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Pain-related neurons in the human cingulate cortex [2]
Abstract
Although it is widely accepted that the cortex participates in pain perception, there is no direct evidence for the existence of cortical neurons that respond to noxious or painful stimuli in humans. Anatomical and neurophysiological studies in animals as well as brain imaging and evoked potential studies in humans suggest that the anterior cingulate cortex (ACC) is an important area for processing sensory information related to pain1, 2, 3, 4, 5, 6, 7. We have now identified single neurons in ACC that respond selectively to painful thermal and mechanical stimuli, supporting a role for the ACC in pain perception.
... (Vogt, 2005) explained that the midline and intralaminar nuclei (MITN) projects to limbic cortex, amygdala and anterior cingulate cortex (ACC). Several studies have studies the role of ACC in pain responses (Barthas et al., 2015;Gasquoine, 2013;Hutchison et al., 1999;Iwata et al., 2005;Vogt et al., 1996Vogt et al., , 1993Xiao and Zhang, 2018). Interestingly, there are no nociceptive labelled lines that projects from L1 neurons to cingulate cortex. ...
... From the thalamus, thermal information is passed on to the next processing centers the somatosensory cortex: primary and secondary somatosensory cortex (S1, S2), insular cortex (Birklein et al., 2005;Downer and Zubek, 1954;Egan et al., 2005;Finger and Frommer, 1970;Gogolla et al., 2014;Greenspan et al., 1999;Hellon et al., 1973b;Landgren, 1957b;Peltz et al., 2011;Penfield and Faulk, 1955;Porter et al., 1993;Rodgers et al., 2008;Singh et al., 2020;Tsuboi et al., 1993;Veldhuijzen et al., 2010bVeldhuijzen et al., , 2010a. The cingulate cortex consisting of anterior, medial and posterior parts plays a major role in the emotional aspect of nociception and can be associated to thermal discomfort (Derbyshire et al., 1997;Devinsky et al., 1995;Fuchs et al., 2014;Hutchison et al., 1999;Kwan et al., 2000a;Vogt et al., 1993;Xiao and Zhang, 2018). ...
... The cingulate cortex: anterior, mid, posterior parts are typically activated during nociceptive processing and are responsible for affective responses (Devinsky et al., 1995;Gasquoine, 2013;Hoffman et al., 2004;Hutchison et al., 1999;Iwata et al., 2005;Nevian, 2017;Ploner et al., 2002;Vogt et al., 1993Vogt et al., , 1996Vogt, n.d.;Xiao and Zhang, 2018). Among the subparts, the anterior cingulate is widely studied in regard to pain processing and emotion. ...
The underlying central mechanisms of thermal coding are very complex and involves mainly the thalamus, somatosensory cortex, insular cortex, cingulate cortex and hypothalamus. The functional dependency of these brain regions in thermal sensation, thermal perception and thermal regulation has been of interest for researchers for decades. The aim of the thesis was to investigate the role of supraspinal circuitry in thermal coding in rodents using a new imaging modality named, functional ultrasound (FUS) imaging. FUS imaging is based on neurovascular coupling i.e., the phenomenon that links neural activity and changes in cerebral blood volume (CBV).Our first study aimed at mapping the matrix of areas activated by innocuous and noxious thermal skin stimulations in anesthetized rats. The outcome of this study was mostly negative. We concluded that innocuous stimuli did not induce any change of CBV. On the contrary, noxious thermal stimulations induced local increase of CBV, but in a non-reproducible manner, due to the physiological factors such as increased arterial blood pressure that leads to high fluctuations in CBV.The second study aimed at deciphering the interplay between the somato-motor, cingulate and hypothalamus regions in thermal processing. We chose to address this question, using FUS imaging on awake and freely moving mice, which allows recording of natural and innate brain responses without the bias of anesthesia. Transcranial FUS imaging was performed while the mice were exposed to either a fixed temperature (neutral 25°C, warm 35°Cand cold 15°C) or varying temperature at a fast and slow pace. Study of the functional connectivity, an indirect measure of brain network’s function and strength, revealed a dichotomy of function between the somato-motor (SM)-cingulate network and the SM-hypothalamic network in cold sensing. Study of the dynamic brain states revealed: i) specific modes for this dichotomy, ii) a mode in which, during static exposure to cold temperature (15°C) the cingulate cortices is differently connected to the other networks studies and finally iii) a ‘resting state’ mode, which is the most frequent of all as is more frequently present at the resting temperature. These results provide key information on the dynamic of networks in cold sensing.
... Des enregistrements de l'activité des neurones dans le cortex cingulaire humain ont montré que certains neurones réagissaient à des stimuli provoquant des sensations de douleur (Hutchison et al., 1999). Ces résultats sont cependant à nuancer par le fait qu'il a été montré qu'il était impossible de dissocier ce réseau de la douleur d'un réseau qui encoderait seulement la saillance (Mouraux et al., 2011) et que stimuler des patients implantés avec des électrodes intracrâniennes au niveau des neurones du cortex cingulaire antérieur ne provoque pas de sensation de douleur (Caruana et al., 2018;Hutchison et al., 1999). ...
... Des enregistrements de l'activité des neurones dans le cortex cingulaire humain ont montré que certains neurones réagissaient à des stimuli provoquant des sensations de douleur (Hutchison et al., 1999). Ces résultats sont cependant à nuancer par le fait qu'il a été montré qu'il était impossible de dissocier ce réseau de la douleur d'un réseau qui encoderait seulement la saillance (Mouraux et al., 2011) et que stimuler des patients implantés avec des électrodes intracrâniennes au niveau des neurones du cortex cingulaire antérieur ne provoque pas de sensation de douleur (Caruana et al., 2018;Hutchison et al., 1999). D'un autre côté, depuis 2014, des électrodes implantées dans le cortex et qui stimulent le cortex cingulaire antérieur permettent d'alléger les sensations de douleur chronique chez les patients qui en sont atteints (Boccard et al., 2014;Levi et al., 2019;Russo and Sheth, 2015;Spooner et al., 2007). ...
... par rapport à l'environnement présent est attrayante (Kolling et al., 2012(Kolling et al., , 2016b. Cette théorie expliquerait pourquoi le dmPFC s'active proportionnellement à l'intensité d'une douleur physique sans pour autant que son activité, quand il est stimulé, provoque de sensation subjective de douleur (Caruana et al., 2018;Hutchison et al., 1999). Cela est aussi cohérent avec l'hypothèse d'un système neural d'alarme, qui réagirait en réponse à toute menace, émise par Eisenberger et Lieberman (Eisenberger and Lieberman, 2004 (Parvizi et al., 2013). ...
Tous les jours, nous prenons des décisions sur les actions que nous souhaitons entreprendre. Ces décisions se fondent sur un compromis entre les bénéfices que nous espérons obtenir après avoir effectué ces actions, et les coûts, en termes d’effort, associés à ces actions. Cette thèse s’intéresse aux bases cérébrales du compromis coûts/bénéfices au travers de trois études menées chez des participants sains à l’aide de l’imagerie par résonance magnétique fonctionnelle. Dans la première étude, nous avons pu dissocier les bases cérébrales du calcul du compromis coûts/bénéfices des bases cérébrales des variables régulant ce calcul. En effet, dans cette étude, le calcul du compromis coûts/bénéfices était associé au cortex préfrontal ventromédian alors que la confiance dans la décision et le temps passé à délibérer étaient associés à des parties plus dorsales du cortex préfrontal médian. La seconde étude a permis de montrer que, dans deux tâches, impliquant un effort mental ou physique, la performance s’expliquait mieux par un biais pavlovien, donnant plus de poids aux gains qu’aux pertes, que par une aversion à la perte, telle qu’elle a été caractérisée principalement dans des tâches de choix. La troisième étude nous a permis de montrer que, même dans une tâche simple d’apprentissage par renforcement, les aires cérébrales liées à l’exécution d’un effort mental étaient recrutées au moment du calcul du compromis coûts/bénéfices, suggérant que cette tâche n’était pas effectuée de manière purement automatique. L’ensemble de nos résultats permet de mieux caractériser les aires cérébrales impliquées dans le compromis coûts/bénéfices et les conditions dans lesquelles ces aires sont actives.
... [11][12][13][14] The anterior cingulate cortex (ACC), in contrast, is involved in the processing of the aversive response to pain, [15][16][17][18][19] and activity in this region increases in response to noxious stimuli. [20][21][22][23][24][25] The activation of ACC, in turn, enhances pain aversion. 23,26 Excitatory glutamate signaling in neurons from different regions of the brain strongly impacts the regulation of pain behaviors, 7 and this is especially relevant for signaling through α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, which are the primary glutamate receptors in the central nervous system. ...
... 31 Whereas activation of PL-PFC is known to produce anti-nociceptive effects, activity of ACC neurons, on the other hand, plays a key role in processing the aversive response to pain. [15][16][17][18][19][20]26 Previous studies have shown that AMPAkines can specifically increase the nociceptive response in the PL-PFC, 31 and our results on the CPA assays indicate that their activity in the PL-PFC can also reduce painaversion. In contrast, we found that CX516 did not change the nociceptive response in individual excitatory neurons of the ACC. ...
Different brain areas have distinct roles in the processing and regulation of pain and thus may form specific pharmacological targets. Prior research has shown that AMPAkines, a class of drugs that increase glutamate signaling, can enhance descending inhibition from the prefrontal cortex (PFC) and nucleus accumbens. On the other hand, activation of neurons in the anterior cingulate cortex (ACC) is known to produce the aversive component of pain. The impact of AMPAkines on ACC, however, is not known. We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats. Furthermore, AMPAkines did not modulate the nociceptive response of ACC neurons. In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC.
... The activity of ACC neurons in both humans and rodents likely contributes to the transfer of stress induced by observing a conspecific suffering a stressor (Lamm et al., 2011;Carrillo et al., 2019). Aversive stimuli activate the ACC, and ACC mirror neurons in the observer encode the transfer of pain perception (Hutchison et al., 1999;Bastiaansen et al., 2009;Carrillo et al., 2019). Clearly, these findings must be taken into consideration in studies that aim to dissect the role that specific neuronal types in the ACC and neural pathways play in displaying transferred pain and anxiety (Sterley et al., 2018;Smith et al., 2021). ...
... The present study, alongside others (Wang et al., 2015;Tipps et al., 2018;Yin et al., 2020;Jiang et al., 2022), supports the notion that enhanced local inhibition and a consequent reduction in excitation of ACC Pyns promotes, at least in certain types of stress, the transfer of anxiety-like behavior and hyperalgesia. Finally, ACC responds to both observational and authentic stimulus (Hutchison et al., 1999) and some ACC neurons process the nociceptive and fear stimulus simultaneously (Carrillo et al., 2019). Neurons of different ACC circuits differentially encode various emotional states during social transfer (Cruz et al., 2020;Zheng et al., 2020;Smith et al., 2021;Zhang et al., 2022). ...
