Pinprick-induced gamma-band oscillations are not a useful electrophysiological marker of pinprick hypersensitivity in humans.

OBJECTIVE: This study aimed to investigate scalp gamma-band oscillations (GBOs) induced by mechanical stimuli activating skin nociceptors before and after the induction of mechanical hypersensitivity using high-frequency electrical stimulation (HFS) of the skin. METHODS: In twenty healthy volunteers, we recorded the electroencephalogram during robot-controlled mechanical pinprick stimulation (512 mN) applied at the right ventral forearm before and after HFS. RESULTS: HFS induced a significant increase in mechanical pinprick sensitivity, but this increased pinprick sensitivity was, at the group level, not accompanied by a significant increase in GBOs. Visual inspection of the individual data revealed that possible GBOs were present in eight out of twenty participants (40%) and the frequency of these GBOs varied substantially across participants. CONCLUSIONS: Based on the low number of participants showing GBOs we question the (clinical) utility of mechanically-induced GBOs as an electrophysiological marker of pinprick hypersensitivity in humans. SIGNIFICANCE: Mechanical pinprick-induced scalp GBOs are not useful for evaluating mechanical pinprick hypersensitivity in humans.

Perceptual correlates of homosynaptic long-term potentiation in human nociceptive pathways: a replication study.

Animal studies have shown that high-frequency stimulation (HFS) of peripheral C-fibres induces long-term potentiation (LTP) within spinal nociceptive pathways. The aim of this replication study was to assess if a perceptual correlate of LTP can be observed in humans. In 20 healthy volunteers, we applied HFS to the left or right volar forearm. Before and after applying HFS, we delivered single electrical test stimuli through the HFS electrode while a second electrode at the contra-lateral arm served as a control condition. Moreover, to test the efficacy of the HFS protocol, we quantified changes in mechanical pinprick sensitivity before and after HFS of the skin surrounding both electrodes. The perceived intensity was collected for both electrical and mechanical stimuli. After HFS, the perceived pain intensity elicited by the mechanical pinprick stimuli applied on the skin surrounding the HFS-treated site was significantly higher compared to control site (heterotopic effect). Furthermore, we found a higher perceived pain intensity for single electrical stimuli delivered to the HFS-treated site compared to the control site (homotopic effect). Whether the homotopic effect reflects a perceptual correlate of homosynaptic LTP remains to be elucidated.

Central sensitization of nociceptive pathways demonstrated by robot-controlled pinprick-evoked brain potentials.

OBJECTIVE: The aim of this study was to assess the effect of central sensitization, induced by high frequency electrical stimulation of the skin (HFS), on pinprick-evoked brain potentials (PEPs) using robot-controlled mechanical pinprick stimulation and a stimulus evaluation task. METHODS: In 16 healthy volunteers HFS was applied to the right volar forearm. Robot- controlled pinprick stimuli (64 mN) were applied before and 20 minutes after HFS to the skin surrounding the area onto which HFS was applied. During pinprick stimulation, the EEG was recorded and the quality of perception and perceived intensity of the pinprick stimuli was collected. RESULTS: After HFS, the skin surrounding the site at which HFS was delivered showed increased mechanical pinprick sensitivity. Both the early-latency negative peak of PEPs and the later-latency peak were significantly increased after HFS. CONCLUSIONS: This study shows increased PEPs after HFS when they are elicited by a robot-controlled mechanical pinprick stimulator and participants are engaged in a stimulus evaluation task during pinprick stimulation. SIGNIFICANCE: This is the first study that shows a significant increase of both PEP peaks, and therefore, it provides a preferred setup for assessing the function of mechanical nociceptive pathways in the context of central sensitization.

Somatosensory attentional modulations during pain-related movement execution.

