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1.  Anterior insular cortex is necessary for empathetic pain perception 
Brain  2012;135(9):2726-2735.
Empathy refers to the ability to perceive and share another person’s affective state. Much neuroimaging evidence suggests that observing others’ suffering and pain elicits activations of the anterior insular and the anterior cingulate cortices associated with subjective empathetic responses in the observer. However, these observations do not provide causal evidence for the respective roles of anterior insular and anterior cingulate cortices in empathetic pain. Therefore, whether these regions are ‘necessary’ for empathetic pain remains unknown. Herein, we examined the perception of others’ pain in patients with anterior insular cortex or anterior cingulate cortex lesions whose locations matched with the anterior insular cortex or anterior cingulate cortex clusters identified by a meta-analysis on neuroimaging studies of empathetic pain perception. Patients with focal anterior insular cortex lesions displayed decreased discrimination accuracy and prolonged reaction time when processing others’ pain explicitly and lacked a typical interference effect of empathetic pain on the performance of a pain-irrelevant task. In contrast, these deficits were not observed in patients with anterior cingulate cortex lesions. These findings reveal that only discrete anterior insular cortex lesions, but not anterior cingulate cortex lesions, result in deficits in explicit and implicit pain perception, supporting a critical role of anterior insular cortex in empathetic pain processing. Our findings have implications for a wide range of neuropsychiatric illnesses characterized by prominent deficits in higher-level social functioning.
doi:10.1093/brain/aws199
PMCID: PMC3437027  PMID: 22961548
anterior cingulate cortex; anterior insular cortex; empathy; meta-analysis; necessity
2.  Cognition–Emotion Integration in the Anterior Insular Cortex 
Cerebral Cortex (New York, NY)  2012;23(1):20-27.
Both cognitive and affective processes require mental resources. However, it remains unclear whether these 2 processes work in parallel or in an integrated fashion. In this functional magnetic resonance imaging study, we investigated their interaction using an empathy-for-pain paradigm, with simultaneous manipulation of cognitive demand of the tasks and emotional valence of the stimuli. Eighteen healthy adult participants viewed photographs showing other people's hands and feet in painful or nonpainful situations while performing tasks of low (body part judgment) and high (laterality judgment) cognitive demand. Behavioral data showed increased reaction times and error rates for painful compared with nonpainful stimuli under laterality judgment relative to body part judgment, indicating an interaction between cognitive demand and stimulus valence. Imaging analyses showed activity in bilateral anterior insula (AI) and primary somatosensory cortex (SI), but not posterior insula, for main effects of cognitive demand and stimulus valence. Importantly, cognitive demand and stimulus valence showed a significant interaction in AI, SI, and regions of the frontoparietal network. These results suggest that cognitive and emotional processes at least partially share common brain networks and that AI might serve as a key node in a brain network subserving cognition–emotion integration.
doi:10.1093/cercor/bhr367
PMCID: PMC3513949  PMID: 22275476
cognition; emotion; empathy; fMRI; insula
3.  Witnessing hateful people in pain modulates brain activity in regions associated with physical pain and reward 
How does witnessing a hateful person in pain compare to witnessing a likable person in pain? The current study compared the brain bases for how we perceive likable people in pain with those of viewing hateful people in pain. While social bonds are built through sharing the plight and pain of others in the name of empathy, viewing a hateful person in pain also has many potential ramifications. In this functional Magnetic Resonance Imaging (fMRI) study, Caucasian Jewish male participants viewed videos of (1) disliked, hateful, anti-Semitic individuals, and (2) liked, non-hateful, tolerant individuals in pain. The results showed that, compared with viewing liked people, viewing hateful people in pain elicited increased responses in regions associated with observation of physical pain (the insular cortex, the anterior cingulate cortex (ACC), and the somatosensory cortex), reward processing (the striatum), and frontal regions associated with emotion regulation. Functional connectivity analyses revealed connections between seed regions in the left ACC and right insular cortex with reward regions, the amygdala, and frontal regions associated with emotion regulation. These data indicate that regions of the brain active while viewing someone in pain may be more active in response to the danger or threat posed by witnessing the pain of a hateful individual more so than the desire to empathize with a likable person's pain.
doi:10.3389/fpsyg.2013.00772
PMCID: PMC3805980  PMID: 24167496
empathy; observation of pain; social group membership; fMRI; pain matrix
4.  Different circuits for different pain: Patterns of functional connectivity reveal distinct networks for processing pain in self and others 
Social neuroscience  2007;2(3-4):276-291.
The ability to empathize with the suffering of others is critical for maintaining relationships and engaging in prosocial behavior. Recently, a series of studies have demonstrated that while watching other people experience pain (other pain), participants engage the anterior insula (AI) and anterior cingulale cortex (ACC), brain regions involved in the direct experience of pain (self pain). Here we test the hypothesis that common activity in ACC and AI may reflect the operation of distinct but overlapping networks of regions that support perception of self or other pain. To address this possibility, we scanned participants using fMRI while they received noxious thermal stimulation (self pain) or watched short videos of other people sustaining painful injuries (other pain). We isolated overlapping regions for self and other pain in the ACC and AI and then used them as seed regions for two kinds of functional connectivity analyses. These analyses identified areas whose activity co-varied with ACC and AI activity during self or other pain either across time (intra-individual connectivity) or across participants (inter-individual connectivity). Both connectivity analyses identified clusters in the midbrain and periaqueductal gray with greater connectivity to the AI during self pain as opposed to other pain. The opposite pattern was found in the dorsal medial prefrontal cortex, that showed greater connectivity to the ACC and AI during other pain than during self pain using both types of analysis. Intra-individual connectivity analyses also revealed regions in the superior temporal sulcus, posterior cingulate, and precuneus that became more connected to ACC during other pain as compared to self pain. Together, these data demonstrated that regions showing similar activity during self and other pain may nonetheless be part of distinct functional networks. These networks could not have been detected in prior work that examined overlap between self and other pain in terms of average activity, but not connectivity.
