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Glutamatergic response to a low load working memory paradigm in the left dorsolateral prefrontal cortex in patients with mild cognitive impairment: a functional magnetic resonance spectroscopy study

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Abstract

Working memory deficits have been widely reported in mild cognitive impairment (MCI). However, the neural mechanisms of working memory dysfunction in MCI have not been clearly understood. In this study, we used proton functional magnetic resonance spectroscopy (1H-fMRS) and functional magnetic resonance imaging (fMRI) to understand the underlying neurobiology of working memory deficits in patients with MCI. We aimed at detecting the changes in the concentration of glutamate and blood oxygen level dependent (BOLD) activity using 1H-fMRS and fMRI respectively during a low load verbal (0 back and 1 back) working memory in the left dorsolateral prefrontal cortex (DLPFC) between patients with MCI and healthy controls. Fifteen patients with amnestic MCI and twenty two age, gender and education matched healthy controls underwent a low load verbal working memory 1H-fMRS and fMRI. We observed significant increase in glutamate during working memory task (both 0 back and 1 back) in healthy controls and such changes were absent in patients with MCI. However, percent signal changes representing BOLD activity during both 0 back and 1 back was not significantly different between two groups. Our findings suggest that 1H-fMRS complements fMRI in understanding the working memory mechanism in the left DLPFC.

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References

  • Apsvalka, D., Gadie, A., Clemence, M., & Mullins, P. G. (2015). Event-related dynamics of glutamate and BOLD effects measured using functional magnetic resonance spectroscopy (fMRS) at 3T in a repetition suppression paradigm. Neuroimage, 118, 292–300. https://doi.org/10.1016/j.neuroimage.2015.06.015.

    Article  PubMed  Google Scholar 

  • Bednarik, P., Tkac, I., Giove, F., DiNuzzo, M., Deelchand, D. K., Emir, U. E., Eberly, L. E., & Mangia, S. (2015). Neurochemical and BOLD responses during neuronal activation measured in the human visual cortex at 7 tesla. Journal of Cerebral Blood Flow and Metabolism, 35(4), 601–610. https://doi.org/10.1038/jcbfm.2014.233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bokde, A. L., Karmann, M., Born, C., Teipel, S. J., Omerovic, M., Ewers, M., Frodl, T., Meisenzahl, E., Reiser, M., Moller, H. J., & Hampel, H. (2010). Altered brain activation during a verbal working memory task in subjects with amnestic mild cognitive impairment. Journal of Alzheimer's Disease, 21(1), 103–118. https://doi.org/10.3233/JAD-2010-091054.

    Article  PubMed  Google Scholar 

  • Braver, T. S., Cohen, J. D., Nystrom, L. E., Jonides, J., Smith, E. E., & Noll, D. C. (1997). A parametric study of prefrontal cortex involvement in human working memory. Neuroimage, 5(1), 49–62. https://doi.org/10.1006/nimg.1996.0247.

    Article  CAS  PubMed  Google Scholar 

  • Brett Matthew, A. J.-L., Romain, V., & Jean-Baptiste, P. (2002). Region of interest analysis using an SPM toolbox. Paper presented at the 8th international conference on functional mapping of the human brain (pp. 2–6). Sendai: June.

    Google Scholar 

  • Curtis, C. E., & D'Esposito, M. (2003). Persistent activity in the prefrontal cortex during working memory. Trends in Cognitive Sciences, 7(9), 415–423.

    Article  Google Scholar 

  • Dohnel, K., Sommer, M., Ibach, B., Rothmayr, C., Meinhardt, J., & Hajak, G. (2008). Neural correlates of emotional working memory in patients with mild cognitive impairment. Neuropsychologia, 46(1), 37–48. https://doi.org/10.1016/j.neuropsychologia.2007.08.012.

    Article  PubMed  Google Scholar 

  • Hertz, L., & Rodrigues, T. B. (2014). Astrocytic-neuronal-astrocytic pathway selection for formation and degradation of glutamate/GABA. Front Endocrinol (Lausanne), 5, 42. https://doi.org/10.3389/fendo.2014.00042.

    Article  Google Scholar 

  • Huang, Z., Davis, H. I., Yue, Q., Wiebking, C., Duncan, N. W., Zhang, J., Wagner, N. F., Wolff, A., & Northoff, G. (2015). Increase in glutamate/glutamine concentration in the medial prefrontal cortex during mental imagery: A combined functional mrs and fMRI study. Human Brain Mapping, 36(8), 3204–3212. https://doi.org/10.1002/hbm.22841.

    Article  PubMed  Google Scholar 

  • Jacola, L. M., Willard, V. W., Ashford, J. M., Ogg, R. J., Scoggins, M. A., Jones, M. M., Wu, S., & Conklin, H. M. (2014). Clinical utility of the N-back task in functional neuroimaging studies of working memory. Journal of Clinical and Experimental Neuropsychology, 36(8), 875–886. https://doi.org/10.1080/13803395.2014.953039.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kessels, R. P., Molleman, P. W., & Oosterman, J. M. (2011). Assessment of working-memory deficits in patients with mild cognitive impairment and Alzheimer's dementia using Wechsler's working memory index. Aging Clinical and Experimental Research, 23(5–6), 487–490.

    Article  Google Scholar 

  • Kuhn, S., Schubert, F., Mekle, R., Wenger, E., Ittermann, B., Lindenberger, U., & Gallinat, J. (2016). Neurotransmitter changes during interference task in anterior cingulate cortex: Evidence from fMRI-guided functional MRS at 3 T. Brain Structure & Function, 221(5), 2541–2551. https://doi.org/10.1007/s00429-015-1057-0.

    Article  CAS  Google Scholar 

  • Logothetis, N. K., Pauls, J., Augath, M., Trinath, T., & Oeltermann, A. (2001). Neurophysiological investigation of the basis of the fMRI signal. Nature, 412(6843), 150–157. https://doi.org/10.1038/35084005.

    Article  CAS  PubMed  Google Scholar 

  • Mathuranath, P. S., Cherian, J. P., Mathew, R., George, A., Alexander, A., & Sarma, S. P. (2007). Mini mental state examination and the Addenbrooke's cognitive examination: Effect of education and norms for a multicultural population. Neurology India, 55(2), 106–110.

    Article  CAS  Google Scholar 

  • Menon, R., Lekha, V., Justus, S., Sarma, P. S., & Mathuranath, P. (2014). A pilot study on utility of Malayalam version of Addenbrooke's cognitive examination in detection of amnestic mild cognitive impairment: A critical insight into utility of learning and recall measures. Annals of Indian Academy of Neurology, 17(4), 420–425. https://doi.org/10.4103/0972-2327.144018.

    Article  PubMed  PubMed Central  Google Scholar 

  • Michels, L., Martin, E., Klaver, P., Edden, R., Zelaya, F., Lythgoe, D. J., Luchinger, R., Brandeis, D., & O'Gorman, R. L. (2012). Frontal GABA levels change during working memory. PLoS One, 7(4), e31933. https://doi.org/10.1371/journal.pone.0031933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Migo, E. M., Mitterschiffthaler, M., O'Daly, O., Dawson, G. R., Dourish, C. T., Craig, K. J., Simmons, A., Wilcock, G. K., McCulloch, E., Jackson, S. H., Kopelman, M. D., Williams, S. C., & Morris, R. G. (2015). Alterations in working memory networks in amnestic mild cognitive impairment. Neuropsychology, Development, and Cognition. Section B, Aging, Neuropsychology and Cognition, 22(1), 106–127. https://doi.org/10.1080/13825585.2014.894958.

    Article  CAS  PubMed  Google Scholar 

  • Nagel, B. J., Herting, M. M., Maxwell, E. C., Bruno, R., & Fair, D. (2013). Hemispheric lateralization of verbal and spatial working memory during adolescence. Brain and Cognition, 82(1), 58–68. https://doi.org/10.1016/j.bandc.2013.02.007.

    Article  PubMed  PubMed Central  Google Scholar 

  • Niu, H. J., Li, X., Chen, Y. J., Ma, C., Zhang, J. Y., & Zhang, Z. J. (2013). Reduced frontal activation during a working memory task in mild cognitive impairment: A non-invasive near-infrared spectroscopy study. CNS Neuroscience & Therapeutics, 19(2), 125–131. https://doi.org/10.1111/cns.12046.

    Article  CAS  Google Scholar 

  • Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proceedings of the National Academy of Sciences of the United States of America, 87(24), 9868–9872.

    Article  CAS  Google Scholar 

  • Opitz, B., Mecklinger, A., & Friederici, A. D. (2000). Functional asymmetry of human prefrontal cortex: Encoding and retrieval of verbally and nonverbally coded information. Learning & Memory, 7(2), 85–96.

    Article  CAS  Google Scholar 

  • Parasuraman, R. (1998). The attentive brain. Cambridge: MIT Press.

    Google Scholar 

  • Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256(3), 183–194. https://doi.org/10.1111/j.1365-2796.2004.01388.x.

    Article  CAS  PubMed  Google Scholar 

  • Petersen, R. C., Smith, G. E., Waring, S. C., Ivnik, R. J., Tangalos, E. G., & Kokmen, E. (1999). Mild cognitive impairment: Clinical characterization and outcome. Archives of Neurology, 56(3), 303–308.

    Article  CAS  Google Scholar 

  • Petrides, M. (2005). Lateral prefrontal cortex: Architectonic and functional organization. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 360(1456), 781–795. https://doi.org/10.1098/rstb.2005.1631.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ross, B. D. (1991). Biochemical considerations in 1H spectroscopy. Glutamate and glutamine; myo-inositol and related metabolites. NMR in Biomedicine, 4(2), 59–63.

    Article  CAS  Google Scholar 

  • Rothman, D. L., Sibson, N. R., Hyder, F., Shen, J., Behar, K. L., & Shulman, R. G. (1999). In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 354(1387), 1165–1177. https://doi.org/10.1098/rstb.1999.0472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saunders, N. L., & Summers, M. J. (2010). Attention and working memory deficits in mild cognitive impairment. Journal of Clinical and Experimental Neuropsychology, 32(4), 350–357. https://doi.org/10.1080/13803390903042379.

    Article  PubMed  Google Scholar 

  • Saykin, A. J., Wishart, H. A., Rabin, L. A., Flashman, L. A., McHugh, T. L., Mamourian, A. C., & Santulli, R. B. (2004). Cholinergic enhancement of frontal lobe activity in mild cognitive impairment. Brain, 127 (Pt 7, 1574–1583. https://doi.org/10.1093/brain/awh177.

    Article  PubMed  Google Scholar 

  • Sibson, N. R., Dhankhar, A., Mason, G. F., Rothman, D. L., Behar, K. L., & Shulman, R. G. (1998). Stoichiometric coupling of brain glucose metabolism and glutamatergic neuronal activity. Proceedings of the National Academy of Sciences of the United States of America, 95(1), 316–321.

    Article  CAS  Google Scholar 

  • Stanley, J. A., & Raz, N. (2018). Functional magnetic resonance spectroscopy: The "new" MRS for cognitive neuroscience and psychiatry research. Frontiers in Psychiatry, 9, 76. https://doi.org/10.3389/fpsyt.2018.00076.

    Article  PubMed  PubMed Central  Google Scholar 

  • Szatkowski, M., & Attwell, D. (1994). Triggering and execution of neuronal death in brain ischaemia: Two phases of glutamate release by different mechanisms. Trends in Neurosciences, 17(9), 359–365.

    Article  CAS  Google Scholar 

  • Taylor, R., Neufeld, R. W., Schaefer, B., Densmore, M., Rajakumar, N., Osuch, E. A., Williamson, P. C., & Theberge, J. (2015). Functional magnetic resonance spectroscopy of glutamate in schizophrenia and major depressive disorder: Anterior cingulate activity during a color-word Stroop task. NPJ Schizophrenia, 1, 15028. https://doi.org/10.1038/npjschz.2015.28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomason, M. E., Race, E., Burrows, B., Whitfield-Gabrieli, S., Glover, G. H., & Gabrieli, J. D. (2009). Development of spatial and verbal working memory capacity in the human brain. Journal of Cognitive Neuroscience, 21(2), 316–332. https://doi.org/10.1162/jocn.2008.21028.

    Article  PubMed  PubMed Central  Google Scholar 

  • Vijayakumari, A. A., Thomas, B., Menon, R. N., & Kesavadas, C. (2018a). Association between glutamate/glutamine and blood oxygen level dependent signal in the left dorsolateral prefrontal region during verbal working memory. Neuroreport, 29(6), 478–482. https://doi.org/10.1097/WNR.0000000000001000.

    Article  CAS  PubMed  Google Scholar 

  • Vijayakumari, A. A., Thomas, B., Menon, R. N., & Kesavadas, C. (2018b). Task-based metabolic changes in the left dorsolateral prefrontal region during the letter N-back working memory task using proton magnetic resonance spectroscopy. Neuroreport, 29(2), 147–152. https://doi.org/10.1097/WNR.0000000000000943.

    Article  PubMed  Google Scholar 

  • Woodcock, E. A., Anand, C., Khatib, D., Diwadkar, V. A., & Stanley, J. A. (2018). Working memory modulates glutamate levels in the dorsolateral prefrontal cortex during (1)H fMRS. Frontiers in Psychiatry, 9, 66. https://doi.org/10.3389/fpsyt.2018.00066.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yetkin, F. Z., Rosenberg, R. N., Weiner, M. F., Purdy, P. D., & Cullum, C. M. (2006). FMRI of working memory in patients with mild cognitive impairment and probable Alzheimer's disease. European Radiology, 16(1), 193–206. https://doi.org/10.1007/s00330-005-2794-x.

    Article  PubMed  Google Scholar 

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Acknowledgements

The study was financially supported by the Science and Engineering Research Board, Department of Science and Technology, India (Grant no. PDF/2016/000494 dated 28 November 2016 to Dr. Anupa A Vijayakumari). The authors express their deep sense of gratitude to all the research participants who graciously took part in this project, as well as the staff of the Department of Imaging Sciences and Technology at SCTIMST. In addition, we specifically thank Mr. Jithin B and Ms. Anusree TV for their technical