Pain serves to protect against bodily threat, and therefore initiates protective responses such as attending toward threat-relevant information. Since pain is often exacerbated by executing movements, these motor actions may serve as cues for pain. Up to date, however, pain-related attention during movement remains largely unexplored. While it has been shown that the preparation of a pain-related movement leads to enhanced processing of somatosensory information, it is unclear how the actual execution of a movement interacts with somatosensory attention. In the current study, we examined whether somatosensory processing is enhanced at a moving body part when the movement is expected to be associated with pain. Participants were asked to execute hand movements which were occasionally followed by a pain stimulus. To measure somatosensory attention, a task-irrelevant, innocuous tactile probe was presented on either hand to evoke a somatosensory evoked potential (SEP). The results showed an elevation of the N120 SEP at the hand performing a potentially painful movement, indicating heightened attention toward tactile information at the threatened moving hand compared to the non-threatened hand. Additionally, the P200 SEP also showed enlarged responses when performing a pain-related movement compared to a no-pain-related movement. These results show that not only the anticipation, but also the execution of pain-related movements, may modulate the processing of somatosensory input, driven by attentional processes.

No perceptual prioritization of non-nociceptive vibrotactile and visual stimuli presented on a sensitized body part.

High frequency electrical conditioning stimulation (HFS) is an experimental method to induce increased mechanical pinprick sensitivity in the unconditioned surrounding skin (secondary hyperalgesia). Secondary hyperalgesia is thought to be the result of central sensitization, i.e. increased responsiveness of nociceptive neurons in the central nervous system. Vibrotactile and visual stimuli presented in the area of secondary hyperalgesia also elicit enhanced brain responses, a finding that cannot be explained by central sensitization as it is currently defined. HFS may recruit attentional processes, which in turn affect the processing of all stimuli. In this study we have investigated whether HFS induces perceptual biases towards stimuli presented onto the sensitized arm by using Temporal Order Judgment (TOJ) tasks. In TOJ tasks, stimuli are presented in rapid succession on either arm, and participants have to indicate their perceived order. In case of a perceptual bias, the stimuli presented on the attended side are systematically reported as occurring first. Participants performed a tactile and a visual TOJ task before and after HFS. Analyses of participants' performance did not reveal any prioritization of the visual and tactile stimuli presented onto the sensitized arm. Our results provide therefore no evidence for a perceptual bias towards tactile and visual stimuli presented onto the sensitized arm.

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies.

Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities.

Mechanical pinprick pain in patients with unilateral spatial neglect: The influence of space representation on the perception of nociceptive stimuli.

BACKGROUND: Crossing the hands over the midline can reduce the perceived intensity of nociceptive stimuli applied onto the hands. It remains unclear to what extent intact representation of peripersonal space influences this effect. Here we used the crossed-hands paradigm in patients with unilateral spatial neglect, a neuropsychological condition characterized by the inability to detect, attend and respond to contralesional (most often left) stimuli, and spared ability to process stimuli in the non-affected space. METHODS: Sixteen post-stroke patients without unilateral neglect and 11 patients with unilateral spatial neglect received punctate mechanical pinprick stimuli onto their crossed or uncrossed hands. We tested: (i) whether deficits in space representation reduce the possibility of observing 'crossed-hands analgesia', and; (ii) whether placing the contralesional hand, normally lying in the affected space in the healthy space would increase the number of detected stimuli. RESULTS: Our results showed that neglect patients did not exhibit 'crossed-hands' analgesia, but did not provide strong evidence for an improvement in the number of detected stimuli when the contralesional hand was in the healthy space. CONCLUSION: These findings uphold the notion that the perception of nociceptive stimuli is modulated by the relative position of the hands in space, but raise questions about the conditions under which these effects may arise. SIGNIFICANCE: We show that deficits in space representation can influence the processing of mechanical pinprick stimuli. Our results raise several questions on the mechanisms underlying these effects, which are relevant for the clinical practice.

Nucleus accumbens functional connectivity discriminates medication-overuse headache.

Medication-overuse headache (MOH) is a secondary form of headache related to the overuse of triptans, analgesics and other acute headache medications. It is believed that MOH and substance addiction share some similar pathophysiological mechanisms. In this study we examined the whole brain resting state functional connectivity of the dorsal and ventral striatum in 30 patients (15 MOH and 15 non-MOH patients) to investigate if classification algorithms can successfully discriminate between MOH and non-MOH patients on the basis of the spatial pattern of resting state functional connectivity of the dorsal and ventral striatal region of interest. Our results indicated that both nucleus accumbens and dorsal rostral putamen functional connectivity could discriminate between MOH and non-MOH patients, thereby providing possible support to two interpretations. First, that MOH patients show altered reward functionality in line with drug abusers (alterations in functional connectivity of the nucleus accumbens). Second, that MOH patients show inability to break habitual behavior (alterations in functional connectivity of the dorsal striatum). In conclusion, our data showed that MOH patients were characterized by an altered functional connectivity of motivational circuits at rest. These differences could permit the blind discrimination between the two conditions using classification algorithms. Considered overall, our findings might contribute to the development of novel diagnostic measures.

