Katja Wiech

Neurocognitive aspects of pain perception

The perception of pain is sensitive to various mental processes such as the feelings and beliefs that someone has about pain. It is therefore not exclusively driven by the noxious input. Attentional modulation involving the descending pain modulatory system has been examined extensively in neuroimaging studies. However, the investigation of neural mechanisms underlying more complex cognitive modulation is an emerging field in pain research. Recent findings indicate an engagement of the ventrolateral prefrontal cortex during more complex modulation, leading to a change or reappraisal of the emotional significance of pain. Taking placebo-induced analgesia as an example, we discuss the contribution of attention, expectation and reappraisal as three basic mechanisms that are important for the cognitive modulation of pain.

The Effect of Treatment Expectation on Drug Efficacy: Imaging the Analgesic Benefit of the Opioid Remifentanil

An individual’s expectation that a pain treatment will or will not work can alter both its subjective effectiveness and the pain-related activity in the brain. Gloomy Forecasts Prove True A pessimist walks into a hospital. His grim prediction that doctors will be unable to alleviate his back pain proved correct—after several days of various treatments, his pain persisted. According to new results from Bingel and colleagues, the gloomy outlook this patient brought with him into his pain treatment may have ensured that his prediction was a self-fulfilling prophesy. Using sophisticated brain imaging techniques, the authors show that one’s expectation of the success of a pain treatment can markedly influence its effectiveness. In this new study, healthy people were exposed to pain-provoking heat and also given the painkilling opioid drug remifentanil. In advance of each instance of drug administration, the authors informed the subjects that the drug would have no effect, that it would diminish the sensation of pain, or that it would make the pain worse. When subjects expected the drug to be effective, they were not disappointed—they experienced twice as much pain relief as they did when they expected to obtain no benefit from the drug (but did, in fact, get some relief). In contrast, when they expected remifentanil to make the heat pain worse they found that their pain was unchanged. But these subjective reports could be influenced by a host of variables. What was actually happening within the brains of these individuals to shift their pain perceptions so dramatically? With functional magnetic resonance imaging (fMRI), the authors of Bingel et al. examined brain activity during the experiment. Thermal pain itself causes activation of a so-called pain circuit, which encompasses numerous brain regions including the somatosensory cortex, the cingulate cortex, insula, thalamus, and brainstem. Expectation of increased pain was accompanied by more neural activity in the hippocampus, midcingulate cortex, and medial prefrontal cortex—brain areas that mediate mood and anxiety—than was observed in these regions during expectation of analgesia. Conversely, individuals who expected the drug to mitigate their pain showed increases in the anterior cingulate cortex and the striatum, signs that descending mechanisms of pain inhibition were engaged. These clues about how our beliefs can affect the way we experience medical treatment for pain can improve the practice of medicine. A drug with a true biological effect may appear to be ineffective to a patient conditioned to expect failure, whether the patient is enrolled in a clinical trial or treated in a physician’s office. Patient education about treatments can help counteract this problem by shaping beliefs to maximize drug effectiveness. If appropriate treatments are accompanied by encouraging words, a pessimist could become an optimist about his future robust health, and thereby make it so. Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

The influence of negative emotions on pain: Behavioral effects and neural mechanisms

The idea that pain can lead to feelings of frustration, worry, anxiety and depression seems obvious, particularly if it is of a chronic nature. However, there is also evidence for the reverse causal relationship in which negative mood and emotion can lead to pain or exacerbate it. Here, we review findings from studies on the modulation of pain by experimentally induced mood changes and clinical mood disorders. We discuss possible neural mechanisms underlying this modulatory influence focusing on the periaqueductal grey (PAG), amygdala, anterior cingulate cortex (ACC) and anterior insula as key players in both, pain and affective processing.

Threatening a rubber hand that you feel is yours elicits a cortical anxiety response

The feeling of body ownership is a fundamental aspect of self-consciousness. The underlying neural mechanisms can be studied by using the illusion where a person is made to feel that a rubber hand is his or her own hand by brushing the persons hidden real hand and synchronously brushing the artificial hand that is in full view. Here we show that threat to the rubber hand can induce a similar level of activity in the brain areas associated with anxiety and interoceptive awareness (insula and anterior cingulate cortex) as when the persons real hand is threatened. We further show that the stronger the feeling of ownership of the artificial hand, the stronger the threat-evoked neuronal responses in the areas reflecting anxiety. Furthermore, across subjects, activity in multisensory areas reflecting ownership predicted the activity in the interoceptive system when the hand was under threat. Finally, we show that there is activity in medial wall motor areas, reflecting an urge to withdraw the artificial hand when it is under threat. These findings suggest that artificial limbs can evoke the same feelings as real limbs and provide objective neurophysiological evidence that the rubber hand is fully incorporated into the body. These findings are of fundamental importance because they suggest that the feeling of body ownership is associated with changes in the interoceptive systems.

Prestimulus functional connectivity determines pain perception in humans.

Pain is a highly subjective experience that can be substantially influenced by differences in individual susceptibility as well as personality. How susceptibility to pain and personality translate to brain activity is largely unknown. Here, we report that the functional connectivity of two key brain areas before a sensory event reflects the susceptibility to a subsequent noxious stimulus being perceived as painful. Specifically, the prestimulus connectivity among brain areas related to the subjective perception of the body and to the modulation of pain (anterior insular cortex and brainstem, respectively) determines whether a noxious event is perceived as painful. Further, these effects of prestimulus connectivity on pain perception covary with pain-relevant personality traits. More anxious and pain-attentive individuals display weaker descending connectivity to pain modulatory brain areas. We conclude that variations in functional connectivity underlie personality-related differences in individual susceptibility to pain.

