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.

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'.

Cardiac cycle phases affect auditory-evoked potentials, startle eye blink and pre-motor reaction times in response to acoustic startle stimuli.

Startle stimuli evoke lower responses when presented during the early as compared to the late cardiac cycle phase, an effect that has been called 'cardiac modulation of startle' (CMS). The CMS effect may be associated with visceral-afferent neural traffic, as it is reduced in individuals with degeneration of afferent autonomic nerves. The aim of this study was to investigate whether the CMS effect is due a modulation of only early, automatic stages of stimulus processing by baro-afferent neural traffic, or if late stages are also affected. We, therefore, investigated early and late components of auditory-evoked potentials (AEPs) to acoustic startle stimuli (105, 100, 95 dB), which were presented during the early (R-wave +230 ms) or the late cardiac cycle phase (R +530 ms) in two studies. In Study 1, participants were requested to ignore (n = 25) or to respond to the stimuli with button-presses (n = 24). In Study 2 (n = 23), participants were asked to rate the intensity of the stimuli. We found lower EMG startle response magnitudes (both studies) and slower pre-motor reaction times in the early as compared to the late cardiac cycle phase (Study 1). We also observed lower N1 negativity (both studies), but higher P2 (Study 1) and P3 positivity (both studies) in response to stimuli presented in the early cardiac cycle phase. This AEP modulation pattern appears to be specific to the CMS effect, suggesting that early stages of startle stimulus processing are attenuated, whereas late stages are enhanced by baro-afferent neural traffic.

Quantification of Phase-Amplitude Coupling in Neuronal Oscillations: Comparison of Phase-Locking Value, Mean Vector Length, Modulation Index, and Generalized-Linear-Modeling-Cross-Frequency-Coupling.

Phase-amplitude coupling is a promising construct to study cognitive processes in electroencephalography (EEG) and magnetencephalography (MEG). Due to the novelty of the concept, various measures are used in the literature to calculate phase-amplitude coupling. Here, performance of the three most widely used phase-amplitude coupling measures - phase-locking value (PLV), mean vector length (MVL), and modulation index (MI) - and of the generalized linear modeling cross-frequency coupling (GLM-CFC) method is thoroughly compared with the help of simulated data. We combine advantages of previous reviews and use a realistic data simulation, examine moderators and provide inferential statistics for the comparison of all four indices of phase-amplitude coupling. Our analyses show that all four indices successfully differentiate coupling strength and coupling width when monophasic coupling is present. While the MVL was most sensitive to modulations in coupling strengths and width, only the MI and GLM-CFC can detect biphasic coupling. Coupling values of all four indices were influenced by moderators including data length, signal-to-noise-ratio, and sampling rate when approaching Nyquist frequencies. The MI was most robust against confounding influences of these moderators. Based on our analyses, we recommend the MI for noisy and short data epochs with unknown forms of coupling. For high quality and long data epochs with monophasic coupling and a high signal-to-noise ratio, the use of the MVL is recommended. Ideally, both indices are reported simultaneously for one data set.

Modulations of event-related potentials by tactile negative priming.

Negative priming (NP) refers to the finding that responses to previously irrelevant stimuli are impeded relative to responses to new stimuli. To date, NP has been demonstrated in the visual, auditory, and tactile sensory modalities with both inhibitory processes and retrieval-based processes contributing to the effect. To gain deeper insights into the role of both processes, event-related potentials (ERPs) have been measured during NP tasks with visual and separately with auditory stimuli. The specific patterns of ERP correlates are mixed, yet it can generally be concluded from previous research that amplitudes of both the N2 and the P3 reflect important components of NP. We present the first study to assess the ERP correlates of NP in the tactile modality. We observe a significant modulation of the P3 but not of the N2, thus providing tentative support for the existence of modality-specific differences in the ERP correlates of NP.

Emotional stress regulation: The role of relative frontal alpha asymmetry in shaping the stress response.

