Nicotine in action: cigarette smoking modulated homotopic functional connectivity in schizophrenia
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Cigarette smoking is intimately associated with both early onset and increased severity of schizophrenia. The self-medication hypothesis suggests that nicotine can relieve or restore neurocognitive deficits and symptoms associated with schizophrenia. Schizophrenia patients and healthy subjects who smoked showed deficits in communication between their hemispheres. These homotopic connectivity mechanisms associated with both schizophrenia and smoking comorbidity were largely unknown until now. A mixed sample including patients with schizophrenia (22 smokers and 27 non-smokers) and healthy controls (22 smokers and 21 non-smokers) based on clinical diagnoses and cigarette dependence were recruited for the current study. All subjects underwent resting-state functional magnetic resonance imaging to determine possible interactions between schizophrenia and smoking, and to determine the main effects of schizophrenia and smoking on homotopic functional connectivity. Decreased homotopic functional connectivity of the subgenual anterior cingulate cortex suggested a main effect of schizophrenia and smoking—an additive effect. Furthermore, we found an antagonistic interaction effect between schizophrenia and smoking located in the ventrolateral prefrontal cortex (VLPFC). In addition, the connectivity strength of the bilateral VLPFC was negatively correlated with the Positive and Negative Syndrome Scale Negative scores and positively correlated with lifetime smoking. These results suggest that smoking has multiple effects on the modulation of interhemispheric connectivity in schizophrenia. Our findings provide valuable information underlying the pathophysiological mechanisms of schizophrenia and offer a potential target for future clinical treatment of schizophrenia and smoking comorbidity.
KeywordsCigarette smoking Homotopic functional connectivity Schizophrenia Self-medication Ventrolateral prefrontal cortex Subgenual anterior cingulate cortex
This study was funded by the National Natural Science Foundation of China (61533006, 81471653, 81771919 and 61673089), China Postdoctoral Science Foundation (2013 M532229), Sichuan Science and Technology Program (2018TJPT0016), and the “111” project (B12027).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Addicott, M. A., Sweitzer, M. M., Froeliger, B., Rose, J. E., & McClernon, F. J. (2015). Increased functional connectivity in an insula-based network is associated with improved smoking cessation outcomes. Neuropsychopharmacology, 40(11), 2648–2656. https://doi.org/10.1038/npp.2015.114.CrossRefPubMedPubMedCentralGoogle Scholar
- Andreasen, N. C., Pressler, M., Nopoulos, P., Miller, D., & Ho, B. C. (2010). Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biological Psychiatry, 67(3), 255–262. https://doi.org/10.1016/j.biopsych.2009.08.040.CrossRefPubMedGoogle Scholar
- Baker, J. T., Holmes, A. J., Masters, G. A., Yeo, B. T., Krienen, F., Buckner, R. L., et al. (2014). Disruption of cortical association networks in schizophrenia and psychotic bipolar disorder. JAMA Psychiatry, 71(2), 109–118. https://doi.org/10.1001/jamapsychiatry.2013.3469.CrossRefPubMedPubMedCentralGoogle Scholar
- Bersani, G., Quartini, A., Iannitelli, A., Paolemili, M., Ratti, F., Di Biasi, C., et al. (2010). Corpus callosum abnormalities and potential age effect in men with schizophrenia: an MRI comparative study. Psychiatry Research, 183(2), 119–125. https://doi.org/10.1016/j.pscychresns.2010.04.011.CrossRefPubMedGoogle Scholar
- Chang, X., Xi, Y. B., Cui, L. B., Wang, H. N., Sun, J. B., Zhu, Y. Q., et al. (2015). Distinct inter-hemispheric dysconnectivity in schizophrenia patients with and without auditory verbal hallucinations. Scientific Reports, 5, 11218.Google Scholar
- de Ruiter, M. B., Veltman, D. J., Goudriaan, A. E., Oosterlaan, J., Sjoerds, Z., & van den Brink, W. (2009). Response perseveration and ventral prefrontal sensitivity to reward and punishment in male problem gamblers and smokers. Neuropsychopharmacology, 34(4), 1027–1038. https://doi.org/10.1038/npp.2008.175.CrossRefPubMedGoogle Scholar
- Eklund, A., Nichols, T. E., & Knutsson, H. (2016). Cluster failure: Why fMRI inferences for spatial extent have inflated false-positive rates. Proceedings of the National Academy of Sciences of the United States of America, 113(28), 7900–7905. https://doi.org/10.1073/pnas.1602413113.CrossRefPubMedPubMedCentralGoogle Scholar
- Fox, M. D., Buckner, R. L., Liu, H., Chakravarty, M. M., Lozano, A. M., & Pascual-Leone, A. (2014). Resting-state networks link invasive and noninvasive brain stimulation across diverse psychiatric and neurological diseases. Proceedings of the National Academy of Sciences of the United States of America, 111(41), E4367–E4375. https://doi.org/10.1073/pnas.1405003111.CrossRefPubMedPubMedCentralGoogle Scholar
- Ji, G. J., Zhang, Z., Xu, Q., Wang, Z., Wang, J., Jiao, Q., Yang, F., Tan, Q., Chen, G., Zang, Y. F., Liao, W., & Lu, G. (2015). Identifying Corticothalamic network epicenters in patients with idiopathic generalized epilepsy. AJNR. American Journal of Neuroradiology, 36(8), 1494–1500. https://doi.org/10.3174/ajnr.A4308.CrossRefPubMedGoogle Scholar
- Kelly, C., Zuo, X. N., Gotimer, K., Cox, C. L., Lynch, L., Brock, D., Imperati, D., Garavan, H., Rotrosen, J., Castellanos, F. X., & Milham, M. P. (2011). Reduced interhemispheric resting state functional connectivity in cocaine addiction. Biological Psychiatry, 69(7), 684–692. https://doi.org/10.1016/j.biopsych.2010.11.022.CrossRefPubMedPubMedCentralGoogle Scholar
- Khan, M. S., Boileau, I., Kolla, N., & Mizrahi, R. (2018). A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. Translational Psychiatry, 8(1), 38. https://doi.org/10.1038/s41398-017-0080-8.CrossRefPubMedPubMedCentralGoogle Scholar
- Koukouli, F., Rooy, M., Tziotis, D., Sailor, K. A., O'Neill, H. C., Levenga, J., Witte, M., Nilges, M., Changeux, J. P., Hoeffer, C. A., Stitzel, J. A., Gutkin, B. S., DiGregorio, D. A., & Maskos, U. (2017). Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nature Medicine, 23(3), 347–354. https://doi.org/10.1038/nm.4274.CrossRefPubMedPubMedCentralGoogle Scholar
- Moran, L. V., Betts, J. M., Ongur, D., & Janes, A. C. (2017). Neural responses to smoking cues in schizophrenia. Schizophrenia Bulletin. https://doi.org/10.1093/schbul/sbx1085.
