A Functional Magnetic Resonance Imaging Study on Activation of Anterior Cingulate Cortex at Episode and Interictal Phases in Migraine

<sec> <title>Objective:</title> By using amplitude of low-frequency fluctuations (ALFF) we have analyzed activationsin brain regions at different phases in migraineurs. </sec> <sec> <title>Methods:</title> Participants included 41 patients with migraine, 19 in episode and 22 in interictal phase, and 22 controls in the healthy condition. To analyze the brain function of patients and controls, ALFF was used for performing the post-processing in the resting state by scores of Montreal Cognitive Assessment (MoCA) scale, Mini-Mental State Examination (MMSE), Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D). </sec> <sec> <title>Results:</title> The comparison between groups of patients with migraine in the episode or interictal phases, and healthy controls showed that both episode and interictal migraine groups had the similar HAM-A and HAM-D scores (P > 0.05), but higher than that in controls (P < 0.01). For ALFF values of Episode and Interictal groups, the Montreal Neurological Institute (MNI) coordinates of the decreased ALFF were (−9, 42, 9), the voxel size = 215, including the bilateral anterior cingulate cortex (ACC), T =−4.15, without significant differences. Patients in Interictal group were with a stronger activation at MNI coordinates (12, 51, 12), in the bilateral ACC, voxel size = 90, T =3.87. </sec> <sec> <title>Conclusion:</title> ACC plays an adaptive, regulatory role in migraine and is related to multiple brain regions, which may mediate activation through descending anti-nociceptive pathways. ACC is related to opioid receptor and glutamate excitatory regulation. </sec>

Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury

Background: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus results in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. Methods: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC pyramidal neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling.Results: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC pyramidal neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. Conclusions: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.

Rostral Anterior Cingulate Cortex–Ventrolateral Periaqueductal Gray Circuit Underlies Electroacupuncture to Alleviate Hyperalgesia but Not Anxiety-Like Behaviors in Mice With Spared Nerve Injury

Neuropathic pain is a common cause of chronic pain and is often accompanied by negative emotions, making it complex and difficult to treat. However, the neural circuit mechanisms underlying these symptoms remain unclear. Herein, we present a novel pathway associated with comorbid chronic pain and anxiety. Using chemogenetic methods, we found that activation of glutamatergic projections from the rostral anterior cingulate cortex (rACCGlu) to the ventrolateral periaqueductal gray (vlPAG) induced both hyperalgesia and anxiety-like behaviors in sham mice. Inhibition of the rACCGlu-vlPAG pathway reduced anxiety-like behaviors and hyperalgesia in the spared nerve injury (SNI) mice model; moreover, electroacupuncture (EA) effectively alleviated these symptoms. Investigation of the related mechanisms revealed that the chemogenetic activation of the rACCGlu-vlPAG circuit effectively blocked the analgesic effect of EA in the SNI mice model but did not affect the chronic pain-induced negative emotions. This study revealed a novel pathway, the rACCGlu-vlPAG pathway, that mediates neuropathic pain and pain-induced anxiety.

Brain 5-HT2A receptor binding and its neural network related to behavioral inhibition system

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

Context-dependent relationships between locus coeruleus firing patterns and coordinated neural activity in the anterior cingulate cortex

Ascending neuromodulatory projections from the locus coeruleus (LC) affect cortical neural networks via the release of norepinephrine (NE). However, the exact nature of these neuromodulatory effects on neural activity patterns in vivo is not well understood. Here we show that in awake monkeys, LC activation is associated with changes in coordinated activity patterns in the anterior cingulate cortex (ACC). These relationships, which are largely independent of changes in firing rates of individual ACC neurons, depend on the type of LC activation: ACC pairwise correlations tend to be reduced when ongoing (baseline) LC activity increases but enhanced when external events evoke transient LC responses. Both relationships covary with pupil changes that reflect LC activation and arousal. These results suggest that modulations of information processing that reflect changes in coordinated activity patterns in cortical networks can result partly from ongoing, context-dependent, arousal-related changes in activation of the LC-NE system.

Examining the Neural Correlates of Error Awareness in a Large fMRI Study

Goal-directed behaviour is dependent upon the ability to detect errors and implement appropriate post-error adjustments. Accordingly, several studies have explored the neural activity underlying error-monitoring processes, identifying the insula cortex as crucial for error awareness and reporting mixed findings with respect to the anterior cingulate cortex. Variable patterns of activation have previously been attributed to insufficient statistical power. We therefore sought to clarify the neural correlates of error awareness in a large event-related functional magnetic resonance imaging (MRI) study. Four hundred and two healthy participants undertook the Error Awareness Task, a motor Go/No-Go response inhibition paradigm in which participants were required to indicate their awareness of commission errors. Compared to unaware errors, aware errors were accompanied by significantly greater activity in a network of regions including the insula cortex, supramarginal gyrus, and midline structures such as the anterior cingulate cortex and supplementary motor area. Error awareness activity was related to indices of task performance and dimensional measures of psychopathology in select regions including the insula, supramarginal gyrus and supplementary motor area. Taken together, we identified a robust and reliable neural network associated with error awareness.