Neuroscientific results of experimental studies on the control of acute pain with hypnosis and suggested analgesia.

This narrative review summarizes a representative collection of electrophysiological and imaging studies on the neural processes and brain sources underlying hypnotic trance and the effects of hypnotic suggestions on the processing of experimentally induced painful events. It complements several reviews on the effect of hypnosis on brain processes and structures of chronic pain processing. Based on a summary of previous findings on the neuronal processing of experimentally applied pain stimuli and their effects on neuronal brain structures in healthy subjects, three neurophysiological methods are then presented that examine which of these neuronal processes and structures get demonstrably altered by hypnosis and can thus be interpreted as neuronal signatures of the effect of analgesic suggestions: (A) On a more global neuronal level, these are electrical processes of the brain that can be recorded from the cranial surface of the brain with magnetoencephalography (MEG) and electroencephalography (EEG). (B) On a second level, so-called evoked (EPs) or event-related potentials (ERPs) are discussed, which represent a subset of the brain electrical parameters of the EEG. (C) Thirdly, imaging procedures are summarized that focus on brain structures involved in the processing of pain states and belong to the main imaging procedures of magnetic resonance imaging (MRI/fMRI) and positron emission tomography (PET). Finally, these different approaches are summarized in a discussion, and some research and methodological suggestions are made as to how this research could be improved in the future.

Stimulation of peroneal nerves reveals maintained somatosensory representation in transtibial amputees.

Introduction: Several studies have found changes in the organization of the primary somatosensory cortex (SI) after amputation. This SI reorganization was mainly investigated by stimulating neighboring areas to amputation. Unexpectedly, the somatosensory representation of the deafferented limb has rarely been directly tested. Methods: We stimulated the truncated peroneal nerve in 24 unilateral transtibial amputees and 15 healthy controls. The stimulation intensity was adjusted to make the elicited percept comparable between both stimulation sides. Neural sources of the somatosensory-evoked magnetic fields (SEFs) to peroneal stimulation were localized in the contralateral foot/leg areas of SI in 19 patients and 14 healthy controls. Results: We demonstrated the activation of functionally preserved cortical representations of amputated lower limbs. None of the patients reported evoked phantom limb pain (PLP) during stimulation. Stimulation that evoked perceptions in the foot required stronger intensities on the amputated side than on the intact side. In addition to this, stronger stimulation intensities were required for amputees than for healthy controls. Exploratorily, PLP intensity was neither associated with stimulation intensity nor dipole strength nor with differences in Euclidean distances (between SEF sources of the healthy peroneus and mirrored SEF sources of the truncated peroneus). Discussion: Our results provide hope that the truncated nerve may be used to establish both motor control and somatosensory feedback via the nerve trunk when a permanently functional connection between the nerve trunk and the prosthesis becomes available.

Effects of emotional valence and intensity on cognitive and affective empathy after insula lesions.

The insula plays a central role in empathy. However, the complex structure of cognitive (CE) and affective empathy (AE) deficits following insular damage is not fully understood. In the present study, patients with insular lesions (n = 20) and demographically matched healthy controls (n = 24) viewed ecologically valid videos that varied in terms of valence and emotional intensity. The videos showed a person (target) narrating a personal life event. In CE conditions, subjects continuously rated the affective state of the target, while in AE conditions, they continuously rated their own affect. Mean squared error (MSE) assessed deviations between subject and target ratings. Patients differed from controls only in negative, low-intensity AE, rating their own affective state less negative than the target. This deficit was not related to trait empathy, neuropsychological or clinical parameters, or laterality of lesion. Empathic functions may be widely spared after insular damage in a naturalistic, dynamic setting, potentially due to the intact interpretation of social context by residual networks outside the lesion. The particular role of the insula in AE for negative states may evolve specifically in situations that bear higher uncertainty pointing to a threshold role of the insula in online ratings of AE.

Lateralized deficits in arousal processing after insula lesions: Behavioral and autonomic evidence.

