The Hope and Reality of Pain Relief Using Psychological Manipulations.

ABSTRACT: Many patients suffer from chronic pain despite the absence of injury or sufficient biomedical disease to explain their pain. These pains are highly resistant to treatment. Psychological therapies designed to help patients undermine the negative thought and behavioral patterns that maintain pain provide only modest pain relief, leading to suspicion that such pain might be maintained by unconscious processes. An article in this issue of Psychosomatic Medicine provides the first experimental evidence that unconscious negative memories can increase pain unpleasantness. These findings are exciting, but the effect sizes are small, which is consistent with the small effects of psychological therapy. It seems that pain stubbornly resists psychological manipulation, but this work provides some hope that psychological therapy for pain can be improved to provide more effective pain relief.

Stepwise increasing sequential offsets cannot be used to deliver high thermal intensities with little or no perception of pain.

Offset analgesia (OA) is the disproportionate decrease in pain experience following a slight decrease in noxious heat stimulus intensity. We tested whether sequential offsets would allow noxious temperatures to be reached with little or no perception of pain. Forty-eight participants continuously rated their pain experience during trials containing trains of heat stimuli delivered by Peltier thermode. Stimuli were adjusted through either stepwise sequential increases of 2°C and decreases of 1°C or direct step increases of 1°C up to a maximum of 46°C. Step durations (1, 2, 3, or 6 s) varied by trial. Pain ratings generally followed presented temperature, regardless of step condition or duration. For 6-s steps, OA was observed after each decrease, but the overall pain trajectory was unchanged. We found no evidence that sequential offsets could allow for little pain perception during noxious temperature presentation.NEW & NOTEWORTHY Offset analgesia is the disproportionate decrease in pain experience following a slight decrease in noxious heat stimulus intensity. We tested whether sequential offsets would allow noxious temperatures to be reached with little or no perception of pain. We found little evidence of such overall analgesia. In contrast, we observed analgesic effects after each offset with long-duration stimuli, even with relatively low-temperature noxious stimuli.

Suggestions to Reduce Clinical Fibromyalgia Pain and Experimentally Induced Pain Produce Parallel Effects on Perceived Pain but Divergent Functional MRI-Based Brain Activity.

OBJECTIVE: Hypnotic suggestion is an empirically validated form of pain control; however, the underlying mechanism remains unclear. METHODS: Thirteen fibromyalgia patients received suggestions to alter their clinical pain, and 15 healthy controls received suggestions to alter experimental heat pain. Suggestions were delivered before and after hypnotic induction with blood oxygen level-dependent (BOLD) activity measured concurrently. RESULTS: Across groups, suggestion produced substantial changes in pain report (main effect of suggestion, F2, 312 = 585.8; p < .0001), with marginally larger changes after induction (main effect of induction, F1, 312 = 3.6; p = .060). In patients, BOLD response increased with pain report in regions previously associated with pain, including thalamus and anterior cingulate cortex. In controls, BOLD response decreased with pain report. All changes were greater after induction. Region-of-interest analysis revealed largely linear patient responses with increasing pain report. Control responses, however, were higher after suggestion to increase or decrease pain from baseline. CONCLUSIONS: Based on behavioral report alone, the mechanism of suggestion could be interpreted as largely similar regardless of the induction or type of pain experience. The functional magnetic resonance imaging data, however, demonstrated larger changes in brain activity after induction and a radically different pattern of brain activity for clinical pain compared with experimental pain. These findings imply that induction has an important effect on underlying neural activity mediating the effects of suggestion, and the mechanism of suggestion in patients altering clinical pain differs from that in controls altering experimental pain. Patient responses imply that suggestions altered pain experience via corresponding changes in pain-related brain regions, whereas control responses imply suggestion engaged cognitive control.

The use of neuroimaging to advance the understanding of chronic pain: from description to mechanism.