It is known that humans and rodents are capable of transmitting stress to their naïve partners via social interaction. However, a comprehensive understanding of transmitted stress, which may differ from authentic stress, thus revealing unique neural mechanisms of social interaction resulting from transmitted stress and the associated anxiety, is missing. We used, in the present study, maternal separation (MS) as a stress model to investigate whether MS causes abnormal behavior in adolescence. A key concern in the analysis of stress transmission is whether the littermates of MS mice who only witness MS stress (‘Partners’) exhibit behavioral abnormalities similar to those of MS mice themselves. Of special interest is the establishment of the neural mechanisms underlying transmitted stress and authentic stress. The results show that Partners, similar to MS mice, exhibit anxiety-like behavior and hyperalgesia after witnessing littermates being subjected to early-life repetitive MS. Electrophysiological analysis revealed that mice subjected to MS demonstrate a reduction in both the excitatory and inhibitory synaptic activities of parvalbumin interneurons (PVINs) in the anterior cingulate cortex (ACC). However, Partners differed from MS mice in showing an increase in the number and excitability of GABAergic PVINs in the ACC and in the ability of chemogenetic PVIN inactivation to eliminate abnormal behavior. Furthermore, the social transfer of anxiety-like behaviour required intact olfactory, but not visual, perception. This study suggests a functional involvement of ACC PVINs in mediating the distinct neural basis of transmitted anxiety.
Significance Statement
The ACC is a critical brain area in physical and social pain and contributes to the exhibition of abnormal behavior. ACC glutamatergic neurons have been shown to encode transmitted stress, but it remains unclear whether inhibitory ACC neurons also play a role. We evaluate, in this study, ACC neuronal, synaptic and network activities and uncover a critical role of PVINs in the expression of transmitted stress in adolescent mice who had witnessed MS of littermates in infancy. Furthermore, inactivation of ACC PVINs blocks transmitted stress. The results suggest that emotional contagion has a severe effect on brain function, and identify a potential target for the treatment of transmitted anxiety.
... Un mecanismo similar de simulación corporalizada está en la base también de nuestra capacidad para comprender el contenido experiencial de las sensaciones dolorosas de los demás. Experimentos de grabación de simples neuronas hechos sobre pacientes neuroquirúrgicos (Hutchison et al., 1999), y experimentos de fMRI (Singer et al., 2004;Morrison et al., 2004;Jackson, Meltzoff y Decety, 2005;Botvinick et al., 2005) y TMS (Avenanti et al., 2005) hechos sobre pacientes sanos, muestran que las mismas estructuras cerebrales son activadas tanto durante la experiencia sujetiva del dolor como durante la observación la observación directa o mediada de otro que está sufriendo la misma condición dolorosa. ...
... Es posible que factores de "alto nivel", como esquemas, defensas, conflictos o actitudes mentales, puedan influir en la activación de las neuronas espejo "desde arriba hacia abajo" (top-down). En este sentido es interesante observar que en los experimentos sobre la percepción del dolor que hemos descrito antes -los pacientes neuroquirúrgicos (Hutchison et al., 1999), con fMRI (Singer et al., 2004;Morrison et al., 2004;Jackson, Meltzoff y Decety, 2005;Botvinick et al., 2005) y TMS (Avenanti et al., 2005), y que demuestran que las mismas estructuras cerebrales son activadas tanto durante la experiencia subjetiva del dolor como durante la observación del dolor ajeno -hay diferencias en las áreas cerebrales activadas a nivel de las neuronas espejo según se viera la parte del cuerpo de otros sometida a la estimulación dolorosa o si estaba fuera de la vista y tuviera que ser imaginada. Singer y Frith (2005), sobre la base de estos hallazgos, han sostenido que ciertas actitudes mentales pueden influir en la respuesta del sistema de las neuronas espejo. ...
... The dmPFC and the ventral ACC are often activated in situations that trigger pain. [102][103][104][105] Neurons in the cingulate cortex respond to physical pain, 106 making it part of the 'pain matrix'. 107 However, cingulotomy, a treatment for chronic pain syndrome, 108 was abandoned, due to inconsistent results and personality changes. ...
... operating does not necessarily mean that the brain area is performing that cognitive process. Stimulating neurons in the human dmPFC and the adjacent ACC did not cause pain, 106,109 suggesting that this area activity is triggered by painful stimuli rather than causing the subjective sensation of pain. It was therefore proposed that the dmPFC/ACC activity is elicited by any salient stimulus that requires a reaction. ...
The dorsomedial prefrontal cortex/dorsal anterior cingulate cortex (dmPFC/dACC) is a brain area subject to many theories and debates over its function(s). Even its precise anatomical borders are subject to much controversy. In the past decades, the dmPFC/dACC has been associated with more than 15 different cognitive processes, which sometimes appear quite unrelated (e.g. body perception, cognitive conflict). As a result, understanding what the dmPFC/dACC does has become a real challenge for many neuroscientists. Several theories of this brain area's function(s) have been developed, leading to successive and competitive publications bearing different models, which sometimes contradict each other. During the last two decades, the lively scientific exchanges around the dmPFC/dACC have promoted fruitful research in cognitive neuroscience.
In this review, we provide an overview of the anatomy of the dmPFC/dACC, summarize the state of the art of functions that have been associated with this brain area and present the main theories aiming at explaining the dmPFC/dACC function(s). We explore the commonalities and the arguments between the different theories.
Finally, we explain what can be learned from these debates for future investigations of the dmPFC/dACC and other brain regions' functions.
... Electrophysiological recordings from ACC neurons in humans and experimental animals demonstrated that ACC neurons respond to noxious stimuli and show increased responses to more significant pain intensity. Nociceptive-specific ACC neurons responded to painful somatic thermal and mechanical stimuli; while some neurons had restricted receptive fields, others had more complex responses possibly related to higher integrative or cognitive functions [53]. Similar results have been observed in nonhuman primates and rodent studies [53][54][55][56]. ...
... Nociceptive-specific ACC neurons responded to painful somatic thermal and mechanical stimuli; while some neurons had restricted receptive fields, others had more complex responses possibly related to higher integrative or cognitive functions [53]. Similar results have been observed in nonhuman primates and rodent studies [53][54][55][56]. Animal behavioral studies found that inhibition of ACC activity through chemical or electrolytic lesions attenuates the affective component of the pain state [57,58], suggesting the role of ACC in pain perception. ...
Abdominal pain, including visceral pain, is prevalent in functional gastrointestinal (GI) disorders (FGIDs), affecting the overall quality of a patient’s life. Neural circuits in the brain encode, store, and transfer pain information across brain regions. Ascending pain signals actively shape brain dynamics; in turn, the descending system responds to the pain through neuronal inhibition. Pain processing mechanisms in patients are currently mainly studied with neuroimaging techniques; however, these techniques have a relatively poor temporal resolution. A high temporal resolution method is warranted to decode the dynamics of the pain processing mechanisms. Here, we reviewed crucial brain regions that exhibited pain-modulatory effects in an ascending and descending manner. Moreover, we discussed a uniquely well-suited method, namely extracellular electrophysiology, that captures natural language from the brain with high spatiotemporal resolution. This approach allows parallel recording of large populations of neurons in interconnected brain areas and permits the monitoring of neuronal firing patterns and comparative characterization of the brain oscillations. In addition, we discussed the contribution of these oscillations to pain states. In summary, using innovative, state-of-the-art methods, the large-scale recordings of multiple neurons will guide us to better understanding of pain mechanisms in FGIDs.
... There was significant reduction in pain (SF-MPQ) for the four ex-football players as a group at 1 month after the initial tPBM series. Pain-related neurons are present in the human ACC [101,102]. Placement of tPBM over the mPFC (target area of DMN) may have also delivered NIR photons to ACC, in close anatomical proximity. Targeting the ACC in SN with tPBM in chronic pain cases could be beneficial. ...
... Decreased NAA in ACC has been reported in chronic pain [110]. The importance of ACC (node in SN), and relevance of ACC and SN to pain were reviewed above (99)(100)(101)(102). ...
Background:
Chronic traumatic encephalopathy, diagnosed postmortem (hyperphosphorylated tau), is preceded by traumatic encephalopathy syndrome with worsening cognition and behavior/mood disturbances, over years. Transcranial photobiomodulation (tPBM) may promote improvements by increasing ATP in compromised/stressed cells and increasing local blood, lymphatic vessel vasodilation.
Objective:
Aim 1: Examine cognition, behavior/mood changes Post-tPBM. Aim 2: MRI changes - resting-state functional-connectivity MRI: salience, central executive, default mode networks (SN, CEN, DMN); magnetic resonance spectroscopy, cingulate cortex.
Methods:
Four ex-players with traumatic encephalopathy syndrome/possible chronic traumatic encephalopathy, playing 11- 16 years, received In-office, red/near-infrared tPBM to scalp, 3x/week for 6 weeks. Two had cavum septum pellucidum.
Results:
The three younger cases (ages 55, 57, 65) improved 2 SD (p < 0.05) on three to six neuropsychological tests/subtests at 1 week or 1 month Post-tPBM, compared to Pre-Treatment, while the older case (age 74) improved by 1.5 SD on three tests. There was significant improvement at 1 month on post-traumatic stress disorder (PTSD), depression, pain, and sleep. One case discontinued narcotic pain medications and had reduced tinnitus. The possible placebo effect is unknown. At 2 months Post-tPBM, two cases regressed. Then, home tPBM was applied to only cortical nodes, DMN (12 weeks); again, significant improvements were seen. Significant correlations for increased SN functional connectivity (FC) over time, with executive function, attention, PTSD, pain, and sleep; and CEN FC, with verbal learning/memory, depression. Increased n-acetyl-aspartate (NAA) (oxygen consumption, mitochondria) was present in anterior cingulate cortex (ACC), parallel to less pain and PTSD.
Conclusion:
After tPBM, these ex-football players improved. Significant correlations of increased SN FC and CEN FC with specific cognitive tests and behavior/mood ratings, plus increased NAA in ACC support beneficial effects from tPBM.
... iEEG measures local field potentials in cortical and deep brain structures with both millimeter and millisecond resolutions, offering the potential to detect rapid-timescale dynamics of neuronal population activity 25 . Several studies have investigated empathic processing using iEEG, providing electrophysiological evidence for the engagement of single neurons in the ACC 26 and broadband activity of insula 27 during the processing of others' pain. However, these studies focused exclusively on a single empathy-related region. ...
Empathy enables understanding and sharing of others’ feelings. Human neuroimaging studies have identified critical brain regions supporting empathy for pain, including the anterior insula (AI), anterior cingulate (ACC), amygdala, and inferior frontal gyrus (IFG). However, to date, the precise spatio-temporal profiles of empathic neural responses and inter-regional communications remain elusive. Here, using intracranial electroencephalography, we investigated electrophysiological signatures of vicarious pain perception. Others’ pain perception induced early increases in high-gamma activity in IFG, beta power increases in ACC, but decreased beta power in AI and amygdala. Vicarious pain perception also altered the beta-band-coordinated coupling between ACC, AI, and amygdala, as well as increased modulation of IFG high-gamma amplitudes by beta phases of amygdala/AI/ACC. We identified a necessary combination of neural features for decoding vicarious pain perception. These spatio-temporally specific regional activities and inter-regional interactions within the empathy network suggest a neurodynamic model of human pain empathy.
