Quality discrimination for noxious stimuli in secondary somatosensory cortex: A MEG‐study

A complex cortical network is believed to encode the multi‐dimensionality of the human pain experience. In the present study, we used magnetoencephalography (MEG) to examine whether the cortical processing of noxious stimuli with different psychophysical properties differs in primary (S1) and secondary (S2) somatosensory cortices. Noxious low (condition 1) and high (condition 2) current density stimulations of equal stimulus intensities were applied at the left forearm in 12 subjects in a randomised order. Concomitantly, subjects had to evaluate the corresponding sensory‐discriminative and affective‐motivational pain dimensions. MEG revealed an increased activation of bilateral secondary somatosensory cortices (S2) during condition 2 compared to condition 1. Higher activations of bilateral S2 were significantly correlated with higher scores for the sensory‐discriminative component during condition 2. In contrast, corresponding scores for the affective‐motivational pain dimension did not differ between both conditions. Therefore, concerning the sensory dimension of the human pain experience we conclude that the S2 cortex is involved in the encoding of quality discrimination.     

Role of primary somatosensory cortex in the coding of pain

The intensity and submodality of pain are widely attributed to stimulus encoding by peripheral and subcortical spinal/trigeminal portions of the somatosensory nervous system. Consistent with this interpretation are studies of surgically anesthetized animals, demonstrating that relationships between nociceptive stimulation and activation of neurons are similar at subcortical levels of somatosensory projection and within the primary somatosensory cortex (in cytoarchitectural areas 3b and 1 of somatosensory cortex, SI). Such findings have led to characterizations of SI as a network that preserves, rather than transforms, the excitatory drive it receives from subcortical levels. Inconsistent with this perspective are images and neurophysiological recordings of SI neurons in lightly anesthetized primates. These studies demonstrate that an extreme anterior position within SI (area 3a) receives input originating predominantly from unmyelinated nociceptors, distinguishing it from posterior SI (areas 3b and 1), long recognized as receiving input predominantly from myelinated afferents, including nociceptors. Of particular importance, interactions between these subregions during maintained nociceptive stimulation are accompanied by an altered SI response to myelinated and unmyelinated nociceptors. A revised view of pain coding within SI cortex is discussed, and potentially significant clinical implications are emphasized.     

Perceiving pain in others: validation of a dual processing model

Accurate perception of another person’s painful distress would appear to be accomplished through sensitivity to both automatic (unintentional, reflexive) and controlled (intentional, purposive) behavioural expression. We examined whether observers would construe diverse behavioural cues as falling within these domains, consistent with cognitive neuroscience findings describing activation of both automatic and controlled neuroregulatory processes. Using online survey methodology, 308 research participants rated behavioural cues as “goal directed vs. non-goal directed,” “conscious vs. unconscious,” “uncontrolled vs. controlled,” “fast vs. slow,” “intentional (deliberate) vs. unintentional,” “stimulus driven (obligatory) vs. self driven,” and “requiring contemplation vs. not requiring contemplation.” The behavioural cues were the 39 items provided by the PROMIS pain behaviour bank [27], constructed to be representative of the diverse possibilities for pain expression. Inter-item correlations among rating scales provided evidence of sufficient internal consistency justifying a single score on an automatic/controlled dimension (excluding the inconsistent fast vs. slow scale). An initial exploratory factor analysis on 151 participant data sets yielded factors consistent with “controlled” and “automatic” actions, as well as behaviours characterized as “ambiguous.” A confirmatory factor analysis using the remaining 151 data sets replicated EFA findings, supporting theoretical predictions that observers would distinguish immediate, reflexive, and spontaneous reactions (primarily facial expression and paralinguistic features of speech) from purposeful and controlled expression (verbal behaviour, instrumental behaviour requiring ongoing, integrated responses). There are implicit dispositions to organize cues signaling pain in others into the well-defined categories predicted by dual process theory.     

