygen saturation (SO(2)) drops from the normal value of about 98% to about 85%. In a trial in which a double-blind administration of either 100% O(2) or sham O(2) was administered, we tested pre- and post-exercise headache, along with fatigue, heart rate (HR) responses, and prostaglandin E(2) (PGE(2)) salivary concentration. Although real O(2) breathing increased SO(2) along with a decrease in pre- and post-exercise headache, fatigue, HR, and PGE(2), placebo O(2) changed neither pre-/post-exercise headache nor SO(2)/HR/PGE(2), but it decreased fatigue. However, in another group of subjects, when sham O(2) was delivered after 2 previous exposures to O(2) (O(2) preconditioning), it decreased fatigue, post-exercise headache, HR, and PGE(2), yet without any increase in SO(2). Three main findings emerge from these data. First, placebo O(2) is effective in reducing post-exercise headache, along with HR and PGE(2) decrease, only after O(2) preconditioning. Second, pre-exercise (at rest) headache is not affected by placebo O(2), which emphasizes the limits of a placebo treatment at high altitude. Third, fatigue is affected by placebo O(2) even without prior O(2) conditioning, which suggests the higher placebo sensitivity of fatigue compared with headache pain at high altitude.

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.

Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway.

Nocebo and placebo effects have been found to modulate several neurochemical systems, such as cholecystokinin, endogenous opioids, and endocannabinoids. Here we show that also the cyclooxygenase-prostaglandins pathway can be modulated by both nocebos and placebos. In fact, we found that negative expectation, the crucial element of the nocebo effect, about headache pain led to the enhancement of the cyclooxygenase-prostaglandins pathway, which, in turn, induced pain worsening. As an experimental model, we studied hypobaric hypoxia headache at high altitude in 2 populations of subjects. Whereas the experimental nocebo group received negative information by a single individual who was informed about the risk of headache, the control group did not know about the possible occurrence of headache. We found a significant increase in headache and salivary prostaglandins and thromboxane in the nocebo group compared to the control group, suggesting that negative expectations enhance cyclooxygenase activity. In addition, placebo administration to headache sufferers at high altitude inhibited the nocebo-related component of pain and prostaglandins synthesis, which indicates that the cyclooxygenase pathway can be modulated by both nocebos and placebos. Our results show for the first time how nocebos and placebos affect the synthesis of prostaglandins, which represent an important target of analgesic drugs, thus emphasizing once again the notion that placebos and drugs may use common biochemical pathways.

Pain as a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems.

Pain is a negative emotional experience that is modulated by a variety of psychological factors through different inhibitory systems. For example, endogenous opioids and cannabinoids have been found to be involved in stress and placebo analgesia. Here we show that when the meaning of the pain experience is changed from negative to positive through verbal suggestions, the opioid and cannabinoid systems are co-activated and these, in turn, increase pain tolerance. We induced ischemic arm pain in healthy volunteers, who had to tolerate the pain as long as possible. One group was informed about the aversive nature of the task, as done in any pain study. Conversely, a second group was told that the ischemia would be beneficial to the muscles, thus emphasizing the usefulness of the pain endurance task. We found that in the second group pain tolerance was significantly higher compared to the first one, and that this effect was partially blocked by the opioid antagonist naltrexone alone and by the cannabinoid antagonist rimonabant alone. However, the combined administration of naltrexone and rimonabant antagonized the increased tolerance completely. Our results indicate that a positive approach to pain reduces the global pain experience through the co-activation of the opioid and cannabinoid systems. These findings may have a profound impact on clinical practice. For example, postoperative pain, which means healing, can be perceived as less unpleasant than cancer pain, which means death. Therefore, the behavioral and/or pharmacological manipulation of the meaning of pain can represent an effective approach to pain management.

Nonlinear analysis of electroencephalogram at rest and during cognitive tasks in patients with schizophrenia.

BACKGROUND: In spite of the large number of studies on schizophrenia, a full understanding of its core pathology still eludes us. The application of the nonlinear theory of electroencephalography (EEG) analysis provides an interesting tool to differentiate between physiologic conditions (e.g., resting state and mathematical task) and normal and pathologic brain activities. The aim of the present study was to investigate nonlinear EEG activity in patients with schizophrenia. METHODS: We recorded 19-lead EEGs in patients with stable schizophrenia and healthy controls under 4 different conditions: eyes closed, eyes open, forward counting and backward counting. A nonlinear measure of complexity was calculated by means of correlation dimension (D2). RESULTS: We included 17 patients and 17 controls in our analysis. Comparing the 2 populations, we observed greater D2 values in the patient group. In controls, increased D2 values were observed during active states (eyes open and the 2 cognitive tasks) compared with baseline conditions. This increase of brain complexity, which can be interpreted as an increase of information processing and integration, was not preserved in the patient population. LIMITATIONS: Patients with schizophrenia were taking antipsychotic medications, so the presence of medication effects cannot be excluded. CONCLUSION: Our results suggest that patients with schizophrenia present changes in brain activity compared with healthy controls, and this pathologic alteration can be successfully studied with nonlinear EEG analysis.

Pain perception and tolerance in patients with frontotemporal dementia.

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 Alzheimer's 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.

Unseen facial and bodily expressions trigger fast emotional reactions.

