Background & Aims

Based on the system of brain-machine interfaces (BMI), exploring whether PL modulates acute and chronic pain by anterior cingulate cortex (ACC) and primary somatosensory cortex (S1); to investigate the role of prelimbic prefrontal cortex (PL) on acute and chronic pain modulation and the mechanism in rats.

Methods

For regulating the neuronal activity in the PL, we injected virus and implanted the optical fiber into the left PL; and for in vivo synchronously recordig the local field potential (LFP) signals of ACC and S1, we implanted the 32-channel silicon electrodes on the right ACC and S1. Furthermore, here we engineered a closed-loop rodent BMI system, which combined the LFP signals recorded from the ACC and S1 with modulating the activity of PL neurons by optogenetics. Finally, through the establishment of acute thermal and mechanical pain, and chronic inflammatory pain model, to observe that whether activated PL, based on BMI system, can modulate the pain sensory and pain aversion by affecting the changes of information flow between ACC and S1, we compared the behavioral changes of thermal paw withdrawal latency, mechanical paw withdrawal threshold and conditioned place preference (CPP) score in the condition of activating PL driven by three different models, BMI, manual and random model.

Results

1.Giving the pin prick (PP) to plantar, we synchronously recorded the pain onset signals through ACC and S1. And we found that the S1 detected the occurrence of pain earlier than ACC, which is manifested in event-related potential (ERP) latency with ACC longer than S1, p<0.05. 2.Compared with random-driven optogenetic activation of PL, BMI-driven and manual-driven can relieve the pain sensory and related aversion, manifesting in decreased Hargreaves withdrawal latency (p<0.01); increased CPP score in the condition of evoked pain by PP stimulation (p<0.05); and increased CPP score under the conditions of evoked pain by 6g von-Frey (vF) filament stimulation and spontaneous pain in CFA-treated rats (p<0.05). 3.Through the analysis by granger causality (GC) analysis, we found that optogenetic activation of PL reduce ACC?S1 directional information flow of high-frequency gamma oscillations (30-80 Hz), and increase mid-frequency alpha and beta oscillations (8-30Hz) ACC?S1 directional flow.

Conclusions

1.The LFP signals recorded from ACC and S1 can be used to detect the evoked and spontaneous pain onset.
2.The closed-loop BMI system is good for the treatment of pain, driving the optogenetics PL activation to relieve pain sensory and pain aversion.
3. 3.The optogenetic PL activation has no impact on the S1?ACC directional information flow; whereas on the ACC?S1 directional information flow, it decreased high-frequency gamma oscillations (30-80 Hz) and increased the mid-frequency alpha and beta oscillations (8-30Hz).