A large body of evidence ascribes a pivotal role in emotion processing to the insular cortex. However, the complex structure and lateralization of emotional deficits following insular damage are not understood. Here, we investigated emotional ratings of valence and arousal and skin conductance responses (SCR) to a graded series of emotionally arousing scenes in patients with left (n = 10) or right (n = 9) insular damage and in healthy controls (n = 18). We found a significant reduction in overall SCRs, arousal ratings and valence extremity scores in right-lesioned patients, as compared to left-lesioned patients and healthy controls. The degree of right insular damage was significantly correlated with the degree of arousal, SCR and extremity attenuation. Additional analyses of correlations between subjective arousal ratings resp. SCR and normative arousal ratings revealed that both lesion groups had evaluative and physiological difficulties to discover changes in stimulus arousal. Although no group differences emerged on overall ratings of valence, analysis of correlations between subjective and normative valence ratings displayed markedly reduced accuracy in right-lesioned patients, as compared to left-lesioned patients and healthy controls. Our findings support the hypothesis that the left and right insulae subserve different functions in emotion processing, potentially due to asymmetrical representations of autonomic information in the left and right human forebrain. The right insula may serve as integral node for sympathetic arousal and cognitive-affective processing.

Trait anxiety predicts amygdalar responses during direct processing of threat-related pictures.

Previous studies on the associations between trait anxiety and amygdalar responses to threat stimuli have resulted in mixed findings, possibly due to sample characteristics, specific tasks, and analytical methods. The present functional magnetic resonance imaging (fMRI) study aimed to investigate linear or non-linear associations between trait anxiety and amygdalar responses in a sample of participants with low, medium, and high trait anxiety scores. During scanning, participants were presented with threat-related or neutral pictures and had either to solve an emotional task or an emotional-unrelated distraction task. Results showed that only during the explicit task trait anxiety was associated with right amygdalar responses to threat-related pictures as compared to neutral pictures. The best model was a cubic model with increased amygdala responses for very low and medium trait anxiety values but decreased amygdala activation for very high trait anxiety values. The findings imply a non-linear relation between trait anxiety and amygdala activation depending on task conditions.

Suggested visual blockade during hypnosis: Top-down modulation of stimulus processing in a visual oddball task.

Several theories of hypnosis assume that responses to hypnotic suggestions are implemented through top-down modulations via a frontoparietal network that is involved in monitoring and cognitive control. The current study addressed this issue re-analyzing previously published event-related-potentials (ERP) (N1, P2, and P3b amplitudes) and combined it with source reconstruction and connectivity analysis methods. ERP data were obtained from participants engaged in a visual oddball paradigm composed of target, standard, and distractor stimuli during a hypnosis (HYP) and a control (CON) condition. In both conditions, participants were asked to count the rare targets presented on a video screen. During HYP participants received suggestions that a wooden board in front of their eyes would obstruct their view of the screen. The results showed that participants' counting accuracy was significantly impaired during HYP compared to CON. ERP components in the N1 and P2 window revealed no amplitude differences between CON and HYP at sensor-level. In contrast, P3b amplitudes in response to target stimuli were significantly reduced during HYP compared to CON. Source analysis of the P3b amplitudes in response to targets indicated that HYP was associated with reduced source activities in occipital and parietal brain areas related to stimulus categorization and attention. We further explored how these brain sources interacted by computing time-frequency effective connectivity between electrodes that best represented frontal, parietal, and occipital sources. This analysis revealed reduced directed information flow from parietal attentional to frontal executive sources during processing of target stimuli. These results provide preliminary evidence that hypnotic suggestions of a visual blockade are associated with a disruption of the coupling within the frontoparietal network implicated in top-down control.

Suggested deafness during hypnosis and simulation of hypnosis compared to a distraction and control condition: A study on subjective experience and cortical brain responses.

Hypnosis is a powerful tool to affect the processing and perception of stimuli. Here, we investigated the effects of hypnosis on the processing of auditory stimuli, the time course of event-related-potentials (ERP; N1 and P3b amplitudes) and the activity of cortical sources of the P3b component. Forty-eight participants completed an auditory oddball paradigm composed of standard, distractor, and target stimuli during a hypnosis (HYP), a simulation of hypnosis (SIM), a distraction (DIS), and a control (CON) condition. During HYP, participants were suggested that an earplug would obstruct the perception of tones and during SIM they should pretend being hypnotized and obstructed to hear the tones. During DIS, participants' attention was withdrawn from the tones by focusing participants' attention onto a film. In each condition, subjects were asked to press a key whenever a target stimulus was presented. Behavioral data show that target hit rates and response time became significantly reduced during HYP and SIM and loudness ratings of tones were only reduced during HYP. Distraction from stimuli by the film was less effective in reducing target hit rate and tone loudness. Although, the N1 amplitude was not affected by the experimental conditions, the P3b amplitude was significantly reduced in HYP and SIM compared to CON and DIS. In addition, source localization results indicate that only a small number of neural sources organize the differences of tone processing between the control condition and the distraction, hypnosis, and simulation of hypnosis conditions. These sources belong to brain areas that control the focus of attention, the discrimination of auditory stimuli, and the organization of behavioral responses to targets. Our data confirm that deafness suggestions significantly change auditory processing and perception but complete deafness is hard to achieve during HYP. Therefore, the term 'deafness' may be misleading and should better be replaced by 'hypoacusis'.