doi:10.1080/17470910701401973
PMCID: PMC2913618  PMID: 18633819
5.  MEG Can Map Short and Long-Term Changes in Brain Activity following Deep Brain Stimulation for Chronic Pain 
PLoS ONE  2012;7(6):e37993.
Deep brain stimulation (DBS) has been shown to be clinically effective for some forms of treatment-resistant chronic pain, but the precise mechanisms of action are not well understood. Here, we present an analysis of magnetoencephalography (MEG) data from a patient with whole-body chronic pain, in order to investigate changes in neural activity induced by DBS for pain relief over both short- and long-term. This patient is one of the few cases treated using DBS of the anterior cingulate cortex (ACC). We demonstrate that a novel method, null-beamforming, can be used to localise accurately brain activity despite the artefacts caused by the presence of DBS electrodes and stimulus pulses. The accuracy of our source localisation was verified by correlating the predicted DBS electrode positions with their actual positions. Using this beamforming method, we examined changes in whole-brain activity comparing pain relief achieved with deep brain stimulation (DBS ON) and compared with pain experienced with no stimulation (DBS OFF). We found significant changes in activity in pain-related regions including the pre-supplementary motor area, brainstem (periaqueductal gray) and dissociable parts of caudal and rostral ACC. In particular, when the patient reported experiencing pain, there was increased activity in different regions of ACC compared to when he experienced pain relief. We were also able to demonstrate long-term functional brain changes as a result of continuous DBS over one year, leading to specific changes in the activity in dissociable regions of caudal and rostral ACC. These results broaden our understanding of the underlying mechanisms of DBS in the human brain.
doi:10.1371/journal.pone.0037993
PMCID: PMC3366994  PMID: 22675503
6.  The Will to Persevere Induced by Electrical Stimulation of the Human Cingulate Gyrus 
Neuron  2013;80(6):10.1016/j.neuron.2013.10.057.
SUMMARY
Anterior cingulate cortex (ACC) is known to be involved in functions such as emotion, pain, and cognitive control. While studies in humans and non-human mammals have advanced our understanding of ACC function, the subjective correlates of ACC activity have remained largely unexplored. In the current study, we show that electrical charge delivery in the anterior mid-cingulate cortex (aMCC) elicits autonomic changes and the expectation of an imminent challenge coupled with a determined attitude to overcome it. Seed-based, resting-state connectivity analysis revealed that the site of stimulation in both patients was at the core of a large-scale distributed network linking aMCC to the frontoinsular and frontopolar as well as some subcortical regions. This report provides compelling, first-person accounts of electrical stimulation of this brain network and suggests its possible involvement in psychopathological conditions that are characterized by a reduced capacity to endure psychological or physical distress.
doi:10.1016/j.neuron.2013.10.057
PMCID: PMC3877748  PMID: 24316296
7.  Comparison of anterior cingulate vs. insular cortex as targets for real-time fMRI regulation during pain stimulation 
Real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback allows learning voluntary control over specific brain areas by means of operant conditioning and has been shown to decrease pain perception. To further increase the effect of rt-fMRI neurofeedback on pain, we directly compared two different target regions of the pain network, notably the anterior insular cortex (AIC) and the anterior cingulate cortex (ACC). Participants for this prospective study were randomly assigned to two age-matched groups of 14 participants each (7 females per group) for AIC and ACC feedback. First, a functional localizer using block-design heat pain stimulation was performed to define the pain-sensitive target region within the AIC or ACC. Second, subjects were asked to down-regulate the BOLD activation in four neurofeedback runs during identical pain stimulation. Data analysis included task-related and functional connectivity analysis. At the behavioral level, pain ratings significantly decreased during feedback vs. localizer runs, but there was no difference between AIC and ACC groups. Concerning neuroimaging, ACC and AIC showed consistent involvement of the caudate nucleus for subjects that learned down-regulation (17/28) in both task-related and functional connectivity analysis. The functional connectivity toward the caudate nucleus is stronger for the ACC while the AIC is more heavily connected to the ventrolateral prefrontal cortex. Consequently, the ACC and AIC are suitable targets for real-time fMRI neurofeedback during pain perception as they both affect the caudate nucleus, although functional connectivity indicates that the direct connection seems to be stronger with the ACC. Additionally, the caudate, an important area involved in pain perception and suppression, could be a good rt-fMRI target itself. Future studies are needed to identify parameters characterizing successful regulators and to assess the effect of repeated rt-fMRI neurofeedback on pain perception.
doi:10.3389/fnbeh.2014.00350
PMCID: PMC4191436  PMID: 25346666
real-time fMRI neurofeedback; realtime fMRI; pain; anterior cingulate cortex (ACC); anterior insular cortex; insular cortex
8.  Association of Callous Traits with Reduced Neural Response to Others’ Pain in Children with Conduct Problems 
Current Biology  2013;23(10):901-905.
