Molecular mechanisms of pain in the anterior cingulate cortex

It is well known that peripheral sensory stimuli, including pain, trigger a series of neuronal activities along the somatosensory pathways as well as the neuronal network in the high brain structures. These neuronal activities not only produce appropriate physiological responses but also induce long-term plastic changes in some of the central synapses. It is believed that long-term synaptic changes help the brain to process and store new information. Such learning is critical for animals and humans to gain new knowledge of changing environment, generate appropriate emotional responses, and avoid dangerous stimuli in the future. In the case of permanent injury, however, the brain fails to distinguish the difference between "useful" and painful stimuli. Long-term synaptic changes work against the system and at least in part contribute to chronic pain. In this short article, the possible molecular mechanisms for long-term plasticity within the anterior cingulate cortex (ACC) will be discussed and reviewed, and it is hypothesized that potentiation of excitatory responses within the ACC contributes to chronic pain and pain-related mental disorders.     

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain‐like behaviors in sciatic nerve‐ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level‐dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve‐ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT‐3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve‐ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin‐2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain‐like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. Synapse 68:235–247, 2014 . © 2014 Wiley Periodicals, Inc.     

Plasticity changes of neuronal activities in central lateral nucleus by stimulation of the anterior cingulate cortex in rat

The medial thalamus (MT) and anterior cingulate cortex (ACC) are essential components in mediating the affective emotional-aspect of pain. Whether ACC modulates the neuron activity in MT has not been elucidated and clarifying this point will further reveal the neurobiological mechanism underlying pain related emotions. In the present study, we used in vivo single unit recording and retrograde tracing technique to demonstrate that the majority of examined neurons in the central lateral nucleus (CL), an important nucleus of MT, responded to noxious stimulation. Tetanic stimulation in the ACC increased spike activities of nociceptive-responding neurons in the CL; retrograde tracing by fluorogold in the CL showed the positive neurons are distributed bilaterally in the ACC. Taken together, we demonstrated descending modulation to nociceptive responses of CL neurons by direct projections from the ACC, which may underlie the neuronal mechanism of negative pain emotions.     

Magnetic resonance spectroscopy of the anterior cingulate cortex in eating disorders

The anterior cingulate cortex plays a key role in eating disorders (ED), but it remains an open question whether there are deviations of the neurochemistry of this region in patients with ED. Seventeen adult female patients with ED (10 with bulimia nervosa, 7 with anorexia nervosa) were compared to 14 matched female healthy controls using single voxel magnetic resonance spectroscopy of the anterior cingulate cortex. Group comparisons did not reveal any differences between patients and controls, but a positive correlation between glutamate and myo-inositol signals with “drive for thinness” in patients with bulimia nervosa was found in exploratory correlation analyses.     

The anterior cingulate cortex and the phonatory control in monkey and man

Electrical stimulation of the anterior cingulate cortex yields vocalization in the monkey. The elicited vocalizations seem to represent primary stimulus responses. Monkeys are not able to perform a vocal conditioning task after ablation of the anterior cingulate cortex. However, they can carry out a lever-pressing conditioning task following destruction of this area. It is hypothesized that the anterior cingulate cortex exerts the volitional control of species-specific vocalizations in monkey. The non-verbal emotional vocal utterances are considered to be the human homologue of monkey's vocalizations. Therefore, bilateral lesion of the anterior cingulate cortex in man should hamper the volitional control of emotional vocal utterances in man as it does in monkeys. One personal observation is reported where after a bilateral infarction of the anterior cingulate cortex the patient's voice showed a permanent lack of emotional expression. The anterior cingulate cortex seems to play the decisive role in the volitional verbalization of emotions.     

Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction of long-term potentiation in rats

Objective

To explore the role of the extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) pathway in the induction of long-term potentiation (LTP) in the anterior cingulate cortex (ACC) that may be implicated in pain-related negative emotion.

Methods

LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK (pERK) and phospho-CREB (pCREB) were examined using immunohistochemistry method.

Results

LTP could be induced stably in ACC slice by high frequency stimulation (2-train, 100 Hz, 1 s), while APv (an antagonist of NMDA receptor) could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 (50 μmol/L), a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 min and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB.

Conclusion

NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion.     

Contribution of the anterior cingulate cortex to laser-pain conditioning in rats

The emotional component of nociception is seldom distinguished from pain behavioral testing. The aim of the present study was to develop a behavioral test that indicates the emotional pain responses using the classical conditioning paradigm. The role of the anterior cingulate cortex (ACC) in the process of this pain conditioning response was also evaluated. In laser-pain conditioning, free moving rats were trained to associate a tone (conditioned stimulus, CS) and short CO₂ laser pulsation (unconditioned stimulus, US). Monotonous tone (800 Hz, 0.6 s) was delivered through a loud-speaker as CS. CO₂ laser pulses (5 W at 50 or 100 ms in duration) applied to the hind paw was adopted as US. The CS–US interval was 0.5 s. Laser-pain conditioning was developed during 40 CS–US pairings. CS and US pairing with 100-ms laser pulse stimuli was more effective in establishing conditioning responses than that of 50-ms stimuli. The conditioning responses remained, tested by presenting CS alone, immediate to and 24 h subsequent to training. The performance of laser-pain conditioning was significantly reduced after bilateral lesioning of the ACC. Similar results were also obtained by bilateral lesions of the amygdala. The conditioning responses were also diminished following morphine treatment. The association between a neutral stimulus and a noxious stimulus could be demonstrated in a Pavlovian conditioning test in free moving rats. Thus, the conditioned response may be employed as a measure of the emotional component of the nociception. It is also suggested that the ACC may play an important role in mediating this conditioning effect.     

Spatial and temporal plasticity of synaptic organization in anterior cingulate cortex following peripheral inflammatory pain: multi-electrode array recordings in rats

To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization,the planar multi-electrode array(MEA)technique and 2-dimensional current source density(2D-CSD)imaging were used in slice preparations of the anterior cingulate cortex(ACC)from rats.Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode.The layer-localization of both local field potentials(LFPs)and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically.Moreover,the induction of long-term potentiation(LTP)and changes in LTP magnitude were also evaluated.We found that under na ve conditions,the current sink was initially generated in layer VI,then spread to layer V and finally confined to layers II–III.This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers(V–VI)to superficial layers(II–III)where intra-and extracortical inputs terminate.In the ACC slices from rats in an inflamed state(for 2 h)caused by intraplantar bee-venom injection,the spatial profile of intra-ACC synaptic organization was significantly changed,showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the na ve and saline controls.The change was more distinct in the superficial layers(II–III)than in the deep site.In terms of temporal properties,the rate of LTP induction was significantly increased in layers II–III by inflammatory pain.However,the magnitude of LTP was not significantly enhanced by this treatment.Taken together,these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC,which may lead to altered synaptic transmission and modulation.     

A meta-analysis of the anterior cingulate contribution to social pain

Many functional magnetic resonance imaging studies have explored the neural correlates of social pain that results from social threat, exclusion, rejection, loss or negative evaluation. Although activations have consistently been reported within the anterior cingulate cortex (ACC), it remains unclear which ACC subdivision is particularly involved. To provide a quantitative estimation of the specific involvement of ACC subdivisions in social pain, we conducted a voxel-based meta-analysis. The literature search identified 46 articles that included 940 subjects, the majority of which used the cyberball task. Significant likelihoods of activation were found in both the ventral and dorsal ACC for both social pain elicitation and self-reported distress during social pain. Self-reported distress involved more specifically the subgenual and pregenual ACC than social pain-related contrasts. The cyberball task involved the anterior midcingulate cortex to a lesser extent than other experimental tasks. During social pain, children exhibited subgenual activations to a greater extent than adults. Finally, the ventro-dorsal gradient of ACC activations in cyberball studies was related to the length of exclusion phases. The present meta-analysis contributes to a better understanding of the role of ACC subdivisions in social pain, and it could be of particular importance for guiding future studies of social pain and its neural underpinnings.     

Real time fMRI feedback of the anterior cingulate and posterior insular cortex in the processing of pain

Self‐regulation of brain activation using real‐time functional magnetic resonance imaging has been used to train subjects to modulate activation in various brain areas and has been associated with behavioral changes such as altered pain perception. The aim of this study was to assess the comparability of upregulation versus downregulation of activation in the rostral anterior cingulate cortex (rACC) and left posterior insula (pInsL) and its effect on pain intensity and unpleasantness. In a first study, we trained 10 healthy subjects to separately upregulate and downregulate the blood oxygenation level‐dependent response in the rACC or pInsL (six trials on 4 days) in response to painful electrical stimulation. The participants learned to significantly downregulate activation in pInsL and rACC and upregulate pInsL but not rACC. Success in the modulation of one region and direction of the modulation was not significantly correlated with success in another condition, indicating that the ability to control pain‐related brain activation is site‐specific. Less covariation between the areas in response to the nociceptive stimulus was positively correlated with learning success. Upregulation or downregulation of either region was unrelated to pain intensity or unpleasantness; however, our subjects did not learn rACC upregulation, which might be important for pain control. A significant increase in pain unpleasantness was found during upregulation of pInsL when covariation with the rACC was low. These initial results suggest that the state of the network involved in the processing of pain needs to be considered in the modulation of pain‐evoked activation and its behavioral effects. Hum Brain Mapp 35:5784–5798, 2014. © 2014 Wiley Periodicals, Inc.     

Sex-specific proteome differences in the anterior cingulate cortex of schizophrenia

Molecular knowledge about schizophrenia—a psychotic, multifactorial mental disorder that affects about 1% of the population worldwide—is limited and no diagnostic biomarkers are available. The comparative proteome analysis of human brain tissue from patients with schizophrenia and healthy controls may supply useful information on both the disorder and potential biomarkers candidates. Here, we present the results of our investigation of anterior cingulate cortex samples from 11 patients and 8 controls. We used two-dimensional gel electrophoresis combined with mass spectrometry, the most traditional approach to studying the proteome, to reveal the differentially expressed proteins in schizophrenia, and western blot to validate some interesting potential biomarker candidates such as dihydropyrimidinase-like 2 and alpha-crystallin, involved in a number of processes such as cytoskeleton arrangement. Most interesting is that our additional sex-specific proteome comparison showed that male and female schizophrenia patients present different patterns of proteome regulation, for instance for the proteins aldolase C, an enzyme of glycolysis, and glutamine synthetase that synthesizes glutamine, responsible for maintain glutamate levels. Our findings not only support previous findings but also indicate areas that warrant further study in schizophrenia.     

Anterior cingulate cortex contributes to the descending facilitatory modulation of pain via dorsal reticular nucleus

Supraspinal centres biphasically modulate spinal nociceptive transmission, including descending inhibition and facilitation. Recent studies have revealed that descending facilitatory modulation is a key mechanism underlying induction and maintenance of neuropathic and inflammatory pain. The anterior cingulate cortex (ACC) is not only involved in the transmission of pain sensation but also plays a role in processing pain-related emotion. The ACC also widely connects with relevant regions of the descending modulation system. Here we used electrophysiological and behavioural techniques to study the possible pathways behind the modulation of spinal nociceptive transmission from the ACC. C-fibre-evoked field potentials in the spinal dorsal horn were produced by electrical stimulation of the sciatic nerve at an intensity high enough to excite C fibres, and paw withdrawal latencies (PWLs) to noxious heating were recorded. The results showed that high-frequency tetanic electrical stimulation of the ACC both unilaterally enhanced the C-fibre-evoked field potentials in the spinal dorsal horn and bilaterally shortened PWLs, indicating a facilitation of spinal nociception. A similar effect was observed after microinjection of N-methyl-d-aspartic acid (NMDA; 10 nm, 1 microL) or homocysteic acid (HCA; 0.1 m, 1 microL) into the ACC. When the dorsal reticular nucleus (DRt) was electrolytically lesioned, ACC-induced facilitation of spinal nociception was blocked. These results imply that: (i) activation of the ACC may facilitate spinal nociception; (ii) NMDA receptors in the ACC may be involved in descending facilitation; and (iii) the DRt plays a crucial role in mediating ACC-induced facilitation of spinal nociception.     

Pain-related aversion induces astrocytic reaction and proinflammatory cytokine expression in the anterior cingulate cortex in rats

Pain involves sensory and affective dimensions. It is well-known that activation of glial cells and a subsequent increase in proinflammatory cytokines contribute to the pathogenesis of pain sensation. However, the role of glial cells and proinflammatory cytokines in pain affect is unclear. Several lines of evidence indicate that the anterior cingulate cortex (ACC) is a key structure for pain affect. Using the formalin-induced conditioned place avoidance (F-CPA) model, which reflects the pain-related negative affective state induced by nociceptive stimuli, we examined the mRNA and protein expression levels of astrocytic markers and proinflammatory cytokines in the ACC. F-CPA produced robust aversion-like behaviors in rats. In parallel, a significant increase of mRNA of astrocytic markers (GFAP and S100B), and proinflammatory cytokines (IL-1β and TNF-α) were observed in the ACC. The protein level of GFAP, IL-1β and TNF-α were also enhanced in the ACC. The results showed for the first time that astrocytes and proinflammatory cytokines are associated with the processing of pain-related aversion and may be crucial players in the affective dimension of pain in rats.     

Shorter sleep duration is associated with lower GABA levels in the anterior cingulate cortex

BackgroundAlterations in the levels of gamma-aminobutyric acid (GABA) and glutamate + glutamine (Glx), which are major inhibitory and excitatory neurotransmitters, respectively, are frequently associated with insomnia. Previous reports also suggested the involvement of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) in insomnia and shorter sleep duration. In the current study, we investigated whether the GABA and Glx levels were altered in the ACC/mPFC in subclinical insomnia while focusing on the sleep duration.MethodsWe examined levels of GABA and Glx in the ACC/mPFC of the brain with magnetic resonance spectroscopy in 166 individuals with subjective sleep complaints but without a diagnosis of insomnia. Participants were divided into two groups according to sleep duration (≥6 h/night: n = 79 vs. < 6 h/night: n = 74), which was measured using a wrist-worn actigraphy. Working memory function and overall subjective sleep quality were assessed with a computerized neuropsychological test and self-report questionnaire, respectively.ResultsGABA levels in the ACC/mPFC were lower in the shorter sleep duration group relative to the longer sleep duration group (t = −2.21, p = 0.03). Glx levels did not differ between the two groups (t = −0.20, p = 0.84). Lower GABA levels were associated with lower spatial working memory performance in the shorter sleep duration group (β = −0.21, p = 0.03), but not the longer sleep duration group (β = 0.04, p = 0.72).ConclusionShorter sleep duration was associated with lower GABA levels in the ACC/mPFC. These findings may provide insight into the underlying mechanisms of impaired working memory function related to insomnia and sleep loss.     

Direct projections from the reticular formation of the medulla oblongata to the anterior cingulate cortex in the mouse and the rat

After injections of horseradish peroxidase into the anterior cingulate cortex of the mouse and the rat, labeled neurons were observed in different nuclei of the reticular formation of the rostral medulla oblongata: ventral part of the nucleus gigantocellularis, nucleus paragigantocellularis and nucleus lateralis reticularis. Other labeled neurons lay scattered outside the nuclear boundaries, often close to the ventral-most border of the medulla. The projection to the cingulate cortex is sparse, with rarely more than 3 cells per case, but constant. Injections into other cortical areas (visual, motor and somatosensory cortex) did not produce labeling in the medullary reticular formation.     

Activation of the caudal anterior cingulate cortex due to task‐related interference in an auditory Stroop paradigm

Successful information processing requires the focusing of attention on a certain stimulus property and the simultaneous suppression of irrelevant information. The Stroop task is a useful paradigm to study such attentional top‐down control in the presence of interference. Here, we investigated the neural correlates of an auditory Stroop task using fMRI. Subjects focused either on tone pitch (relatively high or low; phonetic task) or on the meaning of a spoken word (high/low/good; semantic task), while ignoring the other stimulus feature. We differentiated between task‐related (phonetic incongruent vs. semantic incongruent) and sensory‐level interference (phonetic incongruent vs. phonetic congruent). Task‐related interference activated similar regions as in visual Stroop tasks, including the anterior cingulate cortex (ACC) and the presupplementary motor‐area (pre‐SMA). More specifically, we observed that the very caudal/posterior part of the ACC was activated and not the dorsal/anterior region. Because identical stimuli but different task demands are compared in this contrast, it reflects conflict at a relatively high processing level. A more conventional contrast between incongruent and congruent phonetic trials was associated with a different cluster in the pre‐SMA/ACC which was observed in a large number of previous studies. Finally, functional connectivity analysis revealed that activity within the regions activated in the phonetic incongruent vs. semantic incongruent contrast was more strongly interrelated during semantically vs. phonetically incongruent trials. Taken together, we found (besides activation of regions well‐known from visual Stroop tasks) activation of the very caudal and posterior part of the ACC due to task‐related interference in an auditory Stroop task. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Efferent projections from the anterior thalamic nuclei to the cingulate cortex in the rat

The organization of projections from the anterior thalamic nuclei to the cingulate cortex was analyzed in the rat by the anterograde transport of Phaseolus vulgaris-leucoagglutinin. The rostral part of the anteromedial nucleus projects to layers I, V and VI of the anterior cingulate areas 1 and 2, layers I and III of the ventral orbital area, layers I, V and VI of area 29D of the retrosplenial area, and layers I and V of the caudal part of the retrosplenial granular and agranular areas. In contrast, the caudal part of the anteromedial nucleus projects to layer V of the frontal area 2, and layers I and V of the rostral part of the retrosplenial granular and agranular areas. The interanteromedial nucleus projects to layers I, III and V of the frontal area 2, layer V of the agranular insular area, and layers I, V and VI of area 29D. The anteroventral nucleus projects to layers I and IV of the retrosplenial granular area, whereas the anterodorsal nucleus projects to layers I, III and IV of the same area. Projections from the anteroventral and anterodorsal nuclei were, furthermore, organized such that their ventral parts project to the rostral part of the retrosplenial granular area, whereas their dorsal parts project to the more caudal part. The results suggest that the anterior thalamic nuclei project to more widespread areas and laminae of the cingulate cortex than was previously assumed. The projections are organized such that the anteromedial and interanteromedial nuclei project to layer I and the deep layers of the anterior cingulate and retrosplenial cortex, whereas the anteroventral and anterodorsal nuclei project to the superficial layers of the retrosplenial cortex. These thalamocortical projections may play important roles in behavioral learning such as discriminative avoidance behavior.     

网络游戏成瘾者前扣带回功能连接静息态fMRI研究

目的 探讨青少年网络游戏成瘾者静息态下前扣带回功能连接的变化情况,从功能连接的角度解释前扣带回在网络游戏成瘾中的作用.方法 选择自2011年3月至10月在安徽医科大学附属省立医院心理门诊就诊的网络成瘾者17例为成瘾组,同期招募17例健康志愿者为正常对照组.对34例被试者一般情况进行了解并比较两组之间差异;成瘾组和正常对照组分别进行静息态fMRI扫描,数据采集后进行预处理,分别以左、右前扣带回为感兴趣脑区与全脑进行功能连接分析,比较成瘾组和正常对照组前扣带回功能连接的变化情况.结果 成瘾组每日或每周平均网络游戏时间及网络游戏渴求程度明显高于正常对照组,差异有统计学意义(P＜0.05);在静息态下,正常对照组与网络成瘾组的前扣带回都与前额叶、中后扣带回、伏核、中脑、颞叶及枕叶等脑区存在功能连接关系,与全脑其他脑区比较差异(体素差异)有统计学意义(P＜0.05);但与正常对照组比较,在静息态下成瘾组前扣带回与中脑、扣带回皮层、伏核及辅助运动区功能连接增强,与双侧前额叶、颞叶及枕叶功能连接减弱(P＜0.05).结论 网络游戏成瘾者前扣带回功能连接存在异常并可能与网络游戏成瘾的产生和维持有关.     

Hyperlexia and ambient echolalia in a case of cerebral infarction of the left anterior cingulate cortex and corpus callosum

We report the case of a 69-year-old woman with cerebral infarction in the left anterior cingulate cortex and corpus callosum. She showed hyperlexia, which was a distinctive reading phenomenon, as well as ambient echolalia. Clinical features also included complex disorders such as visual groping, compulsive manipulation of tools, and callosal disconnection syndrome. She read words written on the cover of a book and repeated words emanating from unrelated conversations around her or from hospital announcements. The combination of these two features due to a focal lesion has never been reported previously. The supplementary motor area may control the execution of established subroutines according to external and internal inputs. Hyperlexia as well as the compulsive manipulation of tools could be interpreted as faulty inhibition of preexisting essentially intact motor subroutines by damage to the anterior cingulate cortex reciprocally interconnected with the supplementary motor area.