Prism adaptation contrasts perceptual habituation for repetitive somatosensory stimuli.

Prism adaptation (PA) is a non-invasive procedure that requires performing a visuo-motor pointing task while wearing prism goggles inducing a visual displacement of the pointed target. This procedure involves a reorganization of sensorimotor coordination, and induces long-lasting effects on numerous higher-order cognitive functions in healthy volunteers and neglect patients. Prismatic displacement (PD) of the visual field can be induced when prisms are worn but no sensorimotor task is required. In this case, it is unlikely that any subsequent reorganization takes place. The effects of PD are short-lived in the sense that they last as long as prisms are worn. In this study we aimed, to the best of our knowledge for the first time, at investigating whether PA and PD induce changes in the perception of intensity of nociceptive and non- nociceptive somatosensory stimuli. We induced, in healthy volunteers, PD (experiment 1), or PA (experiment 2) and asked participants to rate the intensity of the stimuli applied to the hand undergoing the visuo-proprioceptive conflict (experiment 1) or adaptation (experiment 2). Our results indicate that: 1) the visuo-proprioceptive conflict induced by PD does not reduce the perceived intensity of the stimuli, 2) PA prevents perceptual habituation for both nociceptive and non-nociceptive somatosensory stimuli. Moreover, to investigate the possible underlying mechanisms of the effects of PA we conducted a third experiment in which stimuli were applied both at the adapted and the non-adapted hand. In line with the results of experiment 2, we found that perceptual habituation was prevented for stimuli applied onto the adapted hand. Moreover, we observed the same finding for stimuli applied onto the non-adapted hand. This result suggests that the detention of habituation is not merely driven by changes in spatial attention allocation. Taken together, these data indicate that prisms can affect the perceived intensity of somatosensory stimuli, but only when PA is induced.

Cerebellar Clustering and Functional Connectivity During Pain Processing.

The cerebellum has been traditionally considered a sensory-motor structure, but more recently has been related to other cognitive and affective functions. Previous research and meta-analytic studies suggested that it could be involved in pain processing. Our aim was to distinguish the functional networks subserved by the cerebellum during pain processing. We used functional magnetic resonance imaging (fMRI) on 12 subjects undergoing mechanical pain stimulation and resting state acquisition. For the analysis of data, we used fuzzy c-mean to cluster cerebellar activity of each participant during nociception. The mean time courses of the clusters were used as regressors in a general linear model (GLM) analysis to explore brain functional connectivity (FC) of the cerebellar clusters. We compared our results with the resting state FC of the same cluster and explored with meta-analysis the behavior profile of the FC networks. We identified three significant clusters: cluster V, involving the culmen and quadrangular lobules (vermis IV-V, hemispheres IV-V-VI); cluster VI, involving the posterior quadrangular lobule and superior semilunar lobule (hemisphere VI, crus 1, crus 2), and cluster VII, involving the inferior semilunar lobule (VIIb, crus1, crus 2). Cluster V was more connected during pain with sensory-motor areas, cluster VI with cognitive areas, and cluster VII with emotional areas. Our results indicate that during the application of mechanical punctate stimuli, the cerebellum is not only involved in sensory functions but also with areas typically associated with cognitive and affective functions. Cerebellum seems to be involved in various aspects of nociception, reflecting the multidimensionality of pain perception.

Prisms for pain. Can visuo-motor rehabilitation strategies alleviate chronic pain?