Summary
Children with conduct problems (CP) persistently violate others’ rights and represent a considerable societal cost [1]. These children also display atypical empathic responses to others’ distress [2], which may partly account for their violent and antisocial behavior. Callous traits index lack of empathy in these children and confer risk for adult psychopathy [3]. Investigating neural responses to others’ pain is an ecologically valid method to probe empathic processing [4], but studies in children with CP have been inconclusive [5, 6]. Using functional magnetic resonance imaging (fMRI), we measured neural responses to pictures of others in pain (versus no pain) in a large sample of children with CP and matched controls. Relative to controls, children with CP showed reduced blood oxygen level-dependent responses to others’ pain in bilateral anterior insula (AI), anterior cingulate cortex (ACC), and inferior frontal gyrus, regions associated with empathy for pain in previous studies [7, 8]. In the CP group, callous traits were negatively associated with responses to others’ pain in AI and ACC. We conclude that children with CP have atypical neural responses to others’ pain. The negative association between callous traits and AI/ACC response could reflect an early neurobiological marker indexing risk for empathic deficits seen in adult psychopathy.
Highlights
•Children with conduct problems showed reduced neural responses to others’ pain•Reductions in anterior insula, anterior cingulate cortex, and inferior frontal gyrus•Callous traits associated with the magnitude of reduction•Findings may reflect early neurobiological risk for adult psychopathy
doi:10.1016/j.cub.2013.04.018
PMCID: PMC3918856  PMID: 23643836
9.  Alteration of neuronal activity after digit amputation in rat anterior cingulate cortex 
Phantom limb pain is experienced by nearly 50 - 80% of the patients following limb amputation. The anterior cingulate cortex (ACC) is a part of the limbic system that is an essential component in mediating the affective and emotional component of pain responses. To explore the role of ACC in the phantom limb pain, we recorded evoked excitatory postsynaptic potentials (EPSPs), cortical network activity and electrophysiological properties of pyramid neurons in adult rat ACC before and after a third hind paw digit amputation using in vivo intracellular or extracellular recording and staining techniques. The recorded neurons were morphologically identified as pyramidal neurons in the ACC region. The spontaneous activity of ACC neurons significantly reduced with a more percentage of down state after amputation, this is correlated with a decrease in spontaneous spikes in medial thalamus. However, the amplitude of the evoked EPSPs was increased significantly shortly after amputation and lasted for up to 7 days. This potentiation is associated with an increase of paired-pulse facilitation (PPF), suggesting the involvement of presynaptic component in this process. No significant difference in membrane properties was observed after amputation. On the other hand, administration of Complete Freund’s Adjuvant (CFA) into the hind paw, a model of inflammatory pain, induced the potentiation of EPSPs in ACC neurons at 7 days after injection. These results demonstrate that digit amputation induced a long-lasting potentiation of synaptic transmission and decrease of cortical network activity in ACC in rats, which might contribute to the phantom limb pain.
PMCID: PMC3601461  PMID: 23525689
Phantom pain; cortex; pyramidal neurons; EPSPs; in vivo; intracellular recording
10.  NMDA NR2A and NR2B Receptors in the Rostral Anterior Cingulate Cortex Contribute to Pain-related Aversion in Male Rats 
Pain  2009;146(1-2):183-193.
NMDA receptors, which are implicated in pain processing, are highly expressed in forebrain areas including the anterior cingulate cortex (ACC). The ACC has been implicated in the affective response to noxious stimuli. Using a combination of immunohistochemical staining, western blot, electrophysiological recording and formalin-induced conditioned place avoidance (F-CPA) rat behavioral model that directly reflects the affective component of pain, the present study examined formalin nociceptive conditioning-induced changes in the expressions of NMDA receptor subunits NR1, NR2A, and NR2B in the rostral ACC (rACC) and its possible functional significance. We found that unilateral intraplantar (i.pl.) injection of dilute formalin with or without contextual conditioning exposure markedly increased the expressions of NMDA receptor subunits NR2A and NR2B but not NR1 in the bilateral rACC. NMDA-evoked currents in rACC neurons were significant greater in formalin-injected rats than that of naïve or normal saline-injected rats. Selectively blocking either NR2A or NR2B subunit in the rACC abolished the acquisition of F-CPA and formalin nociceptive conditioning-induced Fos expression, but did not affect formalin acute nociceptive behaviors and non-nociceptive fear stimulus-induced CPA. These results suggest that both NMDA receptor subunits NR2A and NR2B in the rACC are critically involved in pain-related aversion. Thus, a new strategy targeted at NMDA NR2A or NR2B subunit might be raised for the prevention of pain-related emotional disturbance.