Frontal EEG asymmetry has been proposed as an index of emotional regulation, reflecting both state and trait components, and there is evidence that these factors influence the cortisol response to stress. Here, we asked whether cold pressor stress modulates frontal asymmetry and whether this is predictive of the neuroendocrine stress response. Twenty-four male participants underwent an automatized bilateral feet cold pressor test (bfCPT) and a warm water control procedure in counterbalanced order on two separate days, one week apart. EEG, heart rate and blood pressure were assessed at baseline as well as during and after the bfCPT. Salivary cortisol and subjective ratings of stress and arousal were assessed before and after the bfCPT. The bfCPT led to a significant increase in cortisol, cardiovascular parameters and in subjective ratings of stress and arousal that was absent in the control condition. Furthermore, analysis of relative frontal alpha-band asymmetry revealed a stronger relative right frontal activation during the bfCPT compared to the control condition at electrode pairs F7/8 but not F3/4. However, frontal asymmetry scores during the bfCPT were not predictive for neither physiological responses nor subjective ratings. Moreover, an association between physiological responses and frontal asymmetry assessed during rest at baseline could be observed at electrode pairs F3/F4, with stronger responses being associated with stronger relative right frontal activation. Our results show that cold pressor stress leads to an alteration of emotional processes as reflected in frontal EEG asymmetry at F7/F8. Moreover, physiological responses to the CPT seem to be differentially moderated by trait and state components present in frontal asymmetry.

Influence of acute stress on response inhibition in healthy men: An ERP study.

The current study investigated the influence of acute stress and the resulting cortisol increase on response inhibition and its underlying cortical processes, using EEG. Before and after an acute stressor or a control condition, 39 healthy men performed a go/no-go task while ERPs (N2, P3), reaction times, errors, and salivary cortisol were measured. Acute stress impaired neither accuracy nor reaction times, but differentially affected the neural correlates of response inhibition; namely, stress led to enhanced amplitudes of the N2 difference waves (N2d, no-go minus go), indicating enhanced response inhibition and conflict monitoring. Moreover, participants responding to the stressor with an acute substantial rise in cortisol (high cortisol responders) showed reduced amplitudes of the P3 of the difference waves (P3d, no-go minus go) after the stressor, indicating an impaired evaluation and finalization of the inhibitory process. Our findings indicate that stress leads to a reallocation of cognitive resources to the neural subprocesses of inhibitory control, strengthening premotor response inhibition and the detection of response conflict, while concurrently diminishing the subsequent finalization process within the stream of processing.

Effects of basal and acute cortisol on cognitive flexibility in an emotional task switching paradigm in men.

The stress hormone cortisol is assumed to influence cognitive functions. While cortisol-induced alterations of declarative memory in particular are well-investigated, considerably less is known about its influence on executive functions. Moreover, most research has been focused on slow effects, and rapid non-genomic effects have not been studied. The present study sought to investigate the impact of acute cortisol administration as well as basal cortisol levels on cognitive flexibility, a core executive function, within the non-genomic time frame. Thirty-eight healthy male participants were randomly assigned to intravenously receive either cortisol or a placebo before performing a task switching paradigm with happy and angry faces as stimuli. Cortisol levels were measured at six points during the experiment. Additionally, before the experiment, basal cortisol measures for the cortisol awakening response were collected on three consecutive weekdays immediately following awakening and 30, 45, and 60min after. First and foremost, results showed a pronounced impact of acute and basal cortisol on reaction time switch costs, particularly for angry faces. In the placebo group, low basal cortisol was associated with minimal switch costs, whereas high basal cortisol was related to maximal switch costs. In contrast, after cortisol injection, basal cortisol levels showed no impact. These results show that cognitive flexibility-enhancing effects of acute cortisol administration are only seen in men with high basal cortisol levels. This result supports the context dependency of cortisol administration and shows the relevance of taking basal cortisol levels into account.

Distractor inhibition: Evidence from lateralized readiness potentials.

The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations.

Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation.

Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior.

Cortisol rapidly affects amplitudes of heartbeat-evoked brain potentials--implications for the contribution of stress to an altered perception of physical sensations?