BACKGROUND AND AIMS: Prism adaptation (PA) is a non-invasive procedure in which participants perform a visuo-motor pointing task while wearing prism goggles inducing a lateral displacement of the visual field and a mismatch between the seen and felt position of the pointing hand. PA is thought to induce a reorganization of sensorimotor coordination, and has been used successfully to rehabilitate neglect following right-hemisphere lesions. Because studies have shown that complex regional pain syndrome (CRPS) is associated with neglect-like symptoms, it was proposed that PA could be used to alleviate pain in these patients. DATABASE: A search for peer-reviewed articles on neglect-like symptoms in CRPS and on the use of prisms in CRPS was conducted using the PubMed database. RESULTS: There is still no agreement as to whether CRPS patients really present neglect symptoms and, if they do, what it is that they neglect. Furthermore, there is insufficient data to determine whether PA exerts an effect on CRPS symptoms. Finally, it remains unknown whether neglect can be observed in other types of lateralized pain, or whether PA could be useful for these patients. CONCLUSION: By highlighting open issues, our review provides guidelines for future studies on the use of prisms in pain. The assessment of neglect in patients with CRPS as well as other types of lateralized chronic pain should be characterized using a combination of neuropsychological methods assessing the multiple aspects of neglect in a more refined manner. In addition, further studies should investigate the mechanisms through which PA may modulate pain.

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.

The temporal order judgement of tactile and nociceptive stimuli is impaired by crossing the hands over the body midline.

Crossing the hands over the midline impairs the ability to correctly judge the order of a pair of tactile stimuli, delivered in rapid succession, one to each hand. This impairment, termed crossed-hands deficit, has been attributed to a mismatch between the somatotopic and body-centred frames of reference, onto which somatosensory stimuli are automatically mapped. Whether or not such crossed-hands deficit occurs also when delivering nociceptive stimuli has not been previously investigated. In this study, participants performed a temporal order judgement (TOJ) task in which pairs of either nociceptive or tactile stimuli were delivered, one to each hand, while their arms were either crossed over the body midline or uncrossed. We observed that crossing the hands over the midline significantly decreases the ability to determine the stimulus order when a pair of nociceptive stimuli is delivered to the hands, and that this crossed-hands deficit has a temporal profile similar to that observed for tactile stimuli. These findings suggest that similar mechanisms for integrating somatotopic and body-centred frames of reference underlie the ability to localise both nociceptive and tactile stimuli in space.

Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology.

The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subject's goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes.

Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus spatial location.

The repetition of nociceptive stimuli of identical modality, intensity and location at short (1 s) and constant inter-stimulus interval (ISI) determines a strong habituation of the corresponding electroencephalographic (EEG) responses. To understand what determines this response habituation, we (1) examined the effect of introducing a selective change in the spatial location of the repeated stimulus (i.e., without altering its modality, intensity and timing), and (2) dissected the relative contribution of bottom-up, stimulus-driven spatial changes and top-down, cognitive expectations of such a change. Multichannel EEG was recorded while participants received a triplet of stimuli (S1-S2-S3) delivered to the hand dorsum at 1-s ISI. S3 was delivered either to the same hand as S1 and S2 or to the other hand, and participants were either explicitly informed or not informed of the location of S3. We found that, unlike the introduction of a change in the sensory modality of the repeated stimulus (Valentini et al. in J Cogn Neurosci 23:2822-2837, 2011), introducing a change in its spatial location did not produce a significant dishabituation of the laser-evoked N1, N2 and P2 peaks, but only a small amplitude increase following the P2 peak, maximal on the hemisphere contralateral to the stimulated hand. Furthermore, the magnitude of the elicited responses was not significantly affected by cognitive expectations. Altogether, these results indicate that bottom-up, stimulus-driven novelty resulting from a change in stimulus spatial location does not revert the habituation caused by repetition suppression, but determines a small increase of neural activity over the contralateral central-parietal cortex, likely reflecting shifts in spatial attention.

Objective and self-reported cognitive dysfunction in breast cancer women treated with chemotherapy: a prospective study.