The effects of prior pain experience on neural correlates of empathy for pain: An fMRI study

Neuroimaging studies have revealed partially shared neural substrates for both the actual experience of pain and empathy elicited by the pain of others. We examined whether prior pain exposure increased neural activity in the anterior midcingulate cortex (aMCC) and bilateral anterior insula (AI) as a correlate of empathy for pain. Participants (N = 64: 32 women, 32 men) viewed pictures displaying exposure to pressure pain (pain pictures) and pictures without any cue of pain (neutral pictures). Prior to the experiment, half of the participants were exposed to the same pain stimulus as the one seen in the pain pictures (pain exposure condition); the other half had no such experience (touch exposure condition). A balanced sex ratio was kept, to investigate possible sex differences. In the region-of-interest analyses, participants of the pain exposure condition showed decreased activity in the right AI and the aMCC relative to participants of the touch exposure condition. While in men, no differences were found in relation to their exposure condition, women with pain exposure showed decreased activity in the aMCC and additionally, in bilateral AI. Based on the entire sample, whole brain analyses revealed stronger activation in the retrosplenial cortex, dorsomedial prefrontal cortex, and medial prefrontal cortex in the pain exposure condition. In conclusion, prior pain exposure did not increase, but decreased activity in regions regularly associated with empathy for pain. However, pain experience increased activity in regions associated with memory retrieval, perspective taking, and top-down emotion regulation, which might facilitate empathizing with others.     

A regression analysis study of the primary somatosensory cortex during pain

Several functional imaging studies of pain, using a number of different experimental paradigms and a variety of reference states, have failed to detect activations in the somatosensory cortices, while other imaging studies of pain have reported significant activations in these regions. The role of the somatosensory areas in pain processing has therefore been debated. In the present study the left hand was immersed in painfully cold water (standard cold pressor test) and in nonpainfully cold water during 2 min, and PET-scans were obtained either during the first or the second minute of stimulation. We observed no significant increase of activity in the somatosensory regions when the painful conditions were directly compared with the control conditions. In order to better understand the role of the primary somatosensory cortex (S1) in pain processing we used a regression analysis to study the relation between a ROI (region of interest) in the somatotopic S1-area for the stimulated hand and other regions known to be involved in pain processing. We hypothesized that although no increased activity was observed in the S1 during pain, this region would change its covariation pattern during noxious input as compared to the control stimulation if it is involved in or affected by the processing of pain. In the nonpainful cold conditions widespread regions of the ipsilateral and contralateral somatosensory cortex showed a positive covariation with the activity in the S1-ROI. However, during the first and second minute of pain this regression was significantly attenuated. During the second minute of painful stimulation there was a significant positive covariation between the activity in the S1-ROI and the other regions that are known to be involved in pain processing. Importantly, this relation was significantly stronger for the insula and the orbitofrontal cortex bilaterally when compared to the nonpainful state. The results indicate that the S1-cortex may be engaged in or affected by the processing of pain although no differential activity is observed when pain is compared with the reference condition.     

Empathy hurts: compassion for another increases both sensory and affective components of pain perception

Recent studies demonstrate that some brain structures activated by pain are also engaged when an individual observes someone else in pain, and that these empathy-related responses are modulated as a function of the affective link between the empath and the individual in pain. In this study we test the hypothesis that empathy-evoked activation in the pain network leads to heightened pain perception. After inducing in half of our subjects a state of high empathy for an actor and in the other half a state of low empathy towards him, we measured the sensitivity to heat stimuli of various intensities in healthy participants while they watched the actor being exposed to similar stimuli. Participants in the “high-empathy” group rated painful (but not non-painful) stimuli applied to themselves as more intense and unpleasant than did those in the “low-empathy” group. Positive correlations between state empathy scores and pain ratings further suggest that this perceptual phenomenon depends on the magnitude of empathic response induced in the participants. The effects were observed when subjects watched the model receiving either neutral or painful stimuli, suggesting that it is empathy itself that alters pain perception, and not necessarily the observation of pain behaviors.     