doi:10.1016/j.pain.2009.07.027
PMCID: PMC2764121  PMID: 19695778
NR1; NR2A; NR2B; Anterior cingulate cortex; Formalin-induced conditioned place avoidance (F-CPA); Fos; Pain affect; Rat
11.  Dissociating response conflict and error likelihood in anterior cingulate cortex 
Neuroimaging studies consistently report activity in anterior cingulate cortex (ACC) in conditions of high cognitive demand, leading to the view that ACC plays a crucial role in the control of cognitive processes. According to one prominent theory, the sensitivity of ACC to task difficulty reflects its role in monitoring for the occurrence of competition, or conflict, between responses in order to signal the need for increased cognitive control. However, a contrasting theory proposes that ACC is the recipient rather than source of monitoring signals, and that ACC activity observed in relation to task demand reflects the role of this region in learning about the likelihood of errors. Response conflict and error likelihood are typically confounded, making the theories difficult to distinguish empirically. The present research therefore used detailed computational simulations to derive contrasting predictions regarding ACC activity and error rate as a function of response speed. The simulations demonstrated a clear dissociation between conflict and error likelihood: fast response trials are associated with low conflict but high error likelihood, whereas slow response trials show the opposite pattern. Using the N2 component as an index of ACC activity, an EEG study demonstrated that when conflict and error likelihood are dissociated in this way, ACC activity tracks conflict and is negatively correlated with error likelihood. These findings support the conflict-monitoring theory and suggest that, in speeded decision tasks, ACC activity reflects current task demands rather than the retrospective coding of past performance.
doi:10.1523/JNEUROSCI.3615-09.2009
PMCID: PMC2831178  PMID: 19923284
performance monitoring; reinforcement learning; speed-accuracy trade-off; EEG; cognitive coordination; executive
12.  The influence of visual perspective on the somatosensory steady-state response during pain observation 
The observation and evaluation of other’s pain activate part of the neuronal network involved in the actual experience of pain, including those regions subserving the sensori-discriminative dimension of pain. This was largely interpreted as evidence showing that part of the painful experience can be shared vicariously. Here, we investigated the effect of the visual perspective from which other people’s pain is seen on the cortical response to continuous 25 Hz non-painful somatosensory stimulation (somatosensory steady-state response: SSSR). Based on the shared representation framework, we expected first-person visual perspective (1PP) to yield more changes in cortical activity than third-person visual perspective (3PP) during pain observation. Twenty healthy adults were instructed to rate a series of pseudo-dynamic pictures depicting hands in either painful or non-painful scenarios, presented either in 1PP (0–45° angle) or 3PP (180° angle), while changes in brain activity was measured with a 128-electode EEG system. The ratings demonstrated that the same scenarios were rated on average as more painful when observed from the 1PP than from the 3PP. As expected from previous works, the SSSR response was decreased after stimulus onset over the left caudal part of the parieto-central cortex, contralateral to the stimulation side. Moreover, the difference between the SSSR was of greater amplitude when the painful situations were presented from the 1PP compared to the 3PP. Together, these results suggest that a visuospatial congruence between the viewer and the observed scenarios is associated with both a higher subjective evaluation of pain and an increased modulation in the somatosensory representation of observed pain. These findings are discussed with regards to the potential role of visual perspective in pain communication and empathy.
doi:10.3389/fnhum.2013.00849
PMCID: PMC3856401  PMID: 24367323
pain observation; visual perspective; empathy; electroencephalography; somatosensory steady-state
13.  Contrasting changes in extracellular dopamine and glutamate along the rostrocaudal axis of the anterior cingulate cortex of the rat following an acute d-amphetamine or dopamine challenge 
Neuropharmacology  2014;87:180-187.
There is evidence for functional specificity of subregions along the rostrocaudal axis of the anterior cingulate cortex (ACC). The subregion-specific distribution of dopaminergic afferents and glutamatergic efferents along the ACC make these obvious candidates for coding such regional responses. We investigated this possibility using microdialysis in freely-moving rats to compare changes in extracellular dopamine and glutamate in the rostral (‘rACC': Cg1 and Cg3 (prelimbic area)) and caudal (‘cACC’: Cg1 and Cg2) ACC induced by systemic or local administration of d-amphetamine. Systemic administration of d-amphetamine (3 mg/kg, i.p.) caused a transient increase in extracellular dopamine in the rACC, but an apparent increase in the cACC of the same animals was less clearly defined. Local infusion of d-amphetamine increased dopamine efflux in the rACC, only. Glutamate efflux in the rACC was increased by local infusion of dopamine (5–50 μM), which had negligible effect in the cACC, but only systemic administration of d-amphetamine increased glutamate efflux and only in the cACC. The asymmetry in the neurochemical responses within the rACC and cACC, to the same experimental challenges, could help explain why different subregions are recruited in the response to specific environmental and somatosensory stimuli and should be taken into account when studying the regulation of neurotransmission in the ACC.
This article is part of the Special Issue entitled ‘CNS Stimulants’.
Highlights
•Dopamine and glutamate efflux in two anterior cingulate subregions were compared.•Responses to d-amphetamine depended on subregion and route of drug administration.•These findings could help explain the disparate roles of the two subregions.
doi:10.1016/j.neuropharm.2014.04.003
PMCID: PMC4226319  PMID: 24747182
Anterior cingulate cortex; d-Amphetamine; Dopamine; Glutamate; GLT-1; Microdialysis; 5-HT, 5-hydroxytryptamine (serotonin); ACC, anterior cingulate cortex; cACC, caudal anterior cingulate cortex; AP, anteroposterior; Cg1, cingulate area Cg1; Cg2, cingulate area Cg2; Cg3, cingulate area Cg3; DV, dorsoventral; ECD, electrochemical detection; DA, dopamine; GLT-1, glutamate transporter 1; ML, mediolateral; mPFC, medial prefrontal cortex; NA, noradrenaline; rACC, rostral anterior cingulate cortex; VTA, ventral tegmental area
14.  Why Self-Induced Pain Feels Less Painful than Externally Generated Pain: Distinct Brain Activation Patterns in Self- and Externally Generated Pain 
PLoS ONE  2011;6(8):e23536.