Anticipatory brainstem activity predicts neural processing of pain in humans.

Abstract Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

Tactile discrimination, but not tactile stimulation alone, reduces chronic limb pain

&NA; Chronic pain is often associated with reduced tactile acuity. A relationship exists between pain intensity, tactile acuity and cortical reorganisation. When pain resolves, tactile function improves and cortical organisation normalises. Tactile acuity can be improved in healthy controls when tactile stimulation is associated with a behavioural objective. We hypothesised that, in patients with chronic limb pain and decreased tactile acuity, discriminating between tactile stimuli would decrease pain and increase tactile acuity, but tactile stimulation alone would not. Thirteen patients with complex regional pain syndrome (CRPS) of one limb underwent a waiting period and then ∼2 weeks of tactile stimulation under two conditions: stimulation alone or discrimination between stimuli according to their diameter and location. There was no change in pain (100 mm VAS) or two‐point discrimination (TPD) during a no‐treatment waiting period, nor during the stimulation phase (p > 0.32 for both). Pain and TPD were lower after the discrimination phase [mean (95% CI) effect size for pain VAS = 27 mm (14–40 mm) and for TPD = 5.7 mm (2.9–8.5 mm), p < 0.015 for both]. These gains were maintained at three‐month follow‐up. We conclude that tactile stimulation can decrease pain and increase tactile acuity when patients are required to discriminate between the type and location of tactile stimuli.

The effect of tactile discrimination training is enhanced when patients watch the reflected image of their unaffected limb during training

ABSTRACT In patients with phantom limb pain or complex regional pain syndrome (CRPS), sensory discrimination training increases tactile acuity, normalises cortical reorganisation and decreases pain. In healthy people, sensory cortical response, and tactile acuity, are greater if the participant looks towards the body part being stimulated. Does this effect enhance tactile training in CRPS patients? Ten patients underwent a 30‐min tactile discrimination training session under four conditions (order randomised) in a 2 × 2 design: looking towards or away from the stimulated limb and seeing or not seeing skin. Tactile training imparted long‐term improvement in tactile acuity when patients watched the reflected image of their unaffected limb in a mirror during training (that is, they looked towards the stimulated body part and could see the skin of the opposite body part in the mirror): two‐point discrimination threshold (TPD) was 8 mm less 2 days after training than it was before training ([95% CI = 1.5–14.3 mm], p < 0.001). Although this condition also imparted a greater reduction in resting pain at post‐treatment than the other conditions, and change in pain and change in TPD over the session were strongly related (r = 0.83, p < 0.001), there was no residual effect on pain at 2‐day follow‐up. In the other conditions, tactile acuity had returned to pre‐training levels at 2‐day follow‐up. The results should directly improve management of CRPS, and have implications for rehabilitation of other conditions associated with nervous system injury or disease, for example stroke, in which tactile recovery is a major objective of rehabilitation.

Modulation of pain processing in hyperalgesia by cognitive demand

The relationship between pain and cognitive function is of theoretical and clinical interest, exemplified by observations that attention-demanding activities reduce pain in chronically afflicted patients. Previous studies have concentrated on phasic pain, which bears little correspondence to clinical pain conditions. Indeed, phasic pain is often associated with differential or opposing effects to tonic pain in behavioral, lesion, and pharmacological studies. To address how cognitive engagement interacts with tonic pain, we assessed the influence of an attention-demanding cognitive task on pain-evoked neural responses in an experimental model of chronic pain, the capsaicin-induced heat hyperalgesia model. Using functional magnetic resonance imaging (fMRI), we show that activity in the orbitofrontal and medial prefrontal cortices, insula, and cerebellum correlates with the intensity of tonic pain. This pain-related activity in medial prefrontal cortex and cerebellum was modulated by the demand level of the cognitive task. Our findings highlight a role for these structures in the integration of motivational and cognitive functions associated with a physiological state of injury. Within the limitations of an experimental model of pain, we suggest that the findings are relevant to understanding both the neurobiology and pathophysiology of chronic pain and its amelioration by cognitive strategies.

Decoding the perception of pain from fMRI using multivariate pattern analysis

Pain is known to comprise sensory, cognitive, and affective aspects. Despite numerous previous fMRI studies, however, it remains open which spatial distribution of activity is sufficient to encode whether a stimulus is perceived as painful or not. In this study, we analyzed fMRI data from a perceptual decision-making task in which participants were exposed to near-threshold laser pulses. Using multivariate analyses on different spatial scales, we investigated the predictive capacity of fMRI data for decoding whether a stimulus had been perceived as painful. Our analysis yielded a rank order of brain regions: during pain anticipation, activity in the periaqueductal gray (PAG) and orbitofrontal cortex (OFC) afforded the most accurate trial-by-trial discrimination between painful and non-painful experiences; whereas during the actual stimulation, primary and secondary somatosensory cortex, anterior insula, dorsolateral and ventrolateral prefrontal cortex, and OFC were most discriminative. The most accurate prediction of pain perception from the stimulation period, however, was enabled by the combined activity in pain regions commonly referred to as the ‘pain matrix’. Our results demonstrate that the neural representation of (near-threshold) pain is spatially distributed and can be best described at an intermediate spatial scale. In addition to its utility in establishing structure-function mappings, our approach affords trial-by-trial predictions and thus represents a step towards the goal of establishing an objective neuronal marker of pain perception.