Lateralized Deficits of Disgust Processing After Insula-Basal Ganglia Damage.

A growing body of evidence suggests a role of the insular cortex (IC) and the basal ganglia (BG) in the experience, expression, and recognition of disgust. However, human lesion research, probing this structure-function link, has yielded rather disparate findings in single cases of unilateral and bilateral damage to these areas. Comparative group approaches are needed to elucidate whether disgust-related deficits specifically follow damage to the IC-BG system, or whether there might be a differential hemispheric contribution to disgust processing. We examined emotional processing by means of a comprehensive emotional test battery in four patients with left- and four patients with right-hemispheric lesions to the IC-BG system as well as in 19 healthy controls. While single tests did not provide clear-cut separations of patient groups, composite scores indicated selective group effects for disgust. Importantly, left-lesioned patients presented attenuated disgust composites, while right-lesioned patients showed increased disgust composites, as compared to each other and controls. These findings propose a left-hemispheric basis of disgust, potentially due to asymmetrical representations of autonomic information in the human forebrain. The present study provides the first behavioral evidence of hemispheric lateralization of a specific emotion in the human brain, and contributes to neurobiological models of disgust.

Stimulus arousal drives amygdalar responses to emotional expressions across sensory modalities.

The factors that drive amygdalar responses to emotionally significant stimuli are still a matter of debate - particularly the proneness of the amygdala to respond to negatively-valenced stimuli has been discussed controversially. Furthermore, it is uncertain whether the amygdala responds in a modality-general fashion or whether modality-specific idiosyncrasies exist. Therefore, the present functional magnetic resonance imaging (fMRI) study systematically investigated amygdalar responding to stimulus valence and arousal of emotional expressions across visual and auditory modalities. During scanning, participants performed a gender judgment task while prosodic and facial emotional expressions were presented. The stimuli varied in stimulus valence and arousal by including neutral, happy and angry expressions of high and low emotional intensity. Results demonstrate amygdalar activation as a function of stimulus arousal and accordingly associated emotional intensity regardless of stimulus valence. Furthermore, arousal-driven amygdalar responding did not depend on the visual and auditory modalities of emotional expressions. Thus, the current results are consistent with the notion that the amygdala codes general stimulus relevance across visual and auditory modalities irrespective of valence. In addition, whole brain analyses revealed that effects in visual and auditory areas were driven mainly by high intense emotional facial and vocal stimuli, respectively, suggesting modality-specific representations of emotional expressions in auditory and visual cortices.

Wearing a bike helmet leads to less cognitive control, revealed by lower frontal midline theta power and risk indifference.

A recent study claims that participants wearing a bike helmet behave riskier in a computer-based risk task compared to control participants without a bike helmet. We hypothesized that wearing a bike helmet reduces cognitive control over risky behavior. To test our hypothesis, we recorded participants' EEG brain responses while they played a risk game developed in our laboratory. Previously, we found that, in this risk game, anxious participants showed greater levels of cognitive control as revealed by greater frontal midline theta power, which was associated with less risky decisions. Here, we predicted that cognitive control would be reduced in the helmet group, indicated by reduced frontal midline theta power, and that this group would prefer riskier options in the risk game. In line with our hypothesis, we found that participants in the helmet group showed significantly lower frontal midline theta power than participants in the control group, indicating less cognitive control. We did not replicate the finding of generally riskier behavior in the helmet group. Instead, we found that participants chose the riskier option in about half of trials, no matter how risky the other option was. Our results suggest that wearing a bike helmet reduces cognitive control, as revealed by reduced frontal midline theta power, leading to risk indifference when evaluating potential behaviors.

How words impact on pain.