The somatosensory representation of the human clitoris: An fMRI study

We studied the central representation of pudendal afferents arising from the clitoral nerves in 15 healthy adult female subjects using electrical dorsal clitoral nerve stimulation and fMRI. As a control body region, we electrically stimulated the right hallux in eight subjects. In a block design experiment, we applied bilateral clitoral stimulation and unilateral (right) hallux stimulation. Activation maps were calculated for the contrasts ‘electrical dorsal clitoral nerve stimulation versus rest’ and ‘electrical hallux stimulation versus rest’.A random-effect group analysis for the clitoral stimulation showed significant activations bilateral in the superior and inferior frontal gyri, insulae and putamen and in the postcentral, precentral and inferior parietal gyri (including the primary and secondary somatosensory cortices). No activation was found on the mesial surface of the postcentral gyrus. For the hallux, activations occurred in a similar neuronal network but the activation in the primary somatosensory cortex was localized in the inter-hemispheric fissure.The results of this study demonstrate that the central representation of pudendal afferents arising from the clitoral nerves and sensory inputs from the hallux can be studied and distinguished from each other by fMRI. From the somatotopic order described in the somatosensory homunculus one would expect for electrical clitoral nerve stimulation activation of the mesial wall of the postcentral gyrus. In contrast, we found activations on the lateral surface of the postcentral gyrus.     

Absent median somatosensory evoked potential is a predictor of type I complex regional pain syndrome after stroke

Abstract

Purpose: The objective was to determine whether the abnormal finding of somatosensory evoked potentials (SEPs) associated with the development of type I complex regional pain syndrome (CRPS) after stroke. Methods: This was a retrospective study conducted from January, 2003, to December, 2007. Seventy patients were confirmed as CRPS type I, and one hundred and eighty-two patients were assigned to the control group. The initial clinical data were reviewed including age, gender, main type of stroke, lateralization and location of the lesion, presence of glenohumeral subluxation, and the development of CRPS. Somatosensory evoked potentials tests (SEP) in median nerve (N20) and posterior tibial nerve (P37) were performed. Results: CRPS groups revealed significantly higher incidence of the absent and abnormal hemiplegic median SEP, hemorrhagic stroke, and glenohumeral subluxation (GHS). Binary logistic regression analysis indicated that GHS (exp.(B)?=?4.083, p?<?0.01) with the absent median SEP (exp.(B)?=?3.246, p?<?0.01) were significant independent predictors of CRPS onset. Conclusions: In conclusion, GHS and the absent median SEP at sub-acute phase of stroke were primary predictors of the onset of post-stoke CRPS.

• Implications for Rehabilitation

• Recent investigations have suggested that autonomic, motor and somatosensory abnormalities of CRPS are impairments involving the central nervous system (CNS) as well as the peripheral neurogenic inflammatory process. However, the understanding of the pathophysiology of CRPS is still far from complete.

• The absence of SEP at the sub-acute stage of stroke correlated with the onset of post-stroke CRPS type I.

• The SEP evaluation at the sub-acute period after stroke might be generally used for predicting the concomitant development of post-stroke CRPS type I as well as functional recovery after stroke.

     

The behavioural expression of empathy to others' pain versus others' sadness in young children

Little is known about how children develop or express their empathy for another individual’s pain. The current study compared the behavioural expression of empathy for pain with that for emotion, specifically sadness, in children. One hundred twenty children (60 boys, 60 girls) between the ages of 18 and 36 months (M = 26.44 months; SD = 5.17) were assessed for their empathy-related behavioural responses to simulations of an adult’s pain and sadness, each presented separately. Children were more likely to be distressed by, but also more likely to be prosocially responsive to, another’s sadness. Conversely, children were more likely to actively play during another’s pain. Despite these differences, principal component analyses conducted separately for pain and sadness revealed conceptual similarities across simulation type. Components labelled as Empathic Concern and Personal Distress emerged for both simulations. Hierarchical regression analyses examining the influence of developmental (ie, age, sex) and interindividual (ie, temperament, social-emotional development, language abilities) variables of interest in children’s empathy-related responses were conducted for each pain and sadness component. Age differences emerged only for pain. There were no sex differences for either simulation. Temperament showed some predictive value in how children would respond to sadness. Social-emotional variables showed some predictive value in how children would respond to pain and sadness. Language showed very little predictive value. These findings highlight both conceptual similarities across, and important differences between, children’s expressions of empathy for pain and for sadness. Pain appears to be more easily ignored and results in fewer prosocial responses in children.     