Functional imaging has comprehensively demonstrated that pain involves a number of cortical regions that are often collectively referred to as the pain neuromatrix. This neuromatrix is assumed to be necessary to process the sensory, affective, and cognitive components of pain. Patients who report pain in the apparent absence of injury or disease may experience their symptoms because of dysfunction in one or more components of the pain neuromatrix. Two articles in this edition of Psychosomatic Medicine explore that possibility and provide evidence of altered neural connectivity and activation within components of the pain neuromatrix in patients with low back pain and irritable bowel syndrome. Questions remain as to how best to transition from describing the neural correlates of disease to understanding mechanisms and providing treatments.

Intrinsic variability in the human response to pain is assembled from multiple, dynamic brain processes.

The stimulus-evoked response is the principle measure used to elucidate the timing and spatial location of human brain activity. Brain and behavioural responses to pain are influenced by multiple intrinsic and extrinsic factors and display considerable, natural trial-by-trial variability. However, because the neuronal sources of this variability are poorly understood the functional information it contains is under-exploited for understanding the relationship between brain function and behaviour. We recorded simultaneous EEG-fMRI during rest and noxious thermal stimulation to characterise the relationship between natural fluctuations in behavioural pain-ratings, the spatiotemporal dynamics of brain network responses and intrinsic connectivity. We demonstrate that fMRI response variability in the pain network is: dependent upon its resting-state functional connectivity; modulated by behaviour; and correlated with EEG evoked-potential amplitude. The pre-stimulus default-mode network (DMN) fMRI signal predicts the subsequent magnitude of pain ratings, evoked-potentials and pain network BOLD responses. Additionally, the power of the ongoing EEG alpha oscillation, an index of cortical excitability, modulates the DMN fMRI response to pain. The complex interaction between alpha-power, DMN activity and both the behavioural report of pain and the brain's response to pain demonstrates the neurobiological significance of trial-by-trial variability. Furthermore, we show that multiple, interconnected factors contribute to both the brain's response to stimulation and the psychophysiological emergence of the subjective experience of pain.

Biases in children's and adults' moral judgments.

Two experiments examined biases in children's (5/6- and 7/8-year-olds) and adults' moral judgments. Participants at all ages judged that it was worse to produce harm when harm occurred (a) through action rather than inaction (omission bias), (b) when physical contact with the victim was involved (physical contact principle), and (c) when the harm was produced as a direct means to an end rather than as an unintended but foreseeable side effect of the action (intention principle). The youngest participants, however, did not incorporate benefit when making judgments about situations in which harm to one individual resulted in benefit to five individuals. Older participants showed some preference for benefit resulting from action (commission) as opposed to inaction (omission). The findings are discussed in the context of the theory that moral judgments result, in part, from the operation of an inherent, intuitive moral faculty compared with the theory that moral judgments require development of necessary cognitive abilities.

Offset analgesia is reduced on the palm and increases with stimulus duration.

BACKGROUND: A noxious stimulus following a more intense stimulus often feels less painful than continuous noxious stimulation. This effect, known as offset analgesia (OA), may be due to descending inhibitory control, to changes in peripheral neural transmission or both. The timing and location of noxious thermal stimulation were manipulated to better understand the peripheral and central contributions to OA. METHODS: In a first experiment, participants (n = 29) provided continuous pain ratings as stimuli were delivered to the palm or dorsum of each hand. Offset trials included 44°C (T1), 45°C (T2) and 44°C (T3) stimulation periods. Baseline trials were identical except the T3 temperature fell to 35°C. Constant trials were 44°C throughout. The duration of T1 and T2 was either 1 s or 6 s, whereas T3 was always 12 s. In a second experiment, participants (n = 43) rated pain levels of noxious stimuli presented to the forearms with varying T1 and T2 durations (3, 6, 10 or 13 s) and a 20 s T3 period. RESULTS: OA effects became stronger with increasing inducing durations. OA, however, was not found on the palm even at longer durations. CONCLUSIONS: The increase in OA with duration suggests that accumulated nociceptive signalling is more important to triggering OA than is a decrease in nociceptors' instantaneous firing rates. The lack of OA on the palm, however, implies a key role for the rapidly adapting Type II AMH fibres that may be absent or not readily activated on the palm. Unravelling the relative central and peripheral contribution to OA requires further investigation. SIGNIFICANCE: Offset analgesia (OA) is a fundamentally temporal phenomenon dependent on dynamic changes in stimulus intensity. Here we demonstrate increased OA with increased stimulus duration. This finding implies the more slowly-responding AMH-I peripheral mechanoreceptors contribute to OA. The more rapidly responding AMH-II peripheral mechanoreceptors, however, may be absent or more difficult to activate in the palm where we did not observe OA. This finding implies that the AMH-II receptors are necessary for OA. Our studies suggest methods to unravel the different peripheral and central contributions to OA.