INTRODUCTION: The wording used before and during painful medical procedures might significantly affect the painfulness and discomfort of the procedures. Two theories might account for these effects: the motivational priming theory (Lang, 1995, American Psychologist, 50, 372) and the theory of neural networks (Hebb, 1949, The organization of behavior. New York, NY: Wiley; Pulvermuller, 1999, Behavioral and Brain Sciences, 22, 253; Pulvermüller and Fadiga, 2010, Nature Reviews Neuroscience, 11, 351). METHODS: Using fMRI, we investigated how negative, pain-related, and neutral words that preceded the application of noxious stimuli as priming stimuli affect the cortical processing and pain ratings of following noxious stimuli. RESULTS: Here, we show that both theories are applicable: Stronger pain and stronger activation were observed in several brain areas in response to noxious stimuli preceded by both, negative and pain-related words, respectively, as compared to preceding neutral words, thus supporting motivational priming theory. Furthermore, pain ratings and activation in somatosensory cortices, primary motor cortex, premotor cortex, thalamus, putamen, and precuneus were even stronger for preceding pain-related than for negative words supporting the theory of neural networks. CONCLUSION: Our results explain the influence of wording on pain perception and might have important consequences for clinical work.

What you give is what you get: Payment of one randomly selected trial induces risk-aversion and decreases brain responses to monetary feedback.

In economic studies, it is standard practice to pay out the reward of only one randomly selected trial (pay-one) instead of the total reward accumulated across trials (pay-all), assuming that both methods are equivalent. We tested this assumption by recording electrophysiological activity to reward feedback from participants engaged in a decision-making task under both a pay-one and a pay-all condition. We show that participants are approximately 12% more risk averse in the pay-one condition than in the pay-all condition. Furthermore, we observed that the electrophysiological response to monetary rewards, the reward positivity, is significantly reduced in the pay-one condition relative to the pay-all condition. The difference of brain responses is associated with the difference in risky behavior across conditions. We concluded that the two payment methods lead to significantly different results and are therefore not equivalent.

Expectation of exercise in trained athletes results in a reduction of central processing to nociceptive stimulation.

A single endurance exercise session was shown to lead to a reduction of pain perception and an elevation of mood. We hypothesized that athletes, who regularly practice endurance, might also induce changes in mood and pain processing in expectation of an endurance session. We compared the expectation effects of a 2-h-run on mood and pain processing to a run-free control day (RFC). Fifteen trained runners were assessed with repeated painful and nonpainful pinprick stimulation in a functional magnetic resonance imaging (fMRI) scanner prior to a 2-h-run and at RFC. Pain ratings, pressure pain stimulus-response functions, and euphoria ratings were also assessed. There were no mean expectation effects on any of the behavioral measures. However, highly trained athletes needed more pressure to evoke a pain rating of 46 pre-run vs. RFC but were less euphoric pre-run vs. RFC. Furthermore, analysis of brain activities to painful stimuli applied immediately before the 2-h-run compared to RFC revealed increased activation in the medial prefrontal cortex (mPFC) and reduced activation in posterior insula. Additionally, less trained athletes had reduced activation in posterior insula to painful stimulation pre-run vs. RFC compared to highly trained athletes. The results suggest reduced central pain processing in expectation of an endurance run and an association between the amount of the expectation effect and training frequency which differs depending on the stimuli applied.

Effects of Temporary Functional Deafferentation in Chronic Stroke Patients: Who Profits More?

Temporary functional deafferentation (TFD) by an anesthetic cream on the stroke-affected forearm was shown to improve sensorimotor abilities of stroke patients. The present study investigated different predictors for sensorimotor improvements during TFD and indicated outcome differences between patients grouped in subcortical lesions only and lesions with any cortical involvement. Thirty-four chronic stroke patients were temporarily deafferented on the more affected forearm by an anesthetic cream. Somatosensory performance was assessed using von Frey Hair and grating orientation task; motor performance was assessed by a shape-sorter-drum task. Seven potential predictors were entered into three linear multiple regression models. Furthermore, effects of TFD on outcome variables for the two groups (cortical versus subcortical lesion) were compared. Sex and sensory deficit were significant predictors for changes in motor function while age accounted for changes in grating orienting task. Males, patients with a stronger sensory deficit, and older patients profited more. None of the potential predictors made significant contributions to changes in threshold for touch. Furthermore, there were no differences in sensorimotor improvement between lesion site groups. The effects of TFD together with the low predictability of the investigated parameters suggest that characteristics of patients alone are not suitable to exclude some patients from TFD.

The role of the cerebellum for feedback processing and behavioral switching in a reversal-learning task.