Little is known about the impact of stress and stress hormones on the processing of visceral-afferent signals. Clinical data suggest that cortisol may lower the threshold for interoceptive stimuli, while a pharmacological administration of cortisol decreases the sensitivity for physical symptoms. To clarify the role of cortisol for the processing of interoceptive signals, we investigated 16 healthy men on two occasions, once during the infusion of 4 mg of cortisol and once during the infusion of a placebo substance. Heartbeat-evoked potentials (HEP; derived from resting EEG and ECG, during open and closed eyes), which are psychophysiological indicators for the cortical processing of cardioceptive signals, were measured over 6-min periods once before, and four times after the infusion (1-7, 11-17, 21-27 and 31-37 min). We found that HEP amplitudes were higher during open than during closed eyes between 1 and 17 min after cortisol infusion. There was no effect of cortisol on heart rate. We conclude that cortisol may rapidly modulate the cortical processing of cardioceptive neural signals. These results may have relevance for the effects of stress on the development and maintenance of psychosomatic symptoms.

Stability of heart rate variability indices reflecting parasympathetic activity.

Heart rate variability (HRV) is a measure of autonomic influences on heart rate that has frequently been used as a transsituationally consistent biomarker for cardiovascular health and emotional or cognitive functions. The psychometric properties of HRV however remain unclear. In the present study, we examined the reliability and temporal stability of parasympathetic HRV measures and estimated the portion of variance explained by transsituationally consistent trait variance and by effects of the situation and person-situation interaction with structural equation modeling. The results show good reliability of indices reflecting central parasympathetic control over heart rate and that about 40% of the variance of a single HRV measurement can be explained by effects of the situation and person-situation interaction. An aggregation across at least two measurements may be recommended when using HRV as a transsituationally consistent biomarker or trait.

Tune it down to live it up? Rapid, nongenomic effects of cortisol on the human brain.

The stress hormone cortisol acts on the brain, supporting adaptation and time-adjusted coping processes. Whereas previous research has focused on slow emerging, genomic effects of cortisol, we addressed the rapid, nongenomic cortisol effects on in vivo neuronal activity in humans. Three independent placebo-controlled studies in healthy men were conducted. We observed changes in CNS activity within 15 min after intravenous administration of a physiological dose of 4 mg of cortisol (hydrocortisone). Two of the studies demonstrated a rapid bilateral thalamic perfusion decrement using continuous arterial spin labeling. The third study revealed rapid, cortisol-induced changes in global signal strength and map dissimilarity of the electroencephalogram. Our data demonstrate that a physiological concentration of cortisol profoundly affects the functioning and perfusion of the human brain in vivo via a rapid, nongenomic mechanism. The changes in neuronal functioning suggest that cortisol acts on the thalamic relay of background as well as on task-specific sensory information, allowing focus and facilitation of adaptation to challenges.

Extraversion and its positive emotional core--further evidence from neuroscience.

Converging evidence from self-report data demonstrated that extraversion and dispositional positive affect are systematically related. Several authors therefore considered positive affect as the conceptual core of extraversion. Because the ventral striatum is regarded as a core region in the physiological basis of extraversion, the present study examines the importance of this neural substrate with a special focus on positive affect. Baseline cerebral blood flow was measured in 38 participants and regressed to the extraversion and dispositional positive affect scales. Partial correlational and indirect-effects analyses indicated that striatal blood flow was no longer associated with extraversion when positive affect was statistically controlled. In contrast, when extraversion was statistically controlled, striatal blood flow was still associated with positive affect. This finding suggests that the striatal region is not a biological basis of extraversion per se. Rather, this region sustains positive affect, which in turn appears to be a core feature of extraversion.

Exogenous cortisol facilitates responses to social threat under high provocation.

Stress is one of the most important promoters of aggression. Human and animal studies have found associations between basal and acute levels of the stress hormone cortisol and (abnormal) aggression. Irrespective of the direction of these changes--i.e., increased or decreased aggressive behavior--the results of these studies suggest dramatic alterations in the processing of threat-related social information. Therefore, the effects of cortisol and provocation on social information processing were addressed by the present study. After a placebo-controlled pharmacological manipulation of acute cortisol levels, we exposed healthy individuals to high or low levels of provocation in a competitive aggression paradigm. Influences of cortisol and provocation on emotional face processing were then investigated with reaction times and event-related potentials (ERPs) in an emotional Stroop task. In line with previous results, enhanced early and later positive, posterior ERP components indicated a provocation-induced enhanced relevance for all kinds of social information. Cortisol, however, reduced an early frontocentral bias for angry faces and--despite the provocation-enhancing relevance--led to faster reactions for all facial expressions in highly provoked participants. The results thus support the moderating role of social information processing in the 'vicious circle of stress and aggression'.