Voluntary movement generally inhibits sensory systems. However, it is not clear how such movement influences pain. In the present study, subjects actively or passively experienced mechanical pain or pressure during functional MRI scanning. Pain and pressure were induced using two modified grip strengthener rings, each twined with four crystal bead strings, with polyhedral beads to induce pain, or spherical beads to induce pressure. Subjects held one ring in the left hand and were either asked to squeeze their left hand with their right hand (i.e., active pain or pressure), or to have their left hand squeezed by the experimenter (i.e., passive pain or pressure). Subjects rated the intensity and unpleasantness of the pain sensation lower in the active procedure than in the passive one. Correspondingly, pain-related brain areas were inhibited in the case of self-generated pain, including the primary somatosensory cortex (SI), anterior cingulate cortex (ACC), and the thalamus. These results suggest that active movement behaviorally inhibits concomitant mechanical pain, accompanied by an inhibition of pain response in pain-related brain areas such as the SI cortex. This might be part of the mechanisms underlying the kinesitherapy for pain treatment.
doi:10.1371/journal.pone.0023536
PMCID: PMC3162568  PMID: 21887267
15.  The effect of acupuncture needle combination on central pain processing-an fMRI study 
Molecular Pain  2014;10:23.
Background
Empirical acupuncture treatment paradigm for acute pain utilizing Tendinomuscular Meridians (TMM) calls for the stimulation of Ting Points (TPs) and Gathering point(GP). This study aims to compare the supraspinal neuronal mechanisms associated with both TPs and GP needling (EA3), and TPs needling alone (EA2) with fMRI.
Results
A significant (P < 0.01) difference between pre-scan (heat Pain) HP, and post-EA HP VAS scores in both paradigms was noted (n = 11). The post-EA HP VAS score was significantly (P < 0.05) lower with EA3 comparing to EA2 Within-group random effect analysis indicated that EA3+HP>EA3 (condition EA3+HP subtracted by condition EA3) appeared to exert a significant degree of activity suppression in the affective supraspinal regions including the IPL, anterior cingulate cortex (ACC) and the insular cortex (IN). This level of suppression was not observed in the EA2+HP>EA2 (condition EA2+HP subtracted by condition EA2) within-group random effect analysis Between-group random effect analysis indicated that EA3 induced a significantly (P < 0.01, cluster size threshold 150) higher degree of deactivation than EA2 in several pain related supraspinal regions including the right prefrontal cortex, rostral anterior cingulate (rACC), medial cingulate cortex, left inferior frontal lobe and posterior cerebellum. The 2-factor ANOVA in those regions indicated both rACC and posterior cerebellum had a significant (P < 0.01) needle effect, and the right prefrontal area showed a significant (P < 0.01) HP effect. However, a significant interaction between the two factors was only found in the right prefrontal lobe. Granger causality analysis showed EA3 induced a much higher degree of inference among HP related supraspinal somatosensory, affective and modulatory components than EA2. Deactivation pattern at the medullary-pontine area casted a direct inference on the deactivation pattern of secondary somatosensory cortices which also affected the deactivation of the IN.
Conclusions
While both EA2 and EA3 induced a significant degree of deactivation in the human brain regions related to pain processing, the addition of GP stimulation further exerts an inhibitory effect on the ascending spinoreticular pain pathway. Therefore, different needling position as mandated in different empirical acupuncture treatment paradigms may play a different role in modulating pain related neuronal functions.
doi:10.1186/1744-8069-10-23
PMCID: PMC3986941  PMID: 24667015
TMM; Tendinomuscular meridian; Acupuncture; Analgesia; Analgesic mechanisms; fMRI; Electroacupuncture
16.  Empathic responsiveness in amygdala and anterior cingulate cortex in youths with psychopathic traits 
Background
Psychopathic traits are associated with increases in antisocial behaviors such as aggression and are characterized by reduced empathy for others’ distress. This suggests that psychopathic traits may also impair empathic pain sensitivity. However, whether psychopathic traits affect responses to the pain of others versus the self has not been previously assessed.
Method
We used whole-brain functional magnetic resonance imaging (fMRI) scanning to measure neural activation in 14 adolescents with Oppositional Defiant Disorder or Conduct Disorder and psychopathic traits, as well as 21 healthy controls matched on age, sex, and intelligence. Activation in structures associated with empathic pain perception was assessed as adolescents viewed photographs of pain-inducing injuries. Adolescents imagined either that the body in each photograph was their own or that it belonged to another person. Behavioral and neuroimaging data were analyzed using random-effects analysis of variance.
Results
Youths with psychopathic traits showed reduced activity within regions associated with empathic pain as the depicted pain increased. These regions included rostral anterior cingulate cortex, ventral striatum (putamen), and amygdala. Reductions in amygdala activity particularly occurred when the injury was perceived as occurring to another. Empathic pain responses within both amygdala and rostral anterior cingulate cortex were negatively correlated with the severity of psychopathic traits as indexed by PCL:YV scores.