Previous studies have reported cerebellar activations during error and reward processing. The present study investigated if the cerebellum differentially processes feedback depending on changes in response strategy during reversal learning, as is conceivable given its internal models for movement and thought. Negative relative to positive feedback in an fMRI-based reversal learning task was hypothesized to be associated with increased cerebellar activations. Moreover, increased activations were expected for negative feedback followed by a change in response strategy compared to negative feedback not followed by such a change, and for first positive feedback after compared to final negative feedback before a change, due to updating of internal models. As predicted, activation in lobules VI and VIIa/Crus I was increased for negative relative to positive feedback, and for final negative feedback before a change in response strategy relative to negative feedback not associated with a change. Moreover, activation was increased for first positive feedback after relative to final negative feedback before a change. These findings are consistent with updating of cerebellar internal models to accommodate new behavioral strategies. Recruitment of posterior regions in reversal learning is in line with the cerebellar functional topography, with posterior regions involved in complex motor and cognitive functions.

Anxious gambling: Anxiety is associated with higher frontal midline theta predicting less risky decisions.

In this study, we address the effect of anxiety measured with the State-Trait Anxiety Inventory (STAI) on EEG and risk decisions. We selected 20 high and 20 low anxious participants based on their STAI trait scores in the upper or lower quartile of the norm distribution and implemented a risk game developed in our laboratory. We investigate if high anxious individuals exert more cognitive control, reflected in higher frontal midline theta (FMT) power when they make a risky decision, and if they act less risky compared to low anxious individuals. Participants played a risk game while we recorded their brain responses via EEG. High anxious participants played less risky compared to low anxious participants. Further, high anxious participants showed higher FMT power immediately before they chose one of two risk options, suggesting higher cognitive control during the decision time compared to low anxious participants. Via a mediation analysis, we show that the effect of anxiety on risk behavior is fully mediated by FMT power. Further, questionnaire responses revealed that high anxious participants rated risk situations as riskier compared to low anxious participants. We conclude that anxious individuals perceive risky situations as riskier and thus exert more cognitive control during their risk choices, reflected in higher FMT power, which leads to less risky decisions.

Leg Prosthesis With Somatosensory Feedback Reduces Phantom Limb Pain and Increases Functionality.

Phantom limb pain (PLP) develops in most patients with lower limb amputation. Changes in the peripheral and central nervous system (CNS) are hypothesized to contribute to PLP. Based on ideas to modify neural reorganization within the CNS, the aim of the study was to test, whether prostheses with somatosensory feedback might help to reduce PLP, and increase the functionality of movement with a prosthesis. We therefore equipped the prostheses of 14 lower leg amputees with a simple to use feedback system that provides electrocutaneous feedback to patients' thigh whenever the foot and toes of the prosthesis touch the ground. Two weeks of training with such a feedback prosthesis reduced PLP, increased the functional use of the prosthesis, and increased patients' satisfaction with prosthesis use. We found a significant overall reduction of PLP during the course of the training period. Most patients reported lower PLP intensities at the end of the day while before training they have usually experienced maximal PLP intensities. Furthermore, patients also reported larger walking distances and more stable walking and better posture control while walking on and across a bumpy or soft ground. After training, the majority of participants (9/14) preferred such a feedback system over no feedback. This study extends former observations of a similar training procedure with arm amputees who used a similar feedback training to improve the functionality of an arm prosthesis in manipulating and grasping objects.

Referred cramping phantom hand pain elicited in the face and eliminated by peripheral nerve block.

Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of "being touched at the phantom" persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.

Quantitative sensory testing after macroreplantation: evidence for a specific somatosensory profile.

A comprehensive functional recovery is one of the criteria for successful replantation of an amputated limb. Functionality of a replanted limb is strongly dependent on its regained sensibility. In previous studies concerning the sensibility of replanted limbs, only a few somatosensory submodalities were examined in small samples. The purpose of this study is to provide a full pattern of somatosensory symptoms after replantation. Quantitative sensory testing was performed according to a standardized protocol in a sample of 15 patients who underwent replantation of their upper limb proximal to the radiocarpal joint (macroreplantation). Results indicate that most of these patients showed a specific somatosensory profile characterized by thermal and mechanical hypoesthesia and hyperalgesia in response to pressure pain, whereas no single case of hyperalgesia to heat pain occurred. This distinct profile of impaired somatosensation shares some features of the somatosensory profile of neuropathic pain syndromes. Patients' limbs that were replanted many years before the present quantitative sensory testing showed more sensory deficits than patients with more recent replantations. This knowledge might be helpful in the development of more specific and more successful rehabilitation programs with replanted patients and improves the behavioral function of the replanted limb.