The objective of this study is to investigate if changes in cognitive functions can be recognised in patients undergoing chemotherapy for breast cancer. Forty women with breast cancer and without depression underwent cognitive evaluation before and after 6 months of chemotherapy; emotional evaluation was performed before and after 1, 3 and 6 months of chemotherapy. Self-reported cognitive deficit evaluation was included. Global cognitive functioning before starting chemotherapy was good. After 6 months of treatment there was a significant decline in some cognitive functions, particularly involving the attention subdomain. Objective cognitive deficit resulted independent from the emotional status. On the contrary, self-perceived mental dysfunction was unrelated to the objective cognitive decline, but it was associated with depression and anxiety. Breast cancer chemotherapy can induce domain-specific cognitive dysfunction. Patients' self-perception of mental decline is unrelated to objective cognitive deficit. Breast cancer patients negatively judge their cognitive performances if they have a negative emotional functioning.

Different functions in the cingulate cortex, a meta-analytic connectivity modeling study.

The cingulate cortex is a structurally heterogeneous brain region involved in emotional, cognitive and motor tasks. With the aim of identifying which behavioral domains are associated with the activation of the cingulate cortex, we performed a structure based-meta-analysis using the activation likelihood estimation (ALE), which assesses statistical significant convergence of neuroimaging studies using the BrainMap database. To map the meta-analytic coactivation maps of the cingulate cortex (MACM), we subdivided the parenchyma along the rostro-caudal axis in 12 bilateral equispaced ROIs. ROIs were not chosen according to previously suggested subdivisions, as to obtain a completely data-driven result. Studies were included with one or more activation coordinates in at least one of the 12 pre-defined ROIs. The meta-analytic connectivity profile and behavioral domains profiles were identified for each ROI. Cluster analysis was then performed on the MACM and behavioral domains to group together ROIs with similar profiles. The results showed that the cingulate cortex can be divided in three clusters according to the MACM parcellation and in four according to the behavioral domain-based parcellation. In addition, a behavioral-domain based meta-analysis was conducted and the spatial consistency of functional connectivity patterns across different domain-related ALE results was evaluated by computing probabilistic maps. These maps identified some portions of the cingulate cortex as involved in several tasks. Our results showed the existence of a more specific functional characterization of some portions of the cingulate cortex but also a great multifunctionality of others. By analyzing a large number of studies, structure based meta-analysis can greatly contribute to new insights in the functional significance of brain activations and in the role of specific brain areas in behavior.

The analgesic effect of crossing the arms.

The ability to determine precisely the location of sensory stimuli is fundamental to how we interact with the world; indeed, to our survival. Crossing the hands over the body midline impairs this ability to localize tactile stimuli. We hypothesized that crossing the arms would modulate the intensity of pain evoked by noxious stimulation of the hand. In two separate experiments, we show (1) that the intensity of both laser-evoked painful sensations and electrically-evoked nonpainful sensations were decreased when the arms were crossed over the midline, and (2) that these effects were associated with changes in the multimodal cortical processing of somatosensory information. Critically, there was no change in the somatosensory-specific cortical processing of somatosensory information. Besides studies showing relief of phantom limb pain using mirrors, this is the first evidence that impeding the processes by which the brain localises a noxious stimulus can reduce pain, and that this effect reflects modulation of multimodal neural activities. By showing that the neural mechanisms by which pain emerges from nociception represent a possible target for analgesia, we raise the possibility of novel approaches to the treatment of painful clinical conditions. Crossing the arms over the midline impairs multimodal processing of somatosensory stimuli and induces significant analgesia to noxious hand stimulation.

Idebenone treatment in Friedreich patients: one-year-long randomized placebo-controlled trial.

The authors carried out a 1-year, randomized, placebo-controlled trial of idebenone in 29 patients with Friedreich ataxia. They found significant reductions of interventricular septal thickness and left ventricular mass in the idebenone group vs the placebo group, with no improvement in other heart ultrasound measures or neurologic condition. The absolute cardiac changes were modest, but the findings suggest that larger trials should assess whether idebenone reduces ventricular hypertrophy in patients with Friedreich ataxia.

[A left atrial myxoma. The clinical aspects]. / Mixoma atriale sinistro. Considerazioni cliniche.

The paper describes a case of left atrial myxoma, which was unidentified for many years after the onset of symptoms, with emphasis on the necessity for instrumental investigations (particularly M-mode and two-dimensional echocardiography) in order to obtain an accurate and prompt diagnosis of these affections when the patient's clinical history justifies the suspicion.