Dynamics of brain activity in motor and frontal cortical areas during music listening: a magnetoencephalographic study

There are formidable problems in studying how 'real' music engages the brain over wide ranges of temporal scales extending from milliseconds to a lifetime. In this work, we recorded the magnetoencephalographic signal while subjects listened to music as it unfolded over long periods of time (seconds), and we developed and applied methods to correlate the time course of the regional brain activations with the dynamic aspects of the musical sound. We showed that frontal areas generally respond with slow time constants to the music, reflecting their more integrative mode; motor-related areas showed transient-mode responses to fine temporal scale structures of the sound. The study combined novel analysis techniques designed to capture and quantify fine temporal sequencing from the authentic musical piece (characterized by a clearly defined rhythm and melodic structure) with the extraction of relevant features from the dynamics of the regional brain activations. The results demonstrated that activity in motor-related structures, specifically in lateral premotor areas, supplementary motor areas, and somatomotor areas, correlated with measures of rhythmicity derived from the music. These correlations showed distinct laterality depending on how the musical performance deviated from the strict tempo of the music score, that is, depending on the musical expression.     

Effects of mood on pain responses and pain tolerance: an experimental study in chronic back pain patients

Although chronic pain and depression commonly co-occur, causal relationships have yet to be established. A reciprocal relationship, with depression increasing pain and vice versa, is most frequently suggested, but experimental evidence is needed to validate such a view. The most straightforward approach would be a demonstration that increasing or decreasing depressed mood predictably modifies pain responses. The current experiment tested whether experimentally induced depressed and happy mood have differential effects on pain ratings and tolerance in 55 patients suffering from chronic back pain. Participants were randomly assigned to depressed, neutral (control) or elated mood induction conditions. They completed a physically passive baseline task prior to receiving mood induction, then a clinically relevant physically active task (holding a heavy bag) to elicit pain responses and tolerance. Measures were taken immediately after the baseline task and immediately after the mood induction to assess the changes in mood, pain ratings and tolerance before and after the experimental manipulation. Results indicate that the induction of depressed mood resulted in significantly higher pain ratings at rest and lower pain tolerance, whilst induced happy mood resulted in significantly lower pain ratings at rest and greater pain tolerance. Correlations between changes in mood on the one hand and changes in pain response and pain tolerance on the other hand were consistent with these findings. It is concluded that, in chronic back pain patients, experimentally induced negative mood increases self-reported pain and decreases tolerance for a pain-relevant task, with positive mood having the opposite effect.     

The multilevel organization of vicarious pain responses: effects of pain cues and empathy traits on spinal nociception and acute pain

The shared-representation model of empathy suggests that vicarious pain processes rely partly on the activation of brain systems underlying self-pain in the observer. Here, we tested the hypothesis that self-pain may be facilitated by the vicarious priming of neural systems underlying pain perception. Pictures illustrating painful agents applied to the hand or the foot (sensory information), or painful facial expressions (emotional information) were shown to 43 participants to test the effects of vicarious pain on the nociceptive flexion reflex (NFR) of the lower limb and pain intensity and unpleasantness produced by transcutaneous electrical stimulation applied over the sural nerve. Results confirmed the expected priming effects of vicarious pain on spinal and perceptual processes. However, for comparable pain intensity and arousal evoked by the pain pictures, the facilitation of the NFR and the self-pain unpleasantness measurements was more robust in response to pictures depicting pain sensory compared to emotional information. Furthermore, the facilitation of the NFR by pain pictures was positively correlated with the empathy trait of the observer. In contrast, the change in perceived shock-pain intensity was negatively correlated with empathic traits. This dissociation implies that low-level vicarious priming processes underlying pain facilitation may be downregulated at higher pain-processing stages in individuals reporting higher levels of empathy. We speculate that this process contributes to reducing self-other assimilation and is necessary to adopt higher-order empathic responses and altruistic behaviors.     

Abnormalities of somatosensory perception in patients with painful osteoarthritis normalize following successful treatment.

To investigate the effect of chronic nociceptive pain on somatosensory perception, quantitative sensibility testing was performed in the most painful area and the homologous contralateral side in 14 patients with painful osteoarthritis of the hip. Twelve patients were reassessed in a painfree state 6-14 months following surgery. Von Frey filaments were used to test low-threshold mechanoreceptive function. Pressure pain sensitivity was assessed with a pressure algometer and thermal sensitivity with a Thermotest. Sex- and age-matched controls were examined in the corresponding areas at similar time intervals. There was no statistically significant difference between groups in the sensitivity to light touch and innocuous cold in either session. Compared to controls, patients had increased sensitivity to pressure pain in the most painful area (p < 0.002), bilaterally increased sensitivity to innocuous warmth (p < 0.03), cold pain (p< 0.05) and a tendency toward bilaterally increased sensitivity to heat pain (p = 0.054) before surgery. In the painful area, patients' sensitivity to pressure pain decreased (p < 0.04) and, remaining within normal limits, sensitivity to light touch increased (p < 0.006) compared to values prior to surgery. No statistically significant differences between the groups were seen following surgery, indicating that the sensibility changes had been maintained by chronic nociceptive pain.     