- Patkar, A. A., Gopalakrishnan, R., Lundy, A., Leone, F. T., Certa, K. M., & Weinstein, S. P. (2002). Relationship between tobacco smoking and positive and negative symptoms in schizophrenia. The Journal of Nervous and Mental Disease, 190(9), 604–610. https://doi.org/10.1097/01.NMD.0000030525.40247.B9.CrossRefPubMedGoogle Scholar
- Potvin, S., Lungu, O., Lipp, O., Lalonde, P., Zaharieva, V., Stip, E., Melun, J. P., & Mendrek, A. (2016). Increased ventro-medial prefrontal activations in schizophrenia smokers during cigarette cravings. Schizophrenia Research, 173(1–2), 30–36. https://doi.org/10.1016/j.schres.2016.03.011.CrossRefGoogle Scholar
- Roland, J. L., Snyder, A. Z., Hacker, C. D., Mitra, A., Shimony, J. S., Limbrick, D. D., Raichle, M. E., Smyth, M. D., & Leuthardt, E. C. (2017). On the role of the corpus callosum in interhemispheric functional connectivity in humans. Proceedings of the National Academy of Sciences of the United States of America, 114, 13278–13283. https://doi.org/10.1073/pnas.1707050114.CrossRefPubMedPubMedCentralGoogle Scholar
- Viswanath, H., Velasquez, K. M., Thompson-Lake, D. G., Savjani, R., Carter, A. Q., Eagleman, D., et al. (2015). Alterations in interhemispheric functional and anatomical connectivity are associated with tobacco smoking in humans. Front Hum Neurosci, 9, https://doi.org/10.3389/fnhum.2015.00116.
- Walterfang, M., Wood, A. G., Reutens, D. C., Wood, S. J., Chen, J., Velakoulis, D., McGorry, P. D., & Pantelis, C. (2008). Morphology of the corpus callosum at different stages of schizophrenia: cross-sectional study in first-episode and chronic illness. The British Journal of Psychiatry, 192(6), 429–434. https://doi.org/10.1192/bjp.bp.107.041251.CrossRefPubMedGoogle Scholar
- Walterfang, M., Wood, A. G., Reutens, D. C., Wood, S. J., Chen, J., Velakoulis, D., McGorry, P. D., & Pantelis, C. (2009). Corpus callosum size and shape in first-episode affective and schizophrenia-spectrum psychosis. Psychiatry Research, 173(1), 77–82. https://doi.org/10.1016/j.pscychresns.2008.09.007.CrossRefPubMedGoogle Scholar
- Yang, G. J., Murray, J. D., Repovs, G., Cole, M. W., Savic, A., Glasser, M. F., Pittenger, C., Krystal, J. H., Wang, X. J., Pearlson, G. D., Glahn, D. C., & Anticevic, A. (2014). Altered global brain signal in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 111(20), 7438–7443. https://doi.org/10.1073/pnas.1405289111.CrossRefPubMedPubMedCentralGoogle Scholar
- Yokoyama, N., Sasaki, H., Mori, Y., Ono, M., Tsurumi, K., Kawada, R., Matsumoto, Y., Yoshihara, Y., Sugihara, G., Miyata, J., Murai, T., & Takahashi, H. (2017). Additive effect of cigarette smoking on gray matter abnormalities in schizophrenia. Schizophrenia Bulletin. https://doi.org/10.1093/schbul/sbx1092.
- Yu, D., Yuan, K., Bi, Y., Luo, L., Zhai, J., Liu, B., et al. (2017). Altered interhemispheric resting-state functional connectivity in young male smokers. Addiction Biology, 23(2), 772–780.Google Scholar
- Zhang, R., Wei, Q., Kang, Z., Zalesky, A., Li, M., Xu, Y., Li, L., Wang, J., Zheng, L., Wang, B., Zhao, J., Zhang, J., & Huang, R. (2015). Disrupted brain anatomical connectivity in medication-naive patients with first-episode schizophrenia. Brain Structure & Function, 220(2), 1145–1159. https://doi.org/10.1007/s00429-014-0706-z.CrossRefGoogle Scholar
- Zuo, X. N., Kelly, C., Di Martino, A., Mennes, M., Margulies, D. S., Bangaru, S., et al. (2010). Growing together and growing apart: Regional and sex differences in the lifespan developmental trajectories of functional homotopy. The Journal of Neuroscience, 30(45), 15034–15043. https://doi.org/10.1523/JNEUROSCI.2612-10.2010.CrossRefPubMedPubMedCentralGoogle Scholar