Conclusions
Youths with psychopathic traits show less responsiveness in regions implicated in the affective response to another’s pain as the perceived intensity of this pain increases. Moreover, this reduced responsiveness appears to predict symptom severity.
doi:10.1111/jcpp.12063
PMCID: PMC3716835  PMID: 23488588
Psychopathy; adolescents; empathy; pain; amygdala; Conduct Disorder
17.  Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway 
Molecular Pain  2009;5:51.
Background
Although the mechanisms of short- and long-term potentiation of nociceptive-evoked responses are well known in the spinal cord, including central sensitization, there has been a growing body of information on such events in the cerebral cortex. In view of the importance of anterior cingulate cortex (ACC) in chronic pain conditions, this review considers neuronal plasticities in the thalamocingulate pathway that may be the earliest changes associated with such syndromes.
Results
A single nociceptive electrical stimulus to the sciatic nerve induced a prominent sink current in the layer II/III of the ACC in vivo, while high frequency stimulation potentiated the response of this current. Paired-pulse facilitation by electrical stimulation of midline, mediodorsal and intralaminar thalamic nuclei (MITN) suggesting that the MITN projection to ACC mediates the nociceptive short-term plasticity. The short-term synaptic plasticities were evaluated for different inputs in vitro where the medial thalamic and contralateral corpus callosum afferents were compared. Stimulation of the mediodorsal afferent evoked a stronger short-term synaptic plasticity and effectively transferred the bursting thalamic activity to cingulate cortex that was not true for contralateral stimulation. This short-term enhancement of synaptic transmission was mediated by polysynaptic pathways and NMDA receptors. Layer II/III neurons of the ACC express a short-term plasticity that involves glutamate and presynaptic calcium influx and is an important mechanism of the short-term plasticity.
Conclusion
The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to noxious events. Moreover, these modifications of cingulate synapses appear to regulate afferent signals that may be important to the transition from acute to chronic pain conditions associated with persistent peripheral noxious stimulation. Enhanced and maintained nociceptive activities in cingulate cortex, therefore, can become adverse and it will be important to learn how to regulate such changes in thalamic firing patterns that transmit nociceptive information to ACC in early stages of chronic pain.
doi:10.1186/1744-8069-5-51
PMCID: PMC2745374  PMID: 19732417
18.  What Are You Feeling? Using Functional Magnetic Resonance Imaging to Assess the Modulation of Sensory and Affective Responses during Empathy for Pain 
PLoS ONE  2007;2(12):e1292.
Background
Recent neuroscientific evidence suggests that empathy for pain activates similar neural representations as the first-hand experience of pain. However, empathy is not an all-or-none phenomenon but it is strongly malleable by interpersonal, intrapersonal and situational factors. This study investigated how two different top-down mechanisms – attention and cognitive appraisal - affect the perception of pain in others and its neural underpinnings.
Methodology/Principal Findings
We performed one behavioral (N = 23) and two functional magnetic resonance imaging (fMRI) experiments (N = 18). In the first fMRI experiment, participants watched photographs displaying painful needle injections, and were asked to evaluate either the sensory or the affective consequences of these injections. The role of cognitive appraisal was examined in a second fMRI experiment in which participants watched injections that only appeared to be painful as they were performed on an anesthetized hand. Perceiving pain in others activated the affective-motivational and sensory-discriminative aspects of the pain matrix. Activity in the somatosensory areas was specifically enhanced when participants evaluated the sensory consequences of pain. Perceiving non-painful injections into the anesthetized hand also led to signal increase in large parts of the pain matrix, suggesting an automatic affective response to the putatively harmful stimulus. This automatic response was modulated by areas involved in self/other distinction and valence attribution – including the temporo-parietal junction and medial orbitofrontal cortex.
Conclusions/Significance
Our findings elucidate how top-down control mechanisms and automatic bottom-up processes interact to generate and modulate other-oriented responses. They stress the role of cognitive processing in empathy, and shed light on how emotional and bodily awareness enable us to evaluate the sensory and affective states of others.
doi:10.1371/journal.pone.0001292
PMCID: PMC2144768  PMID: 18091986
19.  Dissociable Intrinsic Connectivity Networks for Salience Processing and Executive Control 
Variations in neural circuitry, inherited or acquired, may underlie important individual differences in thought, feeling, and action patterns. Here, we used task-free connectivity analyses to isolate and characterize two distinct networks typically coactivated during functional MRI tasks. We identified a “salience network,” anchored by dorsal anterior cingulate (dACC) and orbital frontoinsular cortices with robust connectivity to subcortical and limbic structures, and an “executive-control network” that links dorsolateral frontal and parietal neocortices. These intrinsic connectivity networks showed dissociable correlations with functions measured outside the scanner. Prescan anxiety ratings correlated with intrinsic functional connectivity of the dACC node of the salience network, but with no region in the executive-control network, whereas executive task performance correlated with lateral parietal nodes of the executive-control network, but with no region in the salience network. Our findings suggest that task-free analysis of intrinsic connectivity networks may help elucidate the neural architectures that support fundamental aspects of human behavior.