Quantitative testing of pain perception in subjects with PTSD--implications for the mechanism of the coexistence between PTSD and chronic pain

Post-traumatic stress disorder (PTSD) often co-occurs with chronic pain. Neither the underlying mechanism of this comorbidity nor the nature of pain perception among subjects with PTSD is well defined. This study is the first systematic and quantitative evaluation of pain perception and chronic pain in subjects with PTSD. The study group consisted of 32 outpatients with combat- and terror-related PTSD, 29 outpatients with anxiety disorder and 20 healthy controls. Quantitative somatosensory testing included the measurement of warm, cold, light touch and heat-pain thresholds and responses to acute suprathreshold heat and mechanical stimuli. Chronic pain was characterized, and levels of PTSD and anxiety symptomatology were assessed by self-report questionnaires. Subjects with PTSD exhibited higher rates of chronic pain, more intense chronic pain and more painful body regions compared with the other two groups. PTSD severity correlated with chronic pain severity. Thresholds of subjects with PTSD were significantly higher than those of subjects with anxiety and healthy controls, but they perceived suprathreshold stimuli as being much more intense than the other two groups. These results suggest that subjects with PTSD exhibit an intense and widespread chronic pain and a unique sensory profile of hyposensitivity to pain accompanied by hyper-reactivity to suprathreshold noxious stimuli. These features may be attributed to the manner with which PTSD subjects emotionally interpret and respond to painful stimuli. Alternatively, but not mutually exclusive, the findings may reflect altered sensory processing among these subjects.     

Bilateral activation of the trigeminothalamic tract by acute orofacial cutaneous and muscle pain in humans

The conscious perception of somatosensory stimuli is thought to be located in the contralateral cerebral cortex. However, recent human brain imaging investigations in the spinal system report bilateral primary somatosensory cortex (SI) activations during unilateral noxious stimuli and that this ipsilateral spinal representation may be independent of transcallosal connections. In the trigeminal system, there is primate evidence for an ipsilateral somatosensory pathway through the thalamus to the face SI. However, the organization of the trigeminal nociceptive pathway in the human is not clear. The aim of this study was to determine whether noxious stimuli applied to the face are transmitted to the cerebral cortex by bilateral pathways. We used functional magnetic resonance imaging (fMRI) to compare ipsilateral and contralateral activation of the thalamus, SI and secondary somatosensory cortex (SII) during muscle and cutaneous orofacial pain and innocuous facial stimulation in healthy human subjects. We found that both muscle and cutaneous noxious stimuli, from injections of hypertonic saline into the right masseter or overlying skin, evoked bilateral increases in signal intensity in the region encompassing the ventral posterior thalamus as well as the face region of SI and SII. In contrast, innocuous unilateral brushing of the lower lip evoked a strict contralateral ventroposterior thalamic activation, but bilateral activation of SI and SII. These data indicate that, in contrast to innocuous inputs from the face, noxious information ascends bilaterally to the face SI through the ventroposterior thalamus in humans.     

Altered effective connectivity in migraine patients during emotional stimuli: a multi-frequency magnetoencephalography study