The relationship between basal and acute HPA axis activity and aggressive behavior in adults.

The hypothalamic-pituitary-adrenal (HPA) axis seems to play a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. However, most human research on the role of the HPA axis in aggression has been focusing on highly aggressive children and adolescent clinical samples. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 20 healthy male and female adults. We used the Taylor Aggression Paradigm to induce and measure aggression. We assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Salivary free cortisol measures for the cortisol awakening response were obtained on three consecutive weekdays immediately following awakening and 30, 45, and 60 min after. Half of the subjects were provoked with the Taylor Aggression Paradigm to behave aggressively; the other half was not provoked. Acute HPA axis activity was measured four times, once before and three times after the induction of aggression. Basal cortisol levels were significantly and negatively related to aggressive behavior in the provoked group and explained 67% of the behavioral variance. Cortisol levels following the induction of aggression were significantly higher in the provoked group when baseline levels were taken into account. The data implicate that the HPA axis is not only relevant to the expression of aggressive behavior in clinical groups, but also to a large extent in healthy ones.

Exogenous cortisol enhances aggressive behavior in females, but not in males.

The hypothalamic-pituitary-adrenal (HPA) axis plays a major role in the development, elicitation, and enhancement of aggressive behavior in animals. Increasing evidence suggests that this is also true for humans. Here, we report on a study of the role of basal and acute HPA axis activity in a sample of 48 healthy male and female adults. We pharmacologically enhanced cortisol levels and used the Taylor Aggression Paradigm (TAP) to induce and measure aggression (divided into three blocks). Participants either received an oral dose of 20 mg hydrocortisone (cortisol group) or a placebo (placebo group). Half of each group received high or low levels of provocation with the TAP, respectively. Before, we assessed the cortisol awakening response as a trait measure of basal HPA axis activity. Participants in the cortisol group reacted more aggressively in the third block of the TAP compared to the placebo group. Furthermore, gender interacted with treatment: only females, but not males showed enhanced aggressive behavior after cortisol administration. There was no significant difference in males between the placebo and cortisol group. Basal HPA axis activity was negatively related to aggressive behavior, but again only in females and most strongly within the placebo group. This study provides the first evidence for a causal involvement of acute HPA axis activation in aggressive behavior in humans.

Influence of aggression on information processing in the emotional stroop task--an event-related potential study.

Aggression is a common behavior which has frequently been explained as involving changes in higher level information processing patterns. Although researchers have started only recently to investigate information processing in healthy individuals while engaged in aggressive behavior, the impact of aggression on information processing beyond an aggressive encounter remains unclear. In an event-related potential study, we investigated the processing of facial expressions (happy, angry, fearful, and neutral) in an emotional Stroop task after experimentally provoking aggressive behavior in healthy participants. Compared to a non-provoked group, these individuals showed increased early (P2) and late (P3) positive amplitudes for all facial expressions. For the P2 amplitude, the effect of provocation was greatest for threat-related expressions. Beyond this, a bias for emotional expressions, i.e., slower reaction times to all emotional expressions, was found in provoked participants with a high level of trait anger. These results indicate significant effects of aggression on information processing, which last beyond the aggressive encounter even in healthy participants.

Resting cerebral blood flow, attention, and aging.

Aging is accompanied by a decline of fluid cognitive functions, e.g., a slowing of information processing, working memory, and division of attention. This is at least partly due to structural and functional changes in the aging brain. Although a decrement of resting cerebral blood flow (CBF) has been positively associated with cognitive functions in patients with brain diseases, studies with healthy participants have revealed inconsistent results. Therefore, we investigated the relation between resting cerebral blood flow and cognitive functions (tonic and phasic alertness, selective and divided attention) in two samples of healthy young and older participants. We found higher resting CBF and better cognitive performances in the young than in the older sample. In addition, resting CBF was inversely correlated with selective attention in the young and with tonic alertness in the elderly participants. This finding is discussed with regard to the neural efficiency hypothesis of human intelligence.