... The PFC is involved in the sensing of acute painful stimuli (Sakuma et al., 2014;Ong et al., 2018), with both the ACC-PFC and dorsolateral PFC (DLPFC) being activated by noxious stimulation (Hutchison et al., 1999;Nir et al., 2008). In addition, activation of the PFC is correlated with both anticipation and unpleasantness of pain (Lorenz et al., 2002;Porro et al., 2002). ...
The prefrontal cortex (PFC) has justifiably become a significant focus of chronic pain research. Collectively, decades of rodent and human research have provided strong rationale for studying the dysfunction of the PFC as a contributing factor in the development and persistence of chronic pain and as a key supraspinal mechanism for pain-induced comorbidities such as anxiety, depression, and cognitive decline. Chronic pain alters the structure, chemistry, and connectivity of PFC in both humans and rodents. In this review, we broadly summarize the complexities of reported changes within both rodent and human PFC caused by pain and offer insight into potential pharmacological and nonpharmacological approaches for targeting PFC to treat chronic pain and pain-associated comorbidities.
SIGNIFICANCE STATEMENT
Chronic pain is a significant unresolved medical problem causing detrimental changes to physiological, psychological, and behavioral aspects of life. Drawbacks of currently approved pain therapeutics include incomplete efficacy and potential for abuse producing a critical need for novel approaches to treat pain and comorbid disorders. This review provides insight into how manipulation of prefrontal cortex circuits could address this unmet need of more efficacious and safer pain therapeutics.
... The results revealed that the neurons responded similarly to both observation and execution of motor movement, leading to the naming of these cells as "mirror neurons. " 6,7 Further studies of the MNS have shown its participation in recognizing and experiencing primary emotions, 6,8,9 and emotional coloring of gestures or facial expressions seen through the connection with the insula. 10 The main methods for studying mirror neurons are functional magnetic resonance imaging (fMRI), positron emission tomography, transcranial magnetic stimulation (TMS), and electroencephalography (EEG). ...
The perception and comprehension of non-verbal information and body language in humans and higher primates are realized by the mirror neuron system (MNS). Anxiety and depressive symptoms may change social perception, which could manifest as functional changes in the MNS. In this paper, using the inverse electroencephalography (EEG) problem and rhythm suppression, we investigated spatial and frequency distortions of the MNS in 24 patients exhibiting depressive and anxiety symptoms and 23 controls. EEG was recorded during four motor tasks: action observation (where participants observed a hand gesture performed by a demonstrator), imagination, execution, and joint execution (simultaneous execution with the demonstrator). Mu suppression was employed across a wide frequency and spatial range to assess the level of MNS activity, while the sLORETA method was employed to localize the activity sources. The results indicate that the patients demonstrated task-selective mu suppression mainly during observation and joint execution in the frontal, central, and occipital areas of the cortex across a wide frequency range. In contrast, the controls demonstrated clear and pronounced mu rhythm suppression in the central regions of the brain in the upper-frequency range (10.5 – 13 Hz) during all mirroring tasks. These results suggest that patients with anxiety and depressive symptoms engage additional neural resources to complete social tasks, particularly involving auxiliary neural networks located in the frontal associative arrays and visual cortex.
... estudios experimentales han demostrado repetidamente que la ccma está críticamente involucrada en muchas funciones generales, no específicas para el dolor, incluyendo el afecto negativo y el control cognitivo 50 . por ejemplo, la ccm ha estado implicada en la detección de aumento del dolor, dadas sus características de respuesta para estimulación inocua 51-53 y estimulación nociva [54][55] . además, peyron et al. 47 encontraron que el dolor agudo aumentó el Fsc en la ccmin en voluntarios sanos. ...
Está bien establecido que existe una variabilidad individual en la sensibilidad al dolor y a la temperatura. Los estudios de imágenes cerebrales funcionales han encontrado que la variabilidad interindividual al dolor por calor se correlaciona con la actividad cerebral en las áreas de modulación sensorial y del dolor. Así, es posible que esas diferencias individuales estén asociadas a la variabilidad en el espesor de la materia gris de las regiones corticales involucradas en la termorecepción y el dolor. Para probar esto, hemos investigado la relación entre los umbrales térmicos y el espesor cortical en 80 sujetos sanos. Los sujetos fueron sometidos a una sesión psicofísica para determinar sus umbrales en la detección de frío (DF), la detección de calor (DC), del dolor al frío (DolF) y dolor al calor (DolC). De cada sujeto se adquirió una imagen de resonancia magnética estructural de alta resolución. Hemos correlacionado cada medida del umbral al espesor cortical de las regiones asociadas a la termorecepción y al dolor. Los umbrales promedio (± DE) fueron 30.7°C (± 0.8) para DF, 33.8°C (± 0.7) para DC, 11.7°C (± 9.7) para DolF, y 45.3°C (± 2.8) para DolC. El análisis de la materia gris cerebral reveló una fuerte correlación entre una mayor sensibilidad térmica y dolorosa y el engrosamiento de la corteza somatosensorial primaria. Adicionalmente, la mayor sensibilidad a los estímulos fríos se correlacionó con el engrosamiento cortical del lóbulo paracentral, y una mayor DC se correlacionó con la disminución en el espesor en la corteza cingulada media anterior. Hemos encontrado además que una mayor sensibilidad al DolC se correlacionó con la disminución en el espesor de la corteza cingulada media posterior y la corteza orbitofrontal. Estas correlaciones entre la materia gris cerebral y la sensibilidad a la temperatura y al dolor proporcionan las bases neurales para las diferencias individuales en la sensibilidad térmica.
... 27,29,62,70 Nonetheless, researchers agree that a small part of dACC is pain selective. 71 Using genetic neuroimaging approaches, the present study indicates that a subset of dACC might be a painselective area where two pain genes interact. We speculate that OPRM1 and COMT may control gene expression in pain-selective neurons in dACC. ...
Aim
Pain is reconstructed by brain activities and its subjectivity comes from an interplay of multiple factors. The current study aims to understand the contribution of genetic factors to the neural processing of pain. Focusing on the single‐nucleotide polymorphism (SNP) of opioid receptor mu 1 (OPRM1) A 118 G (rs1799971) and catechol‐O‐methyltransferase (COMT) val 158 met (rs4680), we investigated how the two pain genes affect pain processing.
Method
We integrated a genetic approach with functional neuroimaging. We extracted genomic DNA information from saliva samples to genotype the SNP of OPRM1 and COMT. We used a percept‐related model, in which two different levels of perceived pain intensities (“low pain: mildly painful” vs “high pain: severely painful”) were employed as experimental stimuli.
Results
Low pain involves a broader network relative to high pain. The distinct effects of pain genes were observed depending on the perceived pain intensity. The effects of low pain were found in supramarginal gyrus, angular gyrus, and anterior cingulate cortex (ACC) for OPRM1 and in middle temporal gyrus for COMT. For high pain, OPRM1 affected the insula and cerebellum, while COMT affected the middle occipital gyrus and ACC.
Conclusion
OPRM1 primarily affects sensory and cognitive components of pain processing, while COMT mainly influences emotional aspects of pain processing. The interaction of the two pain genes was associated with neural patterns coding for high pain and neural activation in the ACC in response to pain. The proteins encoded by the OPRM1 and COMT may contribute to the firing of pain‐related neurons in the human ACC, a critical center for subjective pain experience.
... 70 CG and pain: Pain perception in response to stimulation was infrequent, although pain-specific neurons have been observed, and CG's role in pain processing is known. [77][78][79] No specific cingulate subregion is exclusively involved in the pain response. 73 Instead, the cingulate regions appear to support a variety of relevant processes. ...
Background
The cingulate gyrus (CG), a brain structure above the corpus callosum, is recognised as part of the limbic system and plays numerous vital roles. However, its full functional capacity is yet to be understood. In recent years, emerging evidence from imaging modalities, supported by electrical cortical stimulation (ECS) findings, has improved our understanding. To our knowledge, there is a limited number of systematic reviews of the cingulate function studied by ECS. We aim to parcellate the CG by reviewing ECS studies.
Design/methods
We searched PubMed and Embase for studies investigating CG using ECS. A total of 30 studies met the inclusion criteria. We evaluated the ECS responses across the cingulate subregions and summarised the reported findings.
Results
We included 30 studies (totalling 887 patients, with a mean age of 31.8±9.8 years). The total number of electrodes implanted within the cingulate was 3028 electrode contacts; positive responses were obtained in 941 (31.1%, median percentages, 32.3%, IQR 22.2%–64.3%). The responses elicited from the CG were as follows. Simple motor (8 studies, 26.7 %), complex motor (10 studies, 33.3%), gelastic with and without mirth (7 studies, 23.3%), somatosensory (9 studies, 30%), autonomic (11 studies, 36.7 %), psychic (8 studies, 26.7%) and vestibular (3 studies, 10%). Visual and speech responses were also reported. Despite some overlap, the results indicate that the anterior cingulate cortex is responsible for most emotional, laughter and autonomic responses, while the middle cingulate cortex controls most complex motor behaviours, and the posterior cingulate cortex (PCC) regulates visual, among various other responses. Consistent null responses have been observed across different regions, emphasising PCC.
Conclusions
Our results provide a segmental mapping of the functional properties of CG, helping to improve precision in the surgical planning of epilepsy.
... Less is known, however, about how the brain, in particular the cortex, dynamically responds to a temporally regulated stimulus (Wager et al., 2013;Sun et al., 2021). Electroencephalography (EEG) provides recordings of oscillatory activity in the cortex both at rest and in response to noxious input with high temporal resolution (Hutchison et al., 1999;Pinheiro et al., 2016;Ploner and May, 2018;Levitt and Saab, 2019;Davis et al., 2020). Resting-state EEG studies have shown both increased and decreased power in peak alpha frequency and theta bands, increased beta-band power with increased event-related desynchronization (ERD) in the same bands, mainly in the frontal, parietal, and occipital cortices, and these studies are in general agreement with fMRI and PET results (De Vries et al., 2013;González-Roldán et al., 2016;Levitt et al., 2020;Rockholt et al., 2023). ...
Introduction
Chronic pain negatively impacts a range of sensory and affective behaviors. Previous studies have shown that the presence of chronic pain not only causes hypersensitivity at the site of injury but may also be associated with pain-aversive experiences at anatomically unrelated sites. While animal studies have indicated that the cingulate and prefrontal cortices are involved in this generalized hyperalgesia, the mechanisms distinguishing increased sensitivity at the site of injury from a generalized site-nonspecific enhancement in the aversive response to nociceptive inputs are not well known.