The rebirth of neuroscience in psychosomatic medicine, Part II: clinical applications and implications for research.

During the second half of the last century, biopsychosocial research in psychosomatic medicine largely ignored the brain. Neuroscience has started to make a comeback in psychosomatic medicine research and promises to advance the field in important ways. In this paper we briefly review select brain imaging research findings in psychosomatic medicine in four key areas: cardiovascular regulation, visceral pain in the context of functional gastrointestinal disorders, acute and chronic somatic pain and placebo. In each area, there is a growing literature that is beginning to define a network of brain areas that participate in the functions in question. Evidence to date suggests that cortical and subcortical areas that are involved in emotion and emotion regulation play an important role in each domain. Neuroscientific research is therefore validating findings from previous psychosomatic research and has the potential to extend knowledge by delineating the biological mechanisms that link mind and body more completely and with greater specificity. We conclude with a discussion of the implications of this work for how research in psychosomatic medicine is conducted, the ways in which neuroscientific advances can lead to new clinical applications in psychosomatic contexts, the implications of this work for the field of medicine more generally, and the priorities for research in the next 5 to 10 years.

Fetal pain: do we know enough to do the right thing?

Raising the possibility of fetal pain continues as a tactic to undermine support for abortion in the US and the UK. This paper examines anatomical and psychological developments in the fetus to assess the possibility of fetal pain. Neurobiological features that develop at 7, 18 and 26 weeks gestation suggest an experience of pain in utero. Pain, however, cannot be inferred from these features because they are not informative about the state of consciousness of the fetus and cannot account for the content of any presumed pain experience. We may be confident the fetus does not experience pain because unique in utero neuroinhibitors and a lack of psychological development maintain unconsciousness and prevent conscious pain experience. Before an infant can experience sensations and emotions, the elements of experience must have their own independent existence in the infant's mind. This is achieved after birth through discoveries made in action and in patterns of adjustment and interaction with a caregiver. Recommendations about anaesthetic practice with the fetus and the newborn or young infant should not focus on pain but on outcomes with obvious, and measurable, importance. In the case of an unwanted pregnancy, the health of the woman should guide anaesthetic practice. In the case of a wanted pregnancy, the survival and long-term health of both the woman and fetus should guide anaesthetic practice. In any case, current evidence does not support efforts to inform women of the potential for fetal pain. Any policy to mitigate fetal pain could expose women to inappropriate intervention, risk and distress.

Modeling pain circuits: how imaging may modify perception.

Pain is the unpleasant sensory experience following tissue damage or the threat of damage. The activation of cortical regions during noxious stimulation is believed a result of the negative affect and sensations generated by the stimulus. How a noxious event is translated into pain experience remains uncertain, and pain that occurs in the absence of a noxious event remains mysterious. Acute pain and chronic pain depend on a categorization of feeling that occurs collectively rather than individually. Capturing that process inside a brain scan is problematic. Resolving this problem requires an approach to imaging that transgress the boundaries of physical and social concepts.

Measuring our natural painkiller.

Studies of the brain during noxious experience converge on the anterior cingulate cortex as a key region in the processing of pain. A recent exciting study extends this understanding to include the anterior cingulate as a center for endogenous opioid activation specific to negative pain affect.

'Imagined guilt' vs 'recollected guilt': implications for fMRI.