BackgroundMigraine is a common and disabling primary headache, which is associated with a wide range of psychiatric comorbidities. However, the mechanisms of emotion processing in migraine are not fully understood yet. The present study aimed to investigate the neural network during neutral, positive, and negative emotional stimuli in the migraine patients.MethodsA total of 24 migraine patients and 24 age- and sex-matching healthy controls were enrolled in this study. Neuromagnetic brain activity was recorded using a whole-head magnetoencephalography (MEG) system upon exposure to human facial expression stimuli. MEG data were analyzed in multi-frequency ranges from 1 to 100 Hz.ResultsThe migraine patients exhibited a significant enhancement in the effective connectivity from the prefrontal lobe to the temporal cortex during the negative emotional stimuli in the gamma frequency (30–90 Hz). Graph theory analysis revealed that the migraine patients had an increased degree and clustering coefficient of connectivity in the delta frequency range (1–4 Hz) upon exposure to positive emotional stimuli and an increased degree of connectivity in the delta frequency range (1–4 Hz) upon exposure to negative emotional stimuli. Clinical correlation analysis showed that the history, attack frequency, duration, and neuropsychological scales of the migraine patients had a negative correlation with the network parameters in certain frequency ranges.ConclusionsThe results suggested that the individuals with migraine showed deviant effective connectivity in viewing the human facial expressions in multi-frequencies. The prefrontal-temporal pathway might be related to the altered negative emotional modulation in migraine. These findings suggested that migraine might be characterized by more universal altered cerebral processing of negative stimuli. Since the significant result in this study was frequency-specific, more independent replicative studies are needed to confirm these results, and to elucidate the neurocircuitry underlying the association between migraine and emotional conditions.     

Functional representation of the finger and face in the human somatosensory cortex: intraoperative intrinsic optical imaging

We applied the intrinsic optical imaging technique to the human primary somatosensory cortex during brain tumor/epilepsy surgery for nine patients. The cortical surface was illuminated with a Xenon light through an operating microscope, and the reflected light, which passed through a 605 nm bandpass filter, was detected by a CCD camera-based optical imaging system. Individual electrical stimulation of five digits induced changes in the reflected light intensities. Visualizing the intrinsic optical responses, we constructed maps of finger representation in Brodmann's area 1. In the maps, response areas of Digits I to V were sequentially aligned along the central sulcus in the crown of the postcentral gyrus from the latero-inferior region (Digit I) to the medio-superior region (Digit V). The neighboring response areas partially overlapped each other, as previously described in the monkey somatosensory cortex. Similar results were obtained in the face region with stimulation of the three branches of the trigeminal nerve. These results suggest that the overlap of the response areas is a common feature in the somatosensory cortex not only in monkeys, but also in humans.     

The primary somatosensory cortex largely contributes to the early part of the cortical response elicited by nociceptive stimuli

Research on the cortical sources of nociceptive laser-evoked brain potentials (LEPs) began almost two decades ago (Tarkka and Treede, 1993). Whereas there is a large consensus on the sources of the late part of the LEP waveform (N2 and P2 waves), the relative contribution of the primary somatosensory cortex (S1) to the early part of the LEP waveform (N1 wave) is still debated.To address this issue we recorded LEPs elicited by the stimulation of four limbs in a large population (n = 35). Early LEP generators were estimated both at single-subject and group level, using three different approaches: distributed source analysis, dipolar source modeling, and probabilistic independent component analysis (ICA).We show that the scalp distribution of the earliest LEP response to hand stimulation was maximal over the central-parietal electrodes contralateral to the stimulated side, while that of the earliest LEP response to foot stimulation was maximal over the central-parietal midline electrodes. Crucially, all three approaches indicated hand and foot S1 areas as generators of the earliest LEP response.Altogether, these findings indicate that the earliest part of the scalp response elicited by a selective nociceptive stimulus is largely explained by activity in the contralateral S1, with negligible contribution from the secondary somatosensory cortex (S2).     

Modulation of pain perception by transcranial magnetic stimulation of left prefrontal cortex

Evidence by functional imaging studies suggests the role of left dorsolateral prefrontal cortex (DLPFC) in the inhibitory control of nociceptive transmission system. Repetitive transcranial magnetic stimulation (rTMS) is able to modulate pain response to capsaicin. In the present study, we evaluated the effect of DLPFC activation (through rTMS) on nociceptive control in a model of capsaicin-induced pain. The study was performed on healthy subjects that underwent capsaicin application on right or left hand. Subjects judged the pain induced by capsaicin through a 0–100 VAS scale before and after 5 Hz rTMS over left and right DLPFC at 10 or 20 min after capsaicin application in two separate groups (8 subjects each). Left DLPFC-rTMS delivered either at 10 and 20 min after capsaicin application significantly decreased spontaneous pain in both hands. Right DLPFC rTMS showed no significant effect on pain measures. According to these results, stimulation of left DLPFC seems able to exert a bilateral control on pain system, supporting the critical antinociceptive role of such area. This could open new perspectives to non-invasive brain stimulation protocols of alternative target area for pain treatment.