doi:10.1523/JNEUROSCI.5587-06.2007
PMCID: PMC2680293  PMID: 17329432
fMRI; functional connectivity; anterior cingulate; insula; salience; anxiety
20.  Neurofeedback of the difference in activation of the anterior cingulate cortex and posterior insular cortex: two functionally connected areas in the processing of pain 
The aim of this study was the analysis of the effect of a learned increase in the dissociation between the rostral anterior cingulate cortex (rACC) and the left posterior insula (pInsL) on pain intensity and unpleasantness and the contribution of each region to the effect, exploring the possibility to influence the perception of pain with neurofeedback methods. We trained ten healthy subjects to increase the difference in the blood oxygenation level-dependent response between the rACC and pInsL to painful electric stimuli. Subjects learned to increase the dissociation with either the rACC (state 1) or the pInsL (state 2) being higher. For feedback we subtracted the signal of one region from the other and provided feedback in four conditions with six trials each yielding two different states: [rACC—pInsL increase (state 1), rACC—pInsL decrease (state 2), pInsL—rACC increase (state 2), pInsL—rACC decrease (state 1)]. Significant changes in the dissociation from trial one to six were seen in all conditions. There were significant changes from trial one to six in the pInsL in three of the four conditions, the rACC showed no significant change. Pain intensity or unpleasantness ratings were unrelated to the dissociation between the regions and the activation in each region. Learning success in the conditions did not significantly correlate and there was no significant correlation between the two respective conditions of one state, i.e., learning to achieve a specific state is not a stable ability. The pInsL seems to be the driving force behind changes in the learned dissociation between the regions. Despite successful differential modulation of activation in areas responsive to the painful stimulus, no corresponding changes in the perception of pain intensity or unpleasantness emerged. Learning to induce different states of dissociation between the areas is not a stable ability since success did not correlate overall or between two conditions of the the same state.
doi:10.3389/fnbeh.2014.00357
PMCID: PMC4197653  PMID: 25360092
real-time fMRI; pain; anterior cingulate cortex; posterior insula; neuromodulation; connectivity
21.  Anterior Insula GABA Levels Correlate with Emotional Aspects of Empathy: A Proton Magnetic Resonance Spectroscopy Study 
PLoS ONE  2014;9(11):e113845.
Background:
Empathy is a multidimensional construct referring to the capacity to understand and share the emotional and affective states of another person. Cerebral γ-aminobutyric acid (GABA)-ergic levels are associated with a variety of neurological and psychiatric disorders. However, the role of the GABA system in different dimensions of empathy has not been investigated.
Materials and Methods:
Thirty-two right-handed healthy volunteers took part in this study. We used proton magnetic resonance spectroscopy to determine GABA concentrations in the anterior insula (AI) and the anterior cingulate cortex (ACC) and to examine the relationship between the GABA concentrations and the subcomponents of empathy evaluated by the Interpersonal Reactivity Index (IRI).
Result:
Pearson correlation analyses (two-tailed) showed that AI GABA was significantly associated with the empathy concern score (r = 0.584, p<0.05) and the personal distress score (r = 0.538, p<0.05) but not significantly associated with other empathy subscales. No significant correlation was found between ACC GABA and empathy subscores.
Conclusion:
Left AI GABA was positively correlated with the emotional aspects of empathy. These preliminary findings call into question whether AI GABA alterations might predict empathy dysfunction in major psychiatric disorders such as autism and schizophrenia, which have been described as deficits in emotional empathic abilities.
doi:10.1371/journal.pone.0113845
PMCID: PMC4242717  PMID: 25419976
22.  Mood influences supra-spinal pain processing separately from attention 
Studies show that inducing a positive mood or diverting attention from pain decreases pain perception. Nevertheless, induction manipulations, such as viewing interesting movies or performing mathematical tasks, often influence both emotional and attentional state. Imaging studies have examined the neural basis of psychological pain modulation, but none has explicitly separated the effects of emotion and attention. Using odors to modulate mood and shift attention from pain, we previously showed that the perceptual consequences of changing mood differed from those of altering attention, with mood primarily altering pain unpleasantness and attention preferentially altering pain intensity. These findings suggest that brain circuits involved in pain modulation provoked by mood or attention are partially separable. Here we used functional MRI to directly compare the neuro-circuitry involved in mood- and attention-related pain modulation. We manipulated independently mood state and attention direction, using tasks involving heat pain and pleasant and unpleasant odors. Pleasant odors, independent of attentional focus, induced positive mood changes and decreased pain unpleasantness and pain-related activity within the anterior cingulate (ACC), medial thalamus (medialTH), and primary and secondary somatosensory cortices. The effects of attentional state were less robust, with only the activity in anterior insular cortex (aIC) showing possible attentional modulation. Lateral inferior frontal cortex (LinfF-BA45/47) activity correlated with mood-related modulation while superior posterior parietal (SPP-BA7) and entorhinal activity correlated with attention-related modulation. ACC activity covaried with LinfF and PAG activity, whereas aIC activity covaried with SPP activity. These findings suggest that separate neuro-modulatory circuits underlie emotional and attentional modulation of pain.
doi:10.1523/JNEUROSCI.3822-08.2009
PMCID: PMC2768393  PMID: 19158297
pain; fMRI; attention; emotion; odor; heat
23.  Altered cingulate sub-region activation accounts for task-related dissociation in ERN amplitude as a function of obsessive-compulsive symptoms 
Neuropsychologia  2010;48(7):2098-2109.