References

[1] Wang, J. and Chen, Z. Neuromodulation for Pain Management[J]. Adv Exp Med Biol, 2019, 1101: 207-223.
[2] Zhang, Q., Manders, T., Tong, A. P., et al. Chronic pain induces generalized enhancement of aversion[J]. Elife, 2017, 6.
[3] Lee, M., Manders, T. R., Eberle, S. E., et al. Activation of corticostriatal circuitry relieves chronic neuropathic pain[J]. J Neurosci, 2015, 35(13): 5247-5259.
[4] Urien, L., Zhang, Q., Martinez, E., et al. Assessment of Aversion of Acute Pain Stimulus through Conditioned Place Aversion[J]. Bio Protoc, 2017, 7(21).
[5] Xiao, Z., Martinez, E., Kulkarni, P. M., et al. Cortical Pain Processing in the Rat Anterior Cingulate Cortex and Primary Somatosensory Cortex[J]. Front Cell Neurosci, 2019, 13: 165.
[6] Singh, A., Patel, D., Li, A., et al. Mapping Cortical Integration of Sensory and Affective Pain Pathways[J]. Curr Biol, 2020, 30(9): 1703-1715.e1705.
[7] Dale, J., Zhou, H., Zhang, Q., et al. Scaling Up Cortical Control Inhibits Pain[J]. Cell Rep, 2018, 23(5): 1301-1313.
[8] Zhou, H., Zhang, Q., Martinez, E., et al. Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex[J]. Nat Commun, 2018, 9(1): 3751.
[9] Carlén, M. What constitutes the prefrontal cortex?[J]. Science, 2017, 358(6362): 478-482.
[10] Ong, W. Y., Stohler, C. S. and Herr, D. R. Role of the Prefrontal Cortex in Pain Processing[J]. Mol Neurobiol, 2019, 56(2): 1137-1166.
[11] Dixon, M. L., Thiruchselvam, R., Todd, R., et al. Emotion and the prefrontal cortex: An integrative review[J]. Psychol Bull, 2017, 143(10): 1033-1081.
[12] Apkarian, A. V., Sosa, Y., Sonty, S., et al. Chronic back pain is associated with decreased prefrontal and thalamic gray matter density[J]. J Neurosci, 2004, 24(46): 10410-10415.
[13] Moayedi, M., Weissman-Fogel, I., Crawley, A. P., et al. Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder[J]. Neuroimage, 2011, 55(1): 277-286.
[14] Geha, P. Y., Baliki, M. N., Harden, R. N., et al. The brain in chronic CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions[J]. Neuron, 2008, 60(4): 570-581.
[15] Borckardt, J. J., Reeves, S. T., Kotlowski, P., et al. Fast left prefrontal rTMS reduces post-gastric bypass surgery pain: findings from a large-scale, double-blind, sham-controlled clinical trial[J]. Brain Stimul, 2014, 7(1): 42-48.
[16] Seminowicz, D. A. and Moayedi, M. The Dorsolateral Prefrontal Cortex in Acute and Chronic Pain[J]. J Pain, 2017, 18(9): 1027-1035.
[17] Vertes, R. P. Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat[J]. Neuroscience, 2006, 142(1): 1-20.
[18] Metz, A. E., Yau, H. J., Centeno, M. V., et al. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain[J]. Proc Natl Acad Sci U S A, 2009, 106(7): 2423-2428.
[19] Zhou, H., Martinez, E., Lin, H. H., et al. Inhibition of the Prefrontal Projection to the Nucleus Accumbens Enhances Pain Sensitivity and Affect[J]. Front Cell Neurosci, 2018, 12: 240.
[20] Martinez, E., Lin, H. H., Zhou, H., et al. Corticostriatal Regulation of Acute Pain[J]. Front Cell Neurosci, 2017, 11: 146.
[21] Zhang Q., Hu S., Talay R., et al. A closed-loop brain-machine interface for the study and treatment of pain[J]. Nat. Biomed. Eng, 2021, in press.
[22] Drake, R. A., Steel, K. A., Apps, R., et al. Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats[J]. Elife, 2021, 10.
[23] Huang, J., Gadotti, V. M., Chen, L., et al. A neuronal circuit for activating descending modulation of neuropathic pain[J]. Nat Neurosci, 2019, 22(10): 1659-1668.
[24] Ossipov, M. H., Morimura, K. and Porreca, F. Descending pain modulation and chronification of pain[J]. Curr Opin Support Palliat Care, 2014, 8(2): 143-151.
[25] Zhu, X., Tang, H. D., Dong, W. Y., et al. Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states[J]. Nat Neurosci, 2021.
[26] Selvarajah, D., Wilkinson, I. D., Fang, F., et al. Structural and Functional Abnormalities of the Primary Somatosensory Cortex in Diabetic Peripheral Neuropathy: A Multimodal MRI Study[J]. Diabetes, 2019, 68(4): 796-806.
[27] Vierck, C. J., Whitsel, B. L., Favorov, O. V., et al. Role of primary somatosensory cortex in the coding of pain[J]. Pain, 2013, 154(3): 334-344.
[28] Bushnell, M. C., Duncan, G. H., Hofbauer, R. K., et al. Pain perception: is there a role for primary somatosensory cortex?[J]. Proc Natl Acad Sci U S A, 1999, 96(14): 7705-7709.