The spontaneous tendency to synchronize our facial expressions with those of others is often termed emotional contagion. It is unclear, however, whether emotional contagion depends on visual awareness of the eliciting stimulus and which processes underlie the unfolding of expressive reactions in the observer. It has been suggested either that emotional contagion is driven by motor imitation (i.e., mimicry), or that it is one observable aspect of the emotional state arising when we see the corresponding emotion in others. Emotional contagion reactions to different classes of consciously seen and "unseen" stimuli were compared by presenting pictures of facial or bodily expressions either to the intact or blind visual field of two patients with unilateral destruction of the visual cortex and ensuing phenomenal blindness. Facial reactions were recorded using electromyography, and arousal responses were measured with pupil dilatation. Passive exposure to unseen expressions evoked faster facial reactions and higher arousal compared with seen stimuli, therefore indicating that emotional contagion occurs also when the triggering stimulus cannot be consciously perceived because of cortical blindness. Furthermore, stimuli that are very different in their visual characteristics, such as facial and bodily gestures, induced highly similar expressive responses. This shows that the patients did not simply imitate the motor pattern observed in the stimuli, but resonated to their affective meaning. Emotional contagion thus represents an instance of truly affective reactions that may be mediated by visual pathways of old evolutionary origin bypassing cortical vision while still providing a cornerstone for emotion communication and affect sharing.

The biochemical and neuroendocrine bases of the hyperalgesic nocebo effect.

Despite the increasing research on placebos in recent times, little is known about the nocebo effect, a phenomenon that is opposite to the placebo effect and whereby expectations of symptom worsening play a crucial role. By studying experimental ischemic arm pain in healthy volunteers and by using a neuropharmacological approach, we found that verbally induced nocebo hyperalgesia was associated to hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, as assessed by means of adrenocorticotropic hormone and cortisol plasma concentrations. Both nocebo hyperalgesia and HPA hyperactivity were antagonized by the benzodiazepine diazepam, suggesting that anxiety played a major role in these effects. The administration of the mixed cholecystokinin (CCK) type-A/B receptor antagonist proglumide blocked nocebo hyperalgesia completely but had no effect on HPA hyperactivity, which suggests a specific involvement of CCK in the hyperalgesic but not in the anxiety component of the nocebo effect. Importantly, both diazepam and proglumide did not show analgesic properties on basal pain, because they acted only on the nocebo-induced pain increase. These data indicate a close relationship between anxiety and nocebo hyperalgesia, in which the CCKergic systems play a key role in anxiety-induced hyperalgesia. These results, together with previous findings showing that placebo analgesia is mediated by endogenous opioids, suggest that the analgesic placebo/hyperalgesic nocebo phenomenon may involve the opposite activation of endogenous opioidergic and CCKergic systems.

Electroencephalographic responses to intraoperative subthalamic stimulation.

This study reports the effects of intraoperative stimulation of the subthalamic nucleus on brain electrical activity in advanced Parkinson's patients. To our knowledge, this is the first study about electroencephalographic responses in the very early phase of deep brain stimulation, during the implantation of the electrodes. We found an increase of gamma band bilaterally over the sensorimotor cortex in the range 45-55 Hz, which was associated with clinical improvement as assessed by means of muscle rigidity decrease. These results indicate that the electroencephalographic gamma responses to deep brain stimulation are present at the very beginning of the treatment process, and may help better understand the short and long-tem effects of deep brain stimulation.

Loss of expectation-related mechanisms in Alzheimer's disease makes analgesic therapies less effective.

Expectation/placebo-related mechanisms and specific effects of therapies show additive effects, such that a therapy is less effective if the placebo component is absent. So far, the placebo component has been disrupted experimentally by using covert administrations of treatments. Here, we show for the first time that disruption of expectation/placebo-related analgesic mechanisms may occur in a clinical condition, Alzheimer's disease (AD). In order to assess the placebo component of a therapy, we used the recently developed open-hidden paradigm. A local anesthetic was applied, either overtly or covertly, to the skin of AD patients to reduce burning pain after venipuncture. The placebo (psychological) component is represented by the difference between the analgesic effect after open (expected) and after hidden (unexpected) application. We correlated the placebo component with both cognitive status and functional connectivity among different brain regions. We found that AD patients with reduced Frontal Assessment Battery scores showed reduced placebo component of the analgesic treatment. We also found that the disruption of the placebo component occurred when reduced connectivity of the prefrontal lobes with the rest of the brain was present. Remarkably, the loss of these placebo-related mechanisms reduced treatment efficacy, such that a dose increase was necessary to produce adequate analgesia. These findings highlight the active role of cognition and prefrontal lobes in the therapeutic outcome and underscore the need of considering a possible revision of the therapeutic approach in Alzheimer patients in order to compensate for the loss of the endogenous expectation and placebo mechanisms.

Pain reactivity in Alzheimer patients with different degrees of cognitive impairment and brain electrical activity deterioration.

Pain perception and autonomic responses to pain are known to be altered in dementia, although the mechanisms are poorly understood. We studied patients with Alzheimer's disease (AD) whose cognitive status was assessed through the Mini Mental State Examination test and whose brain electrical activity was measured by means of quantitative electroencephalography. After assessment of both cognitive impairment and brain electrical activity deterioration, these patients underwent sensory measurements in which the minimum stimulus intensity for both stimulus detection and pain sensation was determined. In addition, heart rate responses to pain threshold x 1.5 were recorded. We found that neither stimulus detection nor pain threshold was correlated to cognitive status and brain electrical activity decline. By contrast, we found a correlation between heart rate responses and deterioration of both cognitive functions and brain electrical activity. In particular, the heart rate increase after pain stimulation was correlated to the presence of slow brain electrical activity (delta and theta frequencies). This correlation was also found for the anticipatory heart rate increase just before pain stimulation. These results indicate that pain anticipation and reactivity depend on both the cognitive status and the frequency bands of the electroencephalogram, whereas both stimulus detection and pain threshold are not affected by the progression of AD. These findings indicate that, whereas the sensory-discriminative components of pain are preserved even in advanced stages of AD, the cognitive and affective functions, which are related to both anticipation and autonomic reactivity, are severely affected. This sensory-affective dissociation is well correlated with the neuropathological findings in AD.