Larger Error-Related Negativities (ERNs) have been consistently found in Obsessive Compulsive Disorder (OCD) patients, and are thought to reflect the activities of a hyperactive cortico-striatal circuit during action monitoring. We previously observed that OC symptomatic students (non-patients) have larger ERNs during errors in a response competition task, yet smaller ERNs in a reinforcement learning task. The finding of a task-specific dissociation suggests that distinct yet partially overlapping medio-frontal systems underlie the ERN in different tasks, and that OC symptoms are associated with functional differences in these systems. Here, we used EEG source localization to identify why OC symptoms are associated with hyperactive ERNs to errors yet hypoactive ERNs when selecting maladaptive actions. At rest, OC symptomatology predicted greater activity in rostral anterior cingulate cortex (rACC) and lower activity in dorsal anterior cingulate cortex (dACC). When compared to a group with low OC symptom scores, the high OC group had greater rACC reactivity during errors in the response competition task and less deactivation of dACC activity during errors in the reinforcement learning task. The degree of activation in these areas correlated with ERN amplitudes during both tasks in the high OC group, but not in the low group. Interactive ACC systems associated avoidance of maladaptive actions were intact in the high OC group, but were related to poorer performance on a third task: probabilistic reversal learning. These novel findings link both tonic and phasic activities in the ACC to action monitoring alterations, including dissociation in performance deficits, in OC symptomatic participants.
doi:10.1016/j.neuropsychologia.2010.03.031
PMCID: PMC2876228  PMID: 20381506
ERN; LORETA; Anterior Cingulate; OCD; Reinforcement Learning; EEG
24.  Differential regulation of morphine antinociceptive effects by endogenous enkephalinergic system in the forebrain of mice 
Molecular Pain  2008;4:41.
Background
Mice lacking the preproenkephalin (ppENK) gene are hyperalgesic and show more anxiety and aggression than wild-type (WT) mice. The marked behavioral changes in ppENK knock-out (KO) mice appeared to occur in supraspinal response to painful stimuli. However the functional role of enkephalins in the supraspinal nociceptive processing and their underlying mechanism is not clear. The aim of present study was to compare supraspinal nociceptive and morphine antinociceptive responses between WT and ppENK KO mice.
Results
The genotypes of bred KO mice were confirmed by PCR. Met-enkephalin immunoreactive neurons were labeled in the caudate-putamen, intermediated part of lateral septum, lateral globus pallidus, intermediated part of lateral septum, hypothalamus, and amygdala of WT mice. Met-enkephalin immunoreactive neurons were not found in the same brain areas in KO mice. Tail withdrawal and von Frey test results did not differ between WT and KO mice. KO mice had shorter latency to start paw licking than WT mice in the hot plate test. The maximal percent effect of morphine treatments (5 mg/kg and 10 mg/kg, i.p.) differed between WT and KO mice in hot plate test. The current source density (CSD) profiles evoked by peripheral noxious stimuli in the primary somatosenstory cortex (S1) and anterior cingulate cortex (ACC) were similar in WT and KO mice. After morphine injection, the amplitude of the laser-evoked sink currents was decreased in S1 while the amplitude of electrical-evoked sink currents was increased in the ACC. These differential morphine effects in S1 and ACC were enhanced in KO mice. Facilitation of synaptic currents in the ACC is mediated by GABA inhibitory interneurons in the local circuitry. Percent increases in opioid receptor binding in S1 and ACC were 5.1% and 5.8%, respectively.
Conclusion
The present results indicate that the endogenous enkephalin system is not involved in acute nociceptive transmission in the spinal cord, S1, and ACC. However, morphine preferentially suppressed supraspinal related nociceptive behavior in KO mice. This effect was reflected in the potentiated differential effects of morphine in the S1 and ACC in KO mice. This potentiation may be due to an up-regulation of opioid receptors. Thus these findings strongly suggest an antagonistic interaction between the endogenous enkephalinergic system and exogenous opioid analgesic actions in the supraspinal brain structures.
doi:10.1186/1744-8069-4-41
PMCID: PMC2569012  PMID: 18826595
25.  COMT Val158Met genotypes differentially influence subgenual cingulate functional connectivity in healthy females 
Brain imaging studies have consistently shown subgenual Anterior Cingulate Cortical (sgACC) involvement in emotion processing. catechol-O-methyltransferase (COMT) Val158 and Met158 polymorphisms may influence such emotional brain processes in specific ways. Given that resting-state fMRI (rsfMRI) may increase our understanding on brain functioning, we integrated genetic and rsfMRI data and focused on sgACC functional connections. No studies have yet investigated the influence of the COMT Val158Met polymorphism (rs4680) on sgACC resting-state functional connectivity (rsFC) in healthy individuals. A homogeneous group of 61 Caucasian right-handed healthy female university students, all within the same age range, underwent rsfMRI. Compared to Met158 homozygotes, Val158 allele carriers displayed significantly stronger rsFC between the sgACC and the left parahippocampal gyrus, ventromedial parts of the inferior frontal gyrus (IFG), and the nucleus accumbens (NAc). On the other hand, compared to Val158 homozygotes, we found in Met158 allele carriers stronger sgACC rsFC with the medial frontal gyrus (MFG), more in particular the anterior parts of the medial orbitofrontal cortex. Although we did not use emotional or cognitive tasks, our sgACC rsFC results point to possible distinct differences in emotional and cognitive processes between Val158 and Met158 allele carriers. However, the exact nature of these directions remains to be determined.
doi:10.3389/fnhum.2014.00481
PMCID: PMC4074702  PMID: 25071511
sgACC; functional connectivity; COMT; females; genotype differences

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