Methods
We compared measured pain responses to peripheral mechanical stimuli applied to a site of chronic pain and at a pain-free site in participants suffering from chronic lower back pain (n = 15) versus pain-free control participants (n = 15) by analyzing behavioral and electroencephalographic (EEG) data.
Results
As expected, participants with chronic pain endorsed enhanced pain with mechanical stimuli in both back and hand. We further analyzed electroencephalographic (EEG) recordings during these evoked pain episodes. Brain oscillations in theta and alpha bands in the medial orbitofrontal cortex (mOFC) were associated with localized hypersensitivity, while increased gamma oscillations in the anterior cingulate cortex (ACC) and increased theta oscillations in the dorsolateral prefrontal cortex (dlPFC) were associated with generalized hyperalgesia.
Discussion
These findings indicate that chronic pain may disrupt multiple cortical circuits to impact nociceptive processing.
... In our ANX symptom-level analysis, the area of the right posterior middle-cingulate gyrus was found to be negatively associated with tense sore or aching muscles during the worst period of anxiety. The cingulate gyrus is involved in processing pain and emotions, containing neurons with large somatic receptive fields and predominantly engaged in nociceptive activation (58). In particular, this brain region could mediate the affective-motivational component of pain processing (18). ...
Background: To gain insights into the role of brain structure and function on anxiety (ANX), we conducted a genetically informed investigation leveraging information from ANX genome-wide association studies available from UK Biobank (UKB; N=380,379), FinnGen Program (N=290,361), and Million Veteran Program (MVP; N=199,611) together with UKB genome-wide data (N=33,224) related to 3,935 brain imaging-derived phenotypes (IDP).
Methods: A genetic correlation analysis between ANX and brain IDPs was performed using linkage disequilibrium score regression. To investigate ANX-brain associations, a two-sample Mendelian randomization (MR) was performed considering multiple methods and sensitivity analyses. A subsequent multivariable MR (MVMR) was executed to distinguish between direct and indirect effects. Finally, a generalized linear model was used to explore the associations of brain IDPs with ANX symptoms.
Results: After false discovery rate correction (FDR q<0.05), we identified 41 brain IDPs genetically correlated with ANX without heterogeneity among the datasets investigated (i.e., UKB, FinnGen, and MVP). Six of these IDPs showed genetically inferred causal effects on ANX. In the subsequent MVMR analysis, reduced area of the right posterior middle-cingulate gyrus (rpMCG; beta=-0.09, P=8.01e-4) and reduced gray-matter volume of the right anterior superior temporal gyrus (raSTG; beta=-0.09, P=1.55e-3) had direct effects on ANX. In the ANX symptom-level analysis, rpMCG was negatively associated with 'tense sore or aching muscles during the worst period of anxiety' (beta=-0.13, P=8.26e-6).
Conclusions: This study identified genetically inferred effects generalizable across large cohorts, contributing to understand how changes in brain structure and function can lead to ANX.
... In rodents, all of these brain regions are also activated while witnessing the distress of others (see Keysers et al., 2022 for a review) and most are necessary for emotional contagion (see Paradiso et al., 2021 for a review). This similarity goes deep: the human literature suggests that reactivating neural representations of the observer's own pain in the cingulate is central to empathy (Hutchison et al., 1999;Lamm et al., 2011;Singer et al., 2004). Rats and mice have a directly homologue cingulate area 24 (van Heukelum et al., 2020;Vogt, 2015), and inhibiting this region reduces emotional contagion in rats Han et al., 2019) and mice (Jeon et al., 2010;Keum et al., 2018;S. ...
Affective empathy, the ability to share the emotions of others, is an important contributor to the richness of our emotional experiences. Here, we review evidence that rodents show signs of fear and pain when they witness the fear and pain of others. This emotional contagion creates a vicarious emotion in the witness that mirrors some level of detail of the emotion of the demonstrator, including its valence and the vicinity of threats, and depends on brain regions such as the cingulate, amygdala, and insula that are also at the core of human empathy. Although it remains impossible to directly know how witnessing the distress of others feels for rodents, and whether this feeling is similar to the empathy humans experience, the similarity in neural structures suggests some analogies in emotional experience across rodents and humans. These neural homologies also reveal that feeling distress while others are distressed must serve an evolutionary purpose strong enough to warrant its stability across ~ 100 millions of years. We propose that it does so by allowing observers to set in motion the very emotions that have evolved to prepare them to deal with threats — with the benefit of triggering them socially , by harnessing conspecifics as sentinels, before the witness personally faces that threat. Finally, we discuss evidence that rodents can engage in prosocial behaviors that may be motivated by vicarious distress or reward.
... Notably, in all prior human neurosurgical cases, lesions of ACC and VMPFC, ACC alone, or the cingulum bundle connecting ACC to more posterior brain regions were necessary for the observed reductions in pain affect (Daum et al., 1995;Davis et al., 1994;Foltz & White, 1962;Freeman & Watts, 1947;Talbot et al., 1995). Further, in both humans and animal models, individual neurons within the ACC (but not VMPFC or rodent homologue infralimbic cortex) have been shown to be pain responsive (Hutchison et al., 1999;Johansen et al., 2001). The absence of more profound effects on pain processing and pain thresholds suggests that spared regions in our sample (e.g., ACC) are more likely than VMPFC to mediate these effects. ...
Pain is strongly modulated by expectations and beliefs. Across species, subregions of ventromedial prefrontal cortex (VMPFC) are implicated in a variety of functions germane to pain, predictions, and learning. Human fMRI studies show that VMPFC activity tracks expectations about pain and mediates expectancy effects on pain-related activity in other brain regions. Prior lesion studies suggest that VMPFC may instead play a more general role in generating affective responses to painful stimuli. To test whether VMPFC is required to generate affective responses to pain or is more specifically involved in expectancy-based pain modulation, we studied responses to heat stimuli in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage. All participants underwent a quantitative sensory testing procedure followed by a pain expectancy task in which cues predicting either low or high pain were followed by intermittent medium intensity heat stimuli. Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expected pain based on predictive cues and failed to update expectations following the covert introduction of unexpected medium temperature stimuli. Consistent with observed expectancy differences, subjective pain unpleasantness ratings in the VMPFC lesion group were more strongly modulated by cue during thermal stimulation. We found no group differences in overall pain sensitivity, nor in relationships between pain and autonomic arousal, suggesting that VMPFC damage specifically enhances the effect of expectations on pain processing, likely driven by impaired integration of new sensory feedback to update expectations about pain. These results provide essential new data regarding the specific functional contribution of VMPFC to pain modulation.
... Most previous attempts to identify pain biomarkers have focused on healthy participants and experimental thermal pain, which ignores natural, spontaneous fluctuations in individuals' chronic pain experience [4][5][6][7] . Even studies of spontaneous chronic pain severity are limited by characterization over short timescales (minutes) due to reliance on ex vivo technologies such as electroencephalography 7 and blood-oxygen-level-dependent functional magnetic resonance imaging 8,9 that are not amenable to frequent, long-term measurement. ...
Chronic pain syndromes are often refractory to treatment and cause substantial suffering and disability. Pain severity is often measured through subjective report, while objective biomarkers that may guide diagnosis and treatment are lacking. Also, which brain activity underlies chronic pain on clinically relevant timescales, or how this relates to acute pain, remains unclear. Here four individuals with refractory neuropathic pain were implanted with chronic intracranial electrodes in the anterior cingulate cortex and orbitofrontal cortex (OFC). Participants reported pain metrics coincident with ambulatory, direct neural recordings obtained multiple times daily over months. We successfully predicted intraindividual chronic pain severity scores from neural activity with high sensitivity using machine learning methods. Chronic pain decoding relied on sustained power changes from the OFC, which tended to differ from transient patterns of activity associated with acute, evoked pain states during a task. Thus, intracranial OFC signals can be used to predict spontaneous, chronic pain state in patients.
... For example, evidence has suggested that the ACC is involved in conflict monitoring (Botvinick et al., 2001;Botvinick, 2007), decision-making (Bush et al., 2002;Gehring and Willoughby, 2002;Kennerley et al., 2006;Botvinick, 2007), reward learning (Hadland et al., 2003;Amiez et al., 2005), and error-processing (Carter et al., 1998;Gehring and Fencsik, 2001;Garavan et al., 2002). The ACC also is involved in pain perception (Rainville et al., 1997;Hutchison et al., 1999;Vogt, 2009), empathetic perception of pain in others (Lloyd et al., 2004), social pain (Eisenberger et al., 2003; though see Wager et al., 2016; for a review see Rotge et al., 2015) and negative affect (Bush et al., 2000;Etkin et al., 2010). Interestingly, there is even evidence suggesting that the ACC is connected to the cardiovascular system via the vagus nerve (Thayer et al., 2012), potentially integrating information about extant stressors. ...
The error negativity/error-related negativity (Ne/ERN) is one of the most well-studied event-related potential (ERP) components in the electroencephalography (EEG) literature. Peaking about 50 ms after the commission of an error, the Ne/ERN is a negative deflection in the ERP waveform that is thought to reflect error processing in the brain. While its relationships to trait constructs such as anxiety are well-documented, there is still little known about how the Ne/ERN may subsequently influence task-related behavior. In other words, does the occurrence of the Ne/ERN trigger any sort of error corrective process, or any other behavioral adaptation to avoid errors? Several theories have emerged to explain how the Ne/ERN may implement or affect behavior on a task, but evidence supporting each has been mixed. In the following manuscript, we review these theories, and then systematically discuss the reasons that there may be discrepancies in the literature. We review both the inherent biological factors of the neural regions that underlie error-processing in the brain, and some of the researcher-induced factors in analytic and experimental choices that may be exacerbating these discrepancies. We end with a table of recommendations for future researchers who aim to understand the relationship between the Ne/ERN and behavior.
... Gallese further categorises three levels upon which intersubjectivity is shared, namely (my interpretation is in parentheses) the phenomenological (experiential-observation), functional (physical modellingaction), and subpersonal (neural mirroring) levels. Supporting the hypothesis with existing empirical research by Hutchison et al. (1999), Calder et al. (2000, and Jarvilehto (2000), Gallese summarises the multi-state sharing in the following way-"the representation and understanding of the observed behaviour of others is made possible through a simulation mechanism that matches action observation and execution onto the same neural substrate" (45). This summary links the experience of viewing with kinesthetic empathy and the shared emotional experience in kinesthetic empathy via neural mirroring. ...
This paper explores the connection between kinesthetic empathy, embodied cognition, and abstract thought and language as a form of extended cognition in audiences of inclusive dance. The exploration grounds itself in the analysis of primary data collected from interviews with audience members of an inclusive dance performance that studied their critical engagement with the concept of disability. Drawn from the interviews are specific choreographic moments and emotions evoked in those audience members, and associates the choreography and emotions with possible experiences of kinesthetic empathy and ways of understanding ability and disability in the context of dance. The analysis contributes to a greater understanding of the impact that takes place when watching inclusive dance performances, and other dance performances that resist or challenge dominant social identity categories. The research contributes to the reduction of the intrinsic instrumental divide in creative work, expanding the spaces into which cultural value can be considered.
... In contrast, invasive neurophysiological recordings can be used to detect events that occur on the order of milliseconds. Prior work using invasive recordings in animal models has shown how neurons in various brain regions process nociceptive inputs [13,[15][16][17][18][19][20][21][22][23]. However, in most of these studies, a single region of the brain was targeted. ...
Pain is known to have sensory and affective components. The sensory pain component is encoded by neurons in the primary somatosensory cortex (S1), whereas the emotional or affective pain experience is in large part processed by neural activities in the anterior cingulate cortex (ACC). The timing of how a mechanical or thermal noxious stimulus triggers activation of peripheral pain fibers is well-known. However, the temporal processing of nociceptive inputs in the cortex remains little studied. Here, we took two approaches to examine how nociceptive inputs are processed by the S1 and ACC. We simultaneously recorded local field potentials in both regions, during the application of a brain-computer interface (BCI). First, we compared event related potentials in the S1 and ACC. Next, we used an algorithmic pain decoder enabled by machine-learning to detect the onset of pain which was used during the implementation of the BCI to automatically treat pain. We found that whereas mechanical pain triggered neural activity changes first in the S1, the S1 and ACC processed thermal pain with a reasonably similar time course. These results indicate that the temporal processing of nociceptive information in different regions of the cortex is likely important for the overall pain experience.
... Early single neuron recordings in cingulotomy patients showed that ACC neurons respond selectively to mechanical and thermal painful stimuli, but not to innocuous stimuli (Hutchison et al., 1999). Likewise, single-unit recordings in rabbits demonstrate that ACC neurons which respond to noxious stimuli have diffuse receptive fields covering the entire body (Sikes and Vogt, 1992). ...
Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms.
... For the anterior cingulate, we have intracranial recordings: Hutchison et al., 1999 documented a single neuron in epileptic patients that responded to the sight of a finger being pin-pricked with increased firing rate, and a recent rodent study revealed that cingulate neurons responding to pain experience have responses that increase with the intensity of the pain experienced by another rat (Carrillo et al., 2019). In contrast, although the insula is central in the neuroimaging literature on empathy, and shows increases of BOLD signal for watching painful compared to nonpainful social stimuli (Jabbi et al., 2007;Jauniaux et al., 2019;Lamm et al., 2011;Meffert et al., 2013;Singer et al., 2004;Timmers et al., 2018;Wicker et al., 2003), and shows patterns that encode painfulness (Corradi-Dell'Acqua et al., 2016;Krishnan et al., 2016;Zhou et al., 2020), we still lack insular intracranial recordings while individuals witness the pain of others. ...
Based on neuroimaging data, the insula is considered important for people to empathize with the pain of others. Here we present intracranial electroencephalographic (iEEG) recordings and single-cell recordings from the human insulae while 7 epilepsy patients rated the intensity of a woman's painful experiences seen in short movie clips. Pain had to be deduced from seeing facial expressions or a hand being slapped by a belt. We found activity in the broadband 20-190 Hz range correlated with the trial-by-trial perceived intensity in the insula for both types of stimuli. Within the insula, some locations had activity correlating with perceived intensity for our facial expressions but not for our hand stimuli, others only for our hand but not our face stimuli, and others for both. The timing of responses to the sight of the hand being hit is best explained by kinematic information; that for our facial expressions, by shape information. Comparing the broadband activity in the iEEG signal with spiking activity from a small number of neurons and an fMRI experiment with similar stimuli, revealed a consistent spatial organization, with stronger associations with intensity more anteriorly, while viewing the hand being slapped.
... Early human electrophysiological studies reported that individual ACC neurons preferentially show increases in firing rate in response to either acute noxious cold stimuli, noxious thermal and mechanical stimuli, or only mechanical stimuli [26]. ACC neurons display differential or graded responses in firing patterns in response to words with high emotional valence and are likely implicated in the salience detection of painful or emotional stimuli [27]. ...
Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult animals are highly plastic and can undergo long-term potentiation (LTP), a phenomenon that is also reported in brain areas for learning and memory (such as the hippocampus). Genetic and pharmacological studies show that inhibiting such cortical LTP can help to reduce behavioral sensitization caused by injury as well as injury-induced emotional changes. In this review, we will summarize recent progress related to synaptic mechanisms for different forms of cortical LTP and their possible contribution to behavioral pain and emotional changes.
... [89][90][91][92][93][94] This interpretation has been supported not only by different neuroimaging studies but also by electrophysiological data in humans reporting singleneuron activations during noxious or painful (pinprick, pinch) cutaneous stimulations. 18 Notably, the same authors reported that the electrical stimulation of the same sites where they recorded pain-sensitive neurons failed to elicit painful or unpleasant sensations, even with high currents. ...
In this review, we retrace the results of 70 years of human cingulate cortex (CC) intracerebral electrical stimulation and discuss its contribution to our understanding of the anatomofunctional and clinical aspects of this wide cortical region. The review is divided into three main sections. In the first section, we report the results obtained by the stimulation of the anterior, middle, and posterior CC, in 30 studies conducted on approximately 1,000 patients from the 1950s to the present day. These studies show that specific manifestations can be reliably associated with specific cingulate subfields, with autonomic, interoceptive, and emotional manifestations clustered in the anterior cingulate, goal-oriented motor behaviors elicited from the anterior midcingulate and a variety of sensory symptoms characterizing the posterior cingulate regions. In the second section, we compare the effect of CC intracerebral electrical stimulation with signs and manifestations characterizing cingulate epilepsy, showing that the stimulation mapping of CC subfields provides precious information for understanding cingulate epileptic manifestations. The last section tackles the issue of the discrepancy emerging when comparing the results of clinical (electrical stimulation, epilepsy) studies-revealing the quintessential affective and motor nature of the CC-with that reported by neuroimaging studies-which focus on high-level cognitive functions. Particular attention will be paid to the hypothesis that CC hosts a "Pain Matrix" specifically involved in pain perception, which we will discuss in the light of the fact that the stimulation of CC (as well as cingulate epileptic seizures) does not induce nociceptive effects.
... However, whether the medial pathway is specialized in processing this particular pain component has been challenged 33 . It has also been shown that the MCC contains neurons responding specifically to nociception 35 and exhibits generalizable multivariate pain-specific representations 36 . Another brain region with a stable representation across individuals was the dpIns, which is among the regions that best track the perceived intensity of pain 37 and are most consistently reported in pain neuroimaging studies 38 . ...
Characterizing cerebral contributions to individual variability in pain processing is crucial for personalized pain medicine, but has yet to be done. In the present study, we address this problem by identifying brain regions with high versus low interindividual variability in their relationship with pain. We trained idiographic pain-predictive models with 13 single-trial functional MRI datasets (n = 404, discovery set) and quantified voxel-level importance for individualized pain prediction. With 21 regions identified as important pain predictors, we examined the interindividual variability of local pain-predictive weights in these regions. Higher-order transmodal regions, such as ventromedial and ventrolateral prefrontal cortices, showed larger individual variability, whereas unimodal regions, such as somatomotor cortices, showed more stable pain representations across individuals. We replicated this result in an independent dataset (n = 124). Overall, our study identifies cerebral sources of individual differences in pain processing, providing potential targets for personalized assessment and treatment of pain. Pain experience is highly individual, but its individual-specific brain features remain unclear. The authors identify brain regions with consistent versus variable representations of pain across a large sample of individuals.
... The anterior cingulate cortex (ACC) is believed to be important for mediating emotional and attentive responses to internal and external noxious stimuli [3,4,[13][14][15][16]. Various electrophysiological experiments have demonstrated that ACC neurons respond to noxious stimuli in different species including mouse, rat, rabbit, monkey and human [17][18][19][20]. More recently, works based on animal models of chronic pain have begun to reveal the cellular and molecular mechanisms of pain-induced LTP in the ACC (see [4] for review). ...
Long-term potentiation (LTP) is the key cellular mechanism for physiological learning and pathological chronic pain. In the anterior cingulate cortex (ACC), postsynaptic recruitment or modification of AMPA receptor (AMPAR) GluA1 contribute to the expression of LTP. Here we report that pyramidal cells in the deep layers of the ACC send direct descending projecting terminals to the dorsal horn of the spinal cord (lamina I-III). After peripheral nerve injury, these projection cells are activated, and postsynaptic excitatory responses of these descending projecting neurons were significantly enhanced. Newly recruited AMPARs contribute to the potentiated synaptic transmission of cingulate neurons. PKA-dependent phosphorylation of GluA1 is important, since enhanced synaptic transmission was abolished in GluA1 phosphorylation site serine-845 mutant mice. Our findings provide strong evidence that peripheral nerve injury induce long-term enhancement of cortical-spinal projecting cells in the ACC. Direct top-down projection system provides rapid and profound modulation of spinal sensory transmission, including painful information. Inhibiting cortical top-down descending facilitation may serve as a novel target for treating neuropathic pain.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19–85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes.
In order for social interactions in general, and empathic understanding in particular to be carried out optimally, an adjustment of the common representations is necessary. If projecting the traits of the self upon others does not require the storage of knowledge about them, empathic understanding necessarily presupposes the inclusion of the catacteristics of others in the personal self. However, empathy means no complete overlap or confusion of one’s emotions with others, so mental flexibility becomes an important aspect of empathy. The individual needs to calibrate his own perspective, which is activated by interaction with the other, or even by his mere imagination. This calibration involves the involvement of executive functions that are mediated by the prefrontal cortex
The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.
The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACCGlu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTADA) by activating local GABAergic interneurons (VTAGABA), and this effect is reinforced after nerve injury. VTADA neurons in turn project to the ACC and synapse to the initial ACCGlu neurons to convey feedback information from emotional changes. Thus, an ACCGlu–VTAGABA–VTADA–ACCGlu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.
Current understanding of the physiological underpinnings of normative pain processing is incomplete. Enhanced knowledge of these systems is necessary to advance our understanding of pain processes as well as to develop effective therapeutic interventions. Previous neuroimaging research suggests a network of interrelated brain regions that seem to be implicated in the processing and experience of pain. Among these, the dorsal anterior cingulate cortex (dACC) plays an important role in the affective aspects of pain signals. The current study leveraged functional MRS to investigate the underlying dynamic shifts in the neurometabolic signature of the human dACC at rest and during acute pain. Results provide support for increased glutamate levels following acute pain administration. Specifically, a 4.6% increase in glutamate was observed during moderate pressure pain compared with baseline. Exploratory analysis also revealed meaningful changes in dACC gamma aminobutyric acid in response to pain stimulation. These data contribute toward the characterization of neurometabolic shifts, which lend insight into the role of the dACC in the pain network. Further research in this area with larger sample sizes could contribute to the development of novel therapeutics or other advances in pain‐related outcomes.
The insula and the cingulate are key brain regions with many heterogenous functions. Both regions are consistently shown to play integral roles in the processing of affective, cognitive, and interoceptive stimuli. The anterior insula (aINS) and the anterior mid-cingulate cortex (aMCC) are two key hubs of the salience network (SN). Beyond the aINS and aMCC, previous 3 Tesla (T) magnetic resonance imaging studies have suggested both structural connectivity (SC) and functional connectivity (FC) between other insular and cingulate subregions. Here, we investigate the SC and FC between insula and cingulate subregions using ultra-high field 7T diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rs-fMRI). DTI revealed strong SC between posterior INS (pINS) and posterior MCC (pMCC), and rs-fMRI revealed strong FC between the aINS and aMCC that was not supported by SC, indicating the likelihood of a mediating structure. Finally, the insular pole had the strongest SC to all cingulate subregions, with a slight preference for the pMCC, indicative of a potential relay node of the insula. Together these finding shed new light on the understanding of insula-cingulate functioning, both within the SN and other cortical processes, through a lens of its SC and FC.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
The Cambridge Handbook of Consciousness is the first of its kind in the field, and its appearance marks a unique time in the history of intellectual inquiry on the topic. After decades during which consciousness was considered beyond the scope of legitimate scientific investigation, consciousness re-emerged as a popular focus of research towards the end of the last century, and it has remained so for nearly 20 years. There are now so many different lines of investigation on consciousness that the time has come when the field may finally benefit from a book that pulls them together and, by juxtaposing them, provides a comprehensive survey of this exciting field. An authoritative desk reference, which will also be suitable as an advanced textbook.
How pain emerges from human brain remains an unresolved question in pain neuroscience. Neuroimaging studies have suggested that all brain areas activated by painful stimuli were also activated by tactile stimuli, and vice versa. Nonetheless, pain-preferential spatial patterns of voxel-level activation in the brain have been observed when distinguishing painful and tactile brain activations using multivariate pattern analysis (MVPA). According to two hypotheses, the neural activity pattern preferentially encoding pain could exist at a global, coarse-grained, regional level, corresponding to the "pain connectome" hypothesis proposing that pain-preferential information may be encoded by the synchronized activity across multiple distant brain regions, and/or exist at a local, fine-grained, voxel level, corresponding to the "intermingled specialized/preferential neurons" hypothesis proposing that neurons responding specially or preferentially to pain could be present and intermingled with non-pain neurons within a voxel. Here, we systematically investigated the spatial scales of pain-distinguishing information in the human brain measured by fMRI using machine learning techniques, and found that pain-distinguishing information could be detected at both coarse-grained spatial scales across widely distributed brain regions and fine-grained spatial scales within many local areas. Importantly, the spatial distribution of pain-distinguishing information in the brain varies across individuals and such inter-individual variations may be related to a person's trait about pain perception, particularly the pain vigilance and awareness. These results provide new insights into the long-standing question of how pain is represented in the human brain and help the identification of characteristic neuroimaging measurements of pain.
Neuroplasticity in cortico-limbic circuits has been implicated in pain persistence and pain modulation in clinical and preclinical studies. The amygdala has emerged as a key player in the emotional-affective dimension of pain and pain modulation. Reciprocal interactions with medial prefrontal cortical regions undergo changes in pain conditions. Other limbic and paralimbic regions have been implicated in pain modulation as well. The cortico-limbic system is rich in opioids and opioid receptors. Preclinical evidence for their pain modulatory effects in different regions of this highly interactive system, potentially opposing functions of different opioid receptors, and knowledge gaps will be described here. There is little information about cell type- and circuit-specific functions of opioid receptor subtypes related to pain processing and pain-related plasticity in the cortico-limbic system. The important role of anterior cingulate cortex (ACC) and amygdala in MOR-dependent analgesia is most well-established, and MOR actions in the mesolimbic system appear to be similar but remain to be determined in mPFC regions other than ACC. Evidence also suggests that KOR signaling generally serves opposing functions whereas DOR signaling in the ACC has similar, if not synergistic effects, to MOR. A unifying picture of pain-related neuronal mechanisms of opioid signaling in different elements of the cortico-limbic circuitry has yet to emerge.
In recent years there has been an increasing awareness that a comprehensive understanding of language, cognitive and affective processes, and social and interpersonal phenomena cannot be achieved without understanding the ways these processes are grounded in bodily states. The term 'embodiment' captures the common denominator of these developments, which come from several disciplinary perspectives ranging from neuroscience, cognitive science, social psychology, and affective sciences. For the first time, this volume brings together these varied developments under one umbrella and furnishes a comprehensive overview of this intellectual movement in the cognitive-behavioral sciences. The chapters review current work on relations of the body to thought, language use, emotion and social relationships as presented by internationally recognized experts in these areas.
In recent years there has been an increasing awareness that a comprehensive understanding of language, cognitive and affective processes, and social and interpersonal phenomena cannot be achieved without understanding the ways these processes are grounded in bodily states. The term 'embodiment' captures the common denominator of these developments, which come from several disciplinary perspectives ranging from neuroscience, cognitive science, social psychology, and affective sciences. For the first time, this volume brings together these varied developments under one umbrella and furnishes a comprehensive overview of this intellectual movement in the cognitive-behavioral sciences. The chapters review current work on relations of the body to thought, language use, emotion and social relationships as presented by internationally recognized experts in these areas.
In recent years there has been an increasing awareness that a comprehensive understanding of language, cognitive and affective processes, and social and interpersonal phenomena cannot be achieved without understanding the ways these processes are grounded in bodily states. The term 'embodiment' captures the common denominator of these developments, which come from several disciplinary perspectives ranging from neuroscience, cognitive science, social psychology, and affective sciences. For the first time, this volume brings together these varied developments under one umbrella and furnishes a comprehensive overview of this intellectual movement in the cognitive-behavioral sciences. The chapters review current work on relations of the body to thought, language use, emotion and social relationships as presented by internationally recognized experts in these areas.
Effective treatments for chronic pain remain limited. Conceptually, a closed-loop neural interface combining sensory signal detection with therapeutic delivery could produce timely and effective pain relief. Such systems are challenging to develop because of difficulties in accurate pain detection and ultrafast analgesic delivery. Pain has sensory and affective components, encoded in large part by neural activities in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), respectively. Meanwhile, studies show that stimulation of the prefrontal cortex (PFC) produces descending pain control. Here, we designed and tested a brain-machine interface (BMI) combining an automated pain detection arm, based on simultaneously recorded local field potential (LFP) signals from the S1 and ACC, with a treatment arm, based on optogenetic activation or electrical deep brain stimulation (DBS) of the PFC in freely behaving rats. Our multiregion neural interface accurately detected and treated acute evoked pain and chronic pain. This neural interface is activated rapidly, and its efficacy remained stable over time. Given the clinical feasibility of LFP recordings and DBS, our findings suggest that BMI is a promising approach for pain treatment.
The pineal gland participates in the internal temporal organization of the vertebrate organism by the rhythmic synthesis of its hormone melatonin. This hormone is considered the darkness hormone because of its unique feature of being synthesized exclusively at night, regardless of the organism activity pattern. The presence and absence of this indolamine help to mark, respectively, dark and light time, i.e., night and day, to the organism. Moreover, the daily duration of the secretory episode of melatonin, synchronized to the duration of the night in the environment, times the several physiological regulatory processes in order to adapt the organism to the annual seasonal environmental variation.
The mechanisms of melatonin production are different among the several classes of vertebrates. In fishes, amphibians, some reptiles and birds, the pineal gland is photosensitive, whereas in mammals the photosensitivity is absent. In this case, the light periodical information is conveyed to the gland through a neural pathway that originates in the retina, projects to the hypothalamic suprachiasmatic region, including the suprachiasmatic nuclei (the circadian biological clock in vertebrates) and, then, indirectly to the pineal gland.
The signal that stimulates melatonin synthesis during the dark period of the daily light/dark cycle, in mammals, is the neurotransmitter noradrenaline, which is released from the sympathetic terminals of neurons whose cell body are located in the superior cervical ganglia. This transmitter interacts with adrenoreceptors in the pinealocytes membrane, resulting in cAMP and calcium elevation that induces melatonin synthesis.
The signaling cascade that involves cAMP triggers and/or increases the arylalkylamine N-acetyltransferase transcription and translation, as well as its activation by phosphorylation and association with 14-3-3 protein. This enzyme converts serotonin into N-acetylserotonin that is then transformed by hydroxyindole-O-methyltransferase into melatonin. These two steps occur only at night.
Melatonin, immediately after being synthesized, is released to the systemic circulation and it influences almost every physiological function in the organisms. It regulates the circadian clock, rest-activity and wake-sleep cycles, immunological system, energy metabolism and many other functions. Melatonin also influences the seasonal rhythms through the variation observed in its plasmatic profile duration according to the length of night. Among the seasonal physiological functions modulated by melatonin are reproduction, immune response, and metabolic adaptations and weight.
Melatonin is an ancestral molecule as it appears soon in the evolutionary chain and it is ubiquitous in the living organisms. It seems that early in evolution melatonin could have had an anti-oxidative role, protecting the primitive life from the possible oxidation process mainly dependent on light and aerobiosis. This property is still conserved by its intracellular direct interaction with other molecules involved in oxidation. Besides, melatonin has its proper receptors, known as MT1, MT2 and MT3 which are found in the central nervous system and peripheral organs.
Thus, melatonin is part of a photo-neuroendocrine temporal system, which adapts the organisms to the external environmental cyclic fluctuations, like day and night and the seasons, regulating most of the physiological regulatory processes, including insulin synthesis and action, playing a putative role in the pathophysiology of diabetes mellitus.
Clinical studies of cingulotomy patients and imaging studies predict that the human cingulate gyrus might display pain-related activity. We now report potentials evoked by painful cutaneous stimulation with a CO2 laser (LEP) and recorded from subdural electrodes over the medial wall of the hemisphere. In response to facial laser stimulation on both sides, a negative (latency 211-242 ms) and then a positive wave (325-352 ms) were recorded from the cortex of right medial wall and from the falcine dura overlying the left medial wall. Medial wall LEPs were similar to scalp LEPs and were largest over the anterior cingulate and superior frontal gyri just anterior to motor cortex contralateral to the side of stimulation. These results demonstrate that there is significant direct nociceptive input to the human anterior cingulate gyrus (Brodmann's area 24).
Light-induced phase shifts of the circadian locomotor rhythm of hamsters can be blocked by agents that alter GABA neurotransmission. The GABA antagonist bicuculline blocks phase delays induced by light and the benzodiazepine diazepam, which can potentiate GABA activity, blocks light-induced phase advances. In the experiments reported here, we found that the bicuculline blockade of phase delays was reduced by agents that mimic or potentiate GABA activity. Conversely, the diazepam blockade of phase advances was reduced by both competitive and noncompetitive antagonists of GABA. This indicates that the GABA-benzodiazepine receptor-ionophore complex is the most likely site of action for the effects of these drugs on circadian rhythms. However, competitive GABA agonists did not mimic the blocking effects of benzodiazepines, nor did the antagonist picrotoxin mimic the blocking effect of bicuculline. Therefore, the classic action of GABA, increased chloride conductance, may not be the effector mechanism in this case. We also found that the GABAB agonist baclofen blocked both phase advances and delays and that the blockade of advances was reversed by the antagonist delta-aminovaleric acid. Taken together, these results indicate that GABA is involved in the regulation of circadian responses to light and that the regulation is mediated by both GABAA and GABAB receptors.
Pain is a diverse sensory and emotional experience that likely involves activation of numerous regions of the brain. Yet, many of these areas are also implicated in the processing of nonpainful somatosensory information. In order to better characterize the processing of pain within the human brain, activation produced by noxious stimuli was compared with that produced by robust innocuous stimuli. Painful heat (47-48 degrees C), nonpainful vibratory (110 Hz), and neutral control (34 degrees C) stimuli were applied to the left forearm of right-handed male subjects. Activation of regions within the diencephalon and telencephalon was evaluated by measuring regional cerebral blood flow using positron emission tomography (15O-water-bolus method). Painful stimulation produced contralateral activation in primary and secondary somatosensory cortices (SI and SII), anterior cingulate cortex, anterior insula, the supplemental motor area of the frontal cortex, and thalamus. Vibrotactile stimulation produced activation in contralateral SI, and bilaterally in SII and posterior insular cortices. A direct comparison of pain and vibrotactile stimulation revealed that both stimuli produced activation in similar regions of SI and SII, regions long thought to be involved in basic somatosensory processing. In contrast, painful stimuli were significantly more effective in activating the anterior insula, a region heavily linked with both somatosensory and limbic systems. Such connections may provide one route through which nociceptive input may be integrated with memory in order to allow a full appreciation of the meaning and dangers of painful stimuli. These data reveal that pain-related activation, although predominantly contralateral in distribution, is more widely dispersed across both cortical and thalamic regions than that produced during innocuous vibrotactile stimulation. This distributed cerebral activation reflects the complex nature of pain, involving discriminative, affective, autonomic, and motoric components. Furthermore, the high degree of interconnectivity among activated regions may account for the difficulty of eliminating pathological pain with discrete CNS lesions.
1. We wished to determine whether there are differences in the spatial pattern and intensity of synaptic activity within the conscious human forebrain when different forms and intensities of innocuous and noxious thermal stimuli are experienced. Accordingly, positron emission tomography (PET) with intravenous injection of H2(15)O was used to detect increases in regional cerebral blood flow (rCBF) in normal humans as they discriminated differences in the intensity of noxious and innocuous thermal stimulation applied to the nondominant (left) arm. After stereotactic registration, subtraction images were formed from each subject by subtracting counts of emissions obtained during lower-intensity stimulation from those obtained during stimulation at higher intensities. A statistical summation analysis (Z score) of individual voxels was performed. In addition, volumes of interest were chosen on the basis of a priori hypotheses and the results of previously published PET studies. In both types of analysis, statistical thresholds were established with corrections for multiple comparisons. 2. Twenty-seven subjects were divided into three groups of nine subjects each for the three phases of this investigation. For studies in which repetitive contact heat stimuli were used, each subject was instructed in magnitude estimation on the basis of a scale for which 0 indicated "no heat sensation," 7 "just barely painful," and 10 "just barely tolerable." For the study of pain elicited by immersion of the hand in cold water, subjects were instructed to use a scale in which 0 represented "no pain" and 10 represented just barely tolerable pain. 3. In the warm-discrimination study, two intensities of innocuous heat (36 and 43 degrees C) were applied with a thermode as repetitive 5-s contacts to the volar forearm for a total of approximately 100 s, 8 stimuli before and 12 during each scan. Each temperature was applied on alternate scans for a total of four scans per subject. Neither stimulus was rated painful. All subjects discriminated the 43 degrees C stimulus (average rating 5.90 +/- 1.43, mean +/- SD) from the 36 degrees C stimulus (1.96 +/- 1.08, mean +/- SD; t = 13.19, P < 0.0001). Significant increases in rCBF to the 43 degrees C stimuli were found in the contralateral ventral posterior thalamus, lenticular nucleus, medial prefrontal cortex (Brodmann's areas 10 and 32), and cerebellar vermis. 4. The procedure for discriminating between noxious and innocuous heat stimuli was identical to that used for warm discrimination except that the stimulation temperatures were 40 and 50 degrees C. All subjects rated the 50 degrees C stimuli as painful (average rating 8.9 +/- 0.9, mean +/- SD) and the 40 degrees C stimuli as warm, but not painful (2.1 +/- 1.0). Significant rCBF increases to 50 degrees C stimuli were found contralaterally in the thalamus, anterior cingulate cortex, premotor cortex, and secondary somatosensory (S2) and posterior insular cortices. Significant activity also appeared within the region of the contralateral anterior insula and lenticular nucleus. The ipsilateral premotor cortex and thalamus, and the medial dorsal midbrain and cerebellar vermis, also showed significant rCBF increases. Cerebral blood flow (CBF) increases just below the threshold for statistical significance were seen in the contralateral sensorimotor cortex [primary motor cortex (M1)/primary somatosensory cortex (S1)]. 5. For discrimination between tonic innocuous cold and tonic cold pain, the left hand was immersed to the wrist, throughout each of six scans, in water kept at an average temperature of either 20.5 +/- 1.15 degrees C (mean +/- SD) or 6.02 +/- 1.18 degrees C (mean +/- SD) on alternate scans. All subjects rated the intensity of the stimuli on a scale in which 0 indicated no pain and 10 represented barely tolerable pain. Subjects rated the 20 degrees C water immersion as painless (average rating 0.18 +/- 0.48, mean +/- SD), but gave ratings indicating i
Mammals manifest circadian behaviour timed by an endogenous clock in the hypothalamic suprachiasmatic nucleus (SCN). Considerable progress has been made in identifying the molecular basis of the circadian clock, but the mechanisms by which it is translated into cyclic firing activity, high during the day and low at night, are still poorly understood. GABA (gamma-aminobutyric acid), a common inhibitory neurotransmitter in the central nervous system, is particularly densely distributed within the SCN, where it is located in the majority of neuronal somata and synaptic terminals. Using an in vitro brain-slice technique, we have now studied the effect of bath-applied GABA on adult SCN neurons at various times of the day. We find that GABA acts as an inhibitory neurotransmitter at night, decreasing the firing frequency; but during the day GABA acts as an excitatory neurotransmitter, increasing the firing frequency. We show that this dual effect, which is mediated by GABA(A) receptors, may be attributed to an oscillation in intracellular chloride concentration. A likely explanation is that the amplitude of the oscillation in firing rate, displayed by individual neurons, is amplified by the dual effect of GABA in the SCN's GABAergic network.
Recent evidence demonstrating multiple regions of human cerebral cortex activated by pain has prompted speculation about their individual contributions to this complex experience. To differentiate cortical areas involved in pain affect, hypnotic suggestions were used to alter selectively the unpleasantness of noxious stimuli, without changing the perceived intensity. Positron emission tomography revealed significant changes in pain-evoked activity within anterior cingulate cortex, consistent with the encoding of perceived unpleasantness, whereas primary somatosensory cortex activation was unaltered. These findings provide direct experimental evidence in humans linking frontal-lobe limbic activity with pain affect, as originally suggested by early clinical lesion studies.
This study demonstrates the involvement of the MT2 (Mel1b) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin. In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt1 and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 microg/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 microg/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 microg/mouse]. Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 microg/mouse, s.c.) nor luzindole (300 microg/mouse, s.c.), which shows 25-fold higher affinity for the MT2 than the mt1 subtype, affected the phase of circadian activity rhythms when given alone at CT 10. All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 microg melatonin. This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.
Neurosurgical and positron emission tomography (PET) human studies and animal electrophysiological studies show that part of the anterior cingulate cortex (ACC) is nociceptive. Since the contribution of the ACC to pain processing is poorly understood, this study employed PET and magnetic resonance (MR) image co-registration in grouped and individual cases to locate regions of altered relative regional cerebral blood flow (rCBF). Seven right-handed, neurologically intact males were subjects; each received neuropsychological and pain threshold testing. Subjects were scanned during infusion of H2[15O]: four randomized scans during innocuous heat stimulation to the back of the left hand and four scans during noxious but bearable heat to the same place. The averaged rCBF values during innocuous stimuli were subtracted from those during noxious stimuli and statistical parametric maps (SPMs) for the group were computed to identify regions of altered relative rCBF. Finally, single-subject PET images of elevated and reduced rCBF were co-registered with MR images and projected onto reconstructions of the medial surface of the hemisphere. The SPM analysis of the group showed one site with elevated rCBF in the midcingulate cortex and one in the perigenual cortex predominantly contralateral to the side of stimulation. There were bilateral sites of reduced rCBF in the cingulofrontal transitional cortex and in the posterior cingulate cortex (PCC). Co-registered PET and MR images for individuals showed that only one case had a single, large region of elevated rCBF, while the others had a number of smaller regions. Six cases had at least one significant elevation of rCBF in the right hemisphere that primarily involved area 24b'; five of these cases also had an elevation in area 32′, while the seventh case had elevated rCBF in these areas in the left hemisphere. The rostral site of elevated rCBF in the group was at the border of areas 24/24’and areas 32/32′, although most cases had a site of elevation more rostral in the perigenual cingulate cortex. The ACC site of reduced rCBF was in areas 8 and 32 and that in the PCC included much of areas 29/30 in the callosal sulcus, areas 23b and 31 on the cingulate gyral surface and parietal area 7m. The localization of relative rCBF changes suggests different roles for the cingulate cortex in pain processing: (i) elevated rCBF in area 24’may be involved in response selection like nocifensive reflex inhibition; (ii) activation of the perigenual cortex may participate in affective responses to noxious stimuli like suffering associated with pain; and (iii) reduced rCBF in areas 8 and 32 may enhance pain perception in the perigenual cortex, while that in the PCC may disengage visually guided processes.
The cingulate gyrus is a major part of the "anatomical limbic system" and, according to classic accounts, is involved in emotion. This view is oversimplified in light of recent clinical and experimental findings that cingulate cortex participates not only in emotion but also in sensory, motor, and cognitive processes. Anterior cingulate cortex, consisting of areas 25 and 24, has been implicated in visceromotor, skeletomotor, and endocrine outflow. These processes include responses to painful stimuli, maternal behavior, vocalization, and attention to action. Since all of these activities have an affective component, it is likely that connections with the amygdala are critical for them. In contrast, posterior cingulate cortex, consisting of areas 29, 30, 23, and 31, contains neurons that monitor eye movements and respond to sensory stimuli. Ablation studies suggest that this region is involved in spatial orientation and memory. It is likely that connections between posterior cingulate and parahippocampal cortices contribute to these processes. We conclude that there is a fundamental dichotomy between the functions of anterior and posterior cingulate cortices. The anterior cortex subserves primarily executive functions related to the emotional control of visceral, skeletal, and endocrine outflow. The posterior cortex subserves evaluative functions such as monitoring sensory events and the organism's own behavior in the service of spatial orientation and memory.
1. Single-unit responses in area 24 of cingulate cortex were examined in halothane-anesthetized rabbits during stimulation of the skin with transcutaneous electrical (TCES, 3-10 mA), mechanical (smooth or serrated forceps to the dorsal body surface or graded pressures of 100-1,500 g to the stabilized ear) and thermal (> 25 degrees C) stimulation. 2. Of 542 units tested in cingulate cortex, 150 responded to noxious TCES (> or = 6 mA), 93 of 221 units tested responded to noxious mechanical (serrated forceps) and 9 of 47 units tested responded to noxious heat (> 43 degrees C) stimuli. Twenty-five percent of the units that responded to noxious mechanical stimuli also responded to noxious heat stimuli. The only innocuous stimulus that evoked activity in cingulate cortex was a "tap" to the skin and this was effective for 11 of 14 tested units. 3. In 74 units that produced excitatory responses to TCES of the contralateral ear, response latency was 166 +/- 11.3 (SE) ms and response duration was 519 +/- 52.1 ms. 4. Twenty of the 150 units that responded to noxious TCES were initially inhibited. These responses were usually < 1 s in duration (17 of 20 units), whereas responses in the other 3 lasted for over 20 s. 5. Most units had broad receptive fields, because noxious mechanical stimuli anywhere on the dorsal surface of the rabbits, including the face and ears, evoked responses. A small number of units for which the entire body surface was tested (3 of 15 units) had receptive fields limited to the ears, rostral back, and forepaws. 6. Fifteen of 33 units tested had no preferential responses to noxious TCES of the ipsilateral and contralateral ears. Of the remaining units, 10 had a greater response to contralateral and 8 had a greater response to ipsilateral stimuli. 7. The locations of 186 units were histologically verified. Most nociceptive cingulate units were in dorsal area 24b in layers III (n = 35), II (n = 13), or V (n = 9). 8. Cortical knifecut lesions were made in five rabbits to determine if the responses in area 24 were dependent on lateral or posterior cortical inputs. These lesions did not alter the percentage of units driven by noxious stimuli nor response latency. 9. Injections of lidocaine were made into medial parts of the thalamus in six animals and injection and recording sites analyzed histologically.(ABSTRACT TRUNCATED AT 400 WORDS)
The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However,
with the use of magnetic resonance imaging and positron emission tomography in humans, it has now been demonstrated that painful
heat causes significant activation of the contralateral anterior cingulate, secondary somatosensory, and primary somatosensory
cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in
similar experiments. Furthermore, the unilateral cingulate activation indicates that this forebrain area, thought to regulate
emotions, contains an unexpectedly specific representation of pain.
We describe microelectrode recording and stimulation techniques to delineate the cellular boundaries and neural projections of stereotactic brain targets. These techniques have applications in the surgery for pain, movement disorders and in psychosurgery. Neuronal records from stereotactic operations including thalamotomy, pallidotomy, cingulotomy and anterior capsulotomy are discussed. These tools are used to distinguish gray matter from white matter, to obtain direct measures of cellular activity in the target, to identify the physiological properties and receptive fields of the subpopulation of neurons at the electrode tip and to avoid lesion making induced injury to adjacent structures. Microelectrode recording and stimulation techniques improve physiological localization and decrease the possibility of unwanted neurological complications with functional stereotactic procedures.
Neurosurgical and positron emission tomography (PET) human studies and animal electrophysiological studies show that part of the anterior cingulate cortex (ACC) is nociceptive. Since the contribution of the ACC to pain processing is poorly understood, this study employed PET and magnetic resonance (MR) image co-registration in grouped and individual cases to locate regions of altered relative regional cerebral blood flow (rCBF). Seven right-handed, neurologically intact males were subjects; each received neuropsychological and pain threshold testing. Subjects were scanned during infusion of H2[15O]: four randomized scans during innocuous heat stimulation to the back of the left hand and four scans during noxious but bearable heat to the same place. The averaged rCBF values during innocuous stimuli were subtracted from those during noxious stimuli and statistical parametric maps (SPMs) for the group were computed to identify regions of altered relative rCBF. Finally, single-subject PET images of elevated and reduced rCBF were co-registered with MR images and projected onto reconstructions of the medial surface of the hemisphere. The SPM analysis of the group showed one site with elevated rCBF in the midcingulate cortex and one in the perigenual cortex predominantly contralateral to the side of stimulation. There were bilateral sites of reduced rCBF in the cingulofrontal transitional cortex and in the posterior cingulate cortex (PCC). Co-registered PET and MR images for individuals showed that only one case had a single, large region of elevated rCBF, while the others had a number of smaller regions. Six cases had at least one significant elevation of rCBF in the right hemisphere that primarily involved area 24b'; five of these cases also had an elevation in area 32', while the seventh case had elevated rCBF in these areas in the left hemisphere. The rostral site of elevated rCBF in the group was at the border of areas 24/24' and areas 32/32' although most cases had a site of elevation more rostral in the perigenual cingulate cortex. The ACC site of reduced rCBF was in areas 8 and 32 and that in the PCC included much of areas 29/30 in the callosal sulcus, areas 23b and 31 on the cingulate gyral surface and parietal area 7m. The localization of relative rCBF changes suggests different roles for the cingulate cortex in pain processing: (i) elevated rCBF in area 24' may be involved in response selection like nocifensive reflex inhibition; (ii) activation of the perigenual cortex may participate in affective responses to noxious stimuli like suffering associated with pain; and (iii) reduced rCBF in areas 8 and 32 may enhance pain perception in the perigenual cortex, while that in the PCC may disengage visually guided processes.
Touching warm and cool bars that are spatially interlaced produces a painful burning sensation resembling that caused by intense, noxious cold. We demonstrated previously that this thermal grill illusion can be explained as an unmasking phenomenon that reveals the central inhibition of pain by thermosensory integration. In order to localize this unmasking in the human brain, we have used positron emission tomography (PET) to compare the cortical activation patterns evoked by the thermal grill and by cool, warm, noxious cold and noxious heat stimuli. The thermal grill illusion produces activation in the anterior cingulate cortex, whereas its component warm and cool stimuli do not. This area is also activated by noxious heat or cold. Thus, increased activity in the anterior cingulate cortex appears to be selectively associated with the perception of thermal pain. Disruption of thermosensory and pain integration may account for the central pain syndrome that can occur after stroke damage.
Binding assays using 2-[125I]iodomelatonin revealed high-affinity, guanosine 5'-O-(3-thiotriphosphate) sensitive, melatonin binding sites (B(max) 1.1 fmol/mg protein) in the human embryonic kidney cell line HEK293. Competition studies using the selective melatonin receptor antagonist luzindole and RT-PCR techniques identified these sites as human Mel1a melatonin receptors. Challenge of HEK293 cells with 1 microM melatonin had no effect on forskolin stimulated cyclic AMP levels, whereas in HEK293 cells engineered to stably over-express the human Mel1a melatonin receptor (B(max) > 400 fmol/mg protein) melatonin dose-dependently inhibited stimulated cyclic AMP levels (IC50 7.7 pM). These data may indicate that certain tissues, expressing low levels of G protein-coupled melatonin receptors, do not display melatonin mediated inhibition of cAMP.
This year marks the silver anniversary of the discovery of the circadian clock function of the mammalian SCN (seeKlein et al. 1991xKlein, D.C., Moore, R.Y., and Reppert, S.M. See all ReferencesKlein et al. 1991. Over the past 25 years, great progress has been made in understanding the physiological basis of mammalian circadian rhythms. Progress has been slower, however, on the cellular, biochemical, molecular, and genetic fronts. The cloning of the first candidate clock gene from a mammal should help ensure that progress over the next 25 years accelerates to CLOCK-breaking speed.
The aims of the study were to use functional magnetic resonance imaging (fMRI) to 1) locate pain-related regions in the anterior cingulate cortex (ACC) of normal human subjects and 2) determine whether each subject's pain-related activation is congruent with ACC regions involved in attention-demanding cognitive processes. Ten normal subjects underwent fMRI with a 1.5-T standard commercial MRI scanner. A conventional gradient echo technique was used to obtain data from a single 4-mm sagittal slice of the left ACC, approximately 3.5 mm from midline. For each subject, interleaved sets of 6 images were obtained during a pain task, an attention-demanding task, and at rest, for a total of 36 images per task. Pain of different intensities was evoked via electrical stimulation of the right median nerve. The attention-demanding task consisted of silent word generation (verbal fluency). Additional experiments obtained data from the right ACC. A pixel-by-pixel statistical analysis of task versus rest images was used to determine task-related activated regions. The pain task resulted in a 1.6-4.0% increase in mean signal intensity within a small region of the ACC. The exact location of this activation varied from subject to subject, but was typically in the posterior part of area 24. The signal intensity changes within this region correlated with pain intensity reported by the subject. The attention-demanding tasks increased the mean signal intensity by 1.3-3.3% in a region anterior and/or superior to the pain-related activation in each subject. The activated region was typically larger than the pain-related activation. In some cases this activation was at or superior to the ACC border, near the supplementary motor area. These regions did not show any pain-intensity-related activation. In one subject both right and left ACC were imaged, revealing bilateral ACC activation during the attention task but only contralateral pain-related activation. These findings shed light on pain- and attention-related cognitive processes. The results provide evidence for a region in the posterior part of the ACC that is involved in pain and a more anterior region involved in other attention-demanding cognitive tasks.
Since the anterior cingulate cortex (ACC) is known to be involved both in nociception and in anticipation that precedes the avoidance of aversive stimuli, the linking of these functions may be processed in the ACC. To test this hypothesis, we recorded single neuronal activities in the ACC of a macaque monkey while it was performing a pain-avoidance task and examined them with nociceptive cutaneous electric stimuli (ES). Thirty-six neurons responded in anticipation of the ES. Of these, 22 neurons were tested with the ES and 11 responded. These neurons could be those that are involved both in nociception and in pain anticipation that precedes the avoidance of noxious stimuli.
Much progress has been made during the past year in the molecular dissection of the circadian clock. Recently identified circadian genes in mouse, Drosophila, and cyanobacteria demonstrate the universal nature of negative feedback regulation as a circadian mechanism; furthermore, the mouse and Drosophila genes are structurally and functionally conserved. In addition, the discovery of brain-independent clocks promises to revolutionize the study of circadian biology.
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