Guilt is thought to maintain social harmony by motivating reparation. This study compared two methodologies commonly used to identify the neural correlates of guilt. The first, imagined guilt, requires participants to read hypothetical scenarios and then imagine themselves as the protagonist. The second, recollected guilt, requires participants to reflect on times they personally experienced guilt. In the fMRI scanner, participants were presented with guilt/neutral memories and guilt/neutral hypothetical scenarios. Contrasts confirmed a priori predictions that guilt memories, relative to guilt scenarios, were associated with significantly greater activity in regions associated with affect [anterior cingulate cortex (ACC), Caudate, Insula, orbital frontal cortex (OFC)] and social cognition [temporal pole (TP), precuneus). Similarly, results indicated that guilt memories, relative to neutral memories, were also associated with greater activity in affective (ACC, amygdala, Insula, OFC) and social cognition (mPFC, TP, precuneus, temporo-parietal junction) regions. There were no significant differences between guilt hypothetical scenarios and neutral hypothetical scenarios in either affective or social cognition regions. The importance of distinguishing between different guilt inductions inside the scanner is discussed. We offer explanations of our results and discuss ideas for future research.

When Pain Brings Gain: Soccer Players Behavior and Admissions Suggest Feigning Injury to Maintain a Favorable Scoreline.

The rules of soccer dictate that play, once halted, cannot continue if a player is injured. Players may take advantage of this rule by feigning injury to preserve beneficial match positions. Thirty Euro 2008 matches, 90 Premier League matches and 63 World Cup 2010 matches were reviewed for the timing and severity of injuries. The number of injuries was compared between teams that benefited from stopping the game and those that did not benefit. The number of low-level injuries, not resulting in substitution or subsequent problems, was directly compared for Benefit and Non-Benefit teams for each 15-min period following kick off. Statistical significance was assessed using appropriate non-parametric tests. In addition, seven current players and three managers were interviewed and were asked about feigning injury. Teams that benefited from game stoppages suffered significantly more minor injuries in the last 15 min of matches compared with those that did not benefit. Four of the players directly admitted feigning injury. When it is beneficial, soccer players can and do successfully feign injury to stop the game. Consequently it is possible that others might also successfully feign injury, pain or disease when motivated to do so.

Distinct BOLD fMRI Responses of Capsaicin-Induced Thermal Sensation Reveal Pain-Related Brain Activation in Nonhuman Primates.

BACKGROUND: Approximately 20% of the adult population suffer from chronic pain that is not adequately treated by current therapies, highlighting a great need for improved treatment options. To develop effective analgesics, experimental human and animal models of pain are critical. Topically/intra-dermally applied capsaicin induces hyperalgesia and allodynia to thermal and tactile stimuli that mimics chronic pain and is a useful translation from preclinical research to clinical investigation. Many behavioral and self-report studies of pain have exploited the use of the capsaicin pain model, but objective biomarker correlates of the capsaicin augmented nociceptive response in nonhuman primates remains to be explored. METHODOLOGY: Here we establish an aversive capsaicin-induced fMRI model using non-noxious heat stimuli in Cynomolgus monkeys (n = 8). BOLD fMRI data were collected during thermal challenge (ON:20 s/42°C; OFF:40 s/35°C, 4-cycle) at baseline and 30 min post-capsaicin (0.1 mg, topical, forearm) application. Tail withdrawal behavioral studies were also conducted in the same animals using 42°C or 48°C water bath pre- and post- capsaicin application (0.1 mg, subcutaneous, tail). PRINCIPAL FINDINGS: Group comparisons between pre- and post-capsaicin application revealed significant BOLD signal increases in brain regions associated with the 'pain matrix', including somatosensory, frontal, and cingulate cortices, as well as the cerebellum (paired t-test, p<0.02, n = 8), while no significant change was found after the vehicle application. The tail withdrawal behavioral study demonstrated a significant main effect of temperature and a trend towards capsaicin induced reduction of latency at both temperatures. CONCLUSIONS: These findings provide insights into the specific brain regions involved with aversive, 'pain-like', responses in a nonhuman primate model. Future studies may employ both behavioral and fMRI measures as translational biomarkers to gain deeper understanding of pain processing and evaluate the preclinical efficacy of novel analgesics.

Are mirror-sensations really synesthetic?

Mirror-sensations, including touch and pain, are often referred to as synesthetic. The term can be challenged, however, because mirror-sensations lack the incongruency and saliency of synesthesia, may involve problems of perspective rather than entangled sensations, and may be easier to generate with suggestion. If mirror-sensations are truly sensations then they might be expected to act like the true sensation and mirror-pain, for example, might inhibit pain at a distance or itch in the same location. These predictions are highly testable.

Caudal cingulate cortex involvement in pain processing: an inter-individual laser evoked potential source localisation study using realistic head models.

Electrophysiological studies have revealed a source of laser pain evoked potentials (LEPs) in cingulate cortex. However, few studies have used realistically shaped head models in the source analysis, which account for individual differences in anatomy and allow detailed anatomical localisation of sources. The aim of the current study was to accurately localise the cingulate source of LEPs in a group of healthy volunteers, using realistic head models, and to assess the inter-individual variability in anatomical location. LEPs, elicited by painful CO(2) laser stimulation of the right forearm, were recorded from 62 electrodes in five healthy subjects. Dipole source localisation (CURRY 4.0) was performed on the most prominent (P2) peak of each LEP data set, using head models derived from each subject's structural magnetic resonance image (MRI).For all subjects, the P2 LEP peak was best explained by a dipole whose origin was in cingulate cortex (mean residual variance was 3.9+/-2.4 %). For four out of five subjects, it was located at the border of the caudal division of left anterior cingulate cortex (area 24/32') with left posterior cingulate cortex (area 23/31). For the fifth subject the dipole was centred in right posterior cingulate cortex (area 31). This study demonstrates that the location of the cingulate source of LEPs is highly consistent across subjects, when analysed in this way, and supports the involvement of caudal cingulate regions in pain processing.

Pain processing during three levels of noxious stimulation produces differential patterns of central activity.

Previous functional imaging studies have demonstrated a number of discrete brain structures that increase activity with noxious stimulation. Of the commonly identified central structures, only the anterior cingulate cortex shows a consistent response during the experience of pain. The insula and thalamus demonstrate reasonable consistency while all other regions, including the lentiform nucleus, somatosensory cortex and prefrontal cortex, are active in no more than half the current studies. The reason for such discrepancy is likely to be due in part to methodological variability and in part to individual variability. One aspect of the methodology which is likely to contribute is the stimulus intensity. Studies vary considerably regarding the intensity of the noxious and non-noxious stimuli delivered. This is likely to produce varying activation of central structures coding for the intensity, affective and cognitive components of pain. Using twelve healthy volunteers and positron emission tomography (PET), the regional cerebral blood flow (rCBF) responses to four intensities of stimulation were recorded. The stimulation was delivered by a CO2 laser and was described subjectively as either warm (not painful), pain threshold just painful), mildly painful or moderately painful. The following group subtractions were made to examine the changing cerebral responses as the stimulus intensity increased: (1) just painful - warm; (2) mild pain - warm; and (3) moderate pain - warm. In addition, rCBF changes were correlated with the subjective stimulus ratings. The results for comparison '1' indicated activity in the contralateral prefrontal (area 10/46/44), bilateral inferior parietal (area 40) and ipsilateral premotor cortices (area 6), possibly reflecting initial orientation and plans for movement. The latter comparisons and correlation analysis indicated a wide range of active regions including bilateral prefrontal, inferior parietal and premotor cortices and thalamic responses, contralateral hippocampus, insula and primary somatosensory cortex and ipsilateral perigenual cingulate cortex (area 24) and medial frontal cortex (area 32). Decreased rCBF was observed in the amygdala region. These responses were interpreted with respect to their contribution to the multidimensional aspects of pain including fear avoidance, affect, sensation and motivation or motor initiation. It is suggested that future studies examine the precise roles of each particular region during the central processing of pain.

Gender differences in patterns of cerebral activation during equal experience of painful laser stimulation.

A previous functional imaging study demonstrated greater female response in the anterior insula and thalamus and left prefrontal activation in men and right prefrontal activation in women during equal heat intensity but unequal pain experience. For the current study, subjective intensities of noxious heat delivered to the back of the right hand were equalized across subjects, and regional cerebral blood flow was recorded by using positron emission tomography. The female subjects required less laser energy before reporting pain, but the difference was not significant. Correlation of regional cerebral blood flow with subjective pain experience in the whole group showed significant bilateral responses in the parietal, lateral premotor, prefrontal, secondary somatosensory, anterior cingulate and insula cortices, as well as the thalamus. There was significantly greater activation in the left, contralateral, prefrontal, primary and secondary somatosensory, parietal, and insula cortices in the male subjects compared with the female subjects and greater response in the perigenual cingulate cortex in the female subjects. Our study is the first to associate consistent pain experience with gender differences in central response. These differences may relate to differential processing of acute pain with implications for clinical disorders that show a female dominance. The subtle behavioral differences and inconsistent findings across studies, however, suggest the need for caution and further experimentation before speculating further.

Visceral afferent pathways and functional brain imaging.

The application of functional imaging to study painful sensations has generated considerable interest regarding insight into brain dysfunction that may be responsible for functional pain such as that suffered in patients with irritable bowel syndrome (IBS). This review provides a brief introduction to the development of brain science as it relates to pain processing and a snapshot of recent functional imaging results with somatic and visceral pain. Particular emphasis is placed on current hypotheses regarding dysfunction of the brain-gut axis in IBS patients. There are clear and interpretable differences in brain activation following somatic as compared with visceral noxious sensation. Noxious visceral distension, particularly of the lower gastrointestinal tract, activates regions associated with unpleasant affect and autonomic responses. Noxious somatic sensation, in contrast, activates regions associated with cognition and skeletomotor responses. Differences between IBS patients and control subjects, however, were far less clear and interpretable. While this is in part due to the newness of this field, it also reflects weaknesses inherent within the current understanding of IBS. Future use of functional imaging to examine IBS and other functional disorders will be more likely to succeed by describing clear theoretical and clinical endpoints.

Feeling the pain of others is associated with self-other confusion and prior pain experience.

Some chronic pain patients and healthy individuals experience pain when observing injury or others in pain. To further understand shared pain, we investigated perspective taking, bodily ownership and tooth pain sensitivity. First, participants who reported shared pain (responders) and those who did not (non-responders) viewed an avatar on a screen. Intermittently, 0-3 circles appeared. Sometimes the participant's and avatar's perspective were consistent, both directly viewed the same circles, and sometimes inconsistent, both directly viewed different circles. Responders were faster than non-responders to identify the number of circles when adopting a consistent perspective. Second, participants sat with their left hand hidden while viewing a rubber hand. All participants reported an illusory sensation of feeling stroking in the rubber hand and a sense of ownership of the rubber hand during synchronous stroking of the rubber and hidden hand. The responders also reported feeling the stroking and a sense of ownership of the rubber hand during asynchronous stroking. For experiment three, participants with either low, moderate, or high tooth sensitivity observed a series of images depicting someone eating an ice-popsicle. Low sensitivity participants never reported pain. In contrast, moderate and high sensitivity participants reported pain in response to an image depicting someone eating an ice popsicle (4 and 19% of the time, respectively) and depicting someone eating an ice-popsicle and expressing pain (23 and 40%, respectively). In summary, responders have reduced ability to distinguish their own and others' visual perspective and enhanced ability to integrate a foreign arm into their bodily representation. The tendency to share pain is also enhanced when an observed pain is commonly experienced by the observer. Shared pain may therefore involve reactivation of pain memories or pain schema that are readily integrated into a self perspective and bodily representation.