[29] Craig, A. D. Pain mechanisms: labeled lines versus convergence in central processing[J]. Annu Rev Neurosci, 2003, 26: 1-30.
[30] Seifert, F. and Maihöfner, C. Central mechanisms of experimental and chronic neuropathic pain: findings from functional imaging studies[J]. Cell Mol Life Sci, 2009, 66(3): 375-390.
[31] De Ridder, D., De Mulder, G., Menovsky, T., et al. Electrical stimulation of auditory and somatosensory cortices for treatment of tinnitus and pain[J]. Prog Brain Res, 2007, 166: 377-388.
[32] Matsuzawa-Yanagida, K., Narita, M., Nakajima, M., et al. Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites[J]. Neuropsychopharmacology, 2008, 33(8): 1952-1965.
[33] Barthas, F., Sellmeijer, J., Hugel, S., et al. The anterior cingulate cortex is a critical hub for pain-induced depression[J]. Biol Psychiatry, 2015, 77(3): 236-245.
[34] Zhao, R., Zhou, H., Huang, L., et al. Neuropathic Pain Causes Pyramidal Neuronal Hyperactivity in the Anterior Cingulate Cortex[J]. Front Cell Neurosci, 2018, 12: 107.
[35] Friesner, I. D., Martinez, E., Zhou, H., et al. Ketamine normalizes high-gamma power in the anterior cingulate cortex in a rat chronic pain model[J]. Mol Brain, 2020, 13(1): 129.
[36] Song, Y., Yao, M., Kemprecos, H., et al. Predictive coding models for pain perception[J]. J Comput Neurosci, 2021.
[37] Sun, G., Wen, Z., Ok, D., et al. Detecting acute pain signals from human EEG[J]. J Neurosci Methods, 2021, 347: 108964.
[38] Shyu, B. C., Sikes, R. W., Vogt, L. J., et al. Nociceptive processing by anterior cingulate pyramidal neurons[J]. J Neurophysiol, 2010, 103(6): 3287-3301.
[39] Vogt, B. A. and Sikes, R. W. The medial pain system, cingulate cortex, and parallel processing of nociceptive information[J]. Prog Brain Res, 2000, 122: 223-235.
[40] Yamamura, H., Iwata, K., Tsuboi, Y., et al. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats[J]. Brain Res, 1996, 735(1): 83-92.
[41] Kung, J. C., Su, N. M., Fan, R. J., et al. Contribution of the anterior cingulate cortex to laser-pain conditioning in rats[J]. Brain Res, 2003, 970(1-2): 58-72.
[42] Zhang, Y., Wang, N., Wang, J. Y., et al. Ensemble encoding of nociceptive stimulus intensity in the rat medial and lateral pain systems[J]. Mol Pain, 2011, 7: 64.
[43] Coghill, R. C., Sang, C. N., Maisog, J. M., et al. Pain intensity processing within the human brain: a bilateral, distributed mechanism[J]. J Neurophysiol, 1999, 82(4): 1934-1943.
[44] LaGraize, S. C., Borzan, J., Peng, Y. B., et al. Selective regulation of pain affect following activation of the opioid anterior cingulate cortex system[J]. Exp Neurol, 2006, 197(1): 22-30.
[45] Qu, C., King, T., Okun, A., et al. Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy[J]. Pain, 2011, 152(7): 1641-1648.
[46] Melzack, R. a. C., K.L. Sensory, motivational, and central control determinants of pain: a new conceptual model. [J]. The Skin Senses., 1968: 423-443.
[47] Zhang, Q., Xiao, Z., Huang, C., et al. Local field potential decoding of the onset and intensity of acute pain in rats[J]. Sci Rep, 2018, 8(1): 8299.
[48] Buzsáki, G., Anastassiou, C. A. and Koch, C. The origin of extracellular fields and currents–EEG, ECoG, LFP and spikes[J]. Nat Rev Neurosci, 2012, 13(6): 407-420.
[49] Schnitzler, A. and Gross, J. Normal and pathological oscillatory communication in the brain[J]. Nat Rev Neurosci, 2005, 6(4): 285-296.
[50] Akam, T. and Kullmann, D. M. Oscillatory multiplexing of population codes for selective communication in the mammalian brain[J]. Nat Rev Neurosci, 2014, 15(2): 111-122.
[51] Fries, P. Rhythms for Cognition: Communication through Coherence[J]. Neuron, 2015, 88(1): 220-235.
[52] Saalmann, Y. B., Pinsk, M. A., Wang, L., et al. The pulvinar regulates information transmission between cortical areas based on attention demands[J]. Science, 2012, 337(6095): 753-756.
[53] Mejias, J. F., Murray, J. D., Kennedy, H., et al. Feedforward and feedback frequency- dependent interactions in a large-scale laminar network of the primate cortex[J]. Sci Adv, 2016, 2(11): e1601335.
[54] Ploner, M., Sorg, C. and Gross, J. Brain Rhythms of Pain[J]. Trends Cogn Sci, 2017, 21(2): 100-110.

Presenting Author

Fei Zeng

Poster Authors

Fei Zeng

Ph.D

The First Affiliated Hospital Of Nanchang University

Lead Author

E-mail

Topics

  • Mechanisms: Biological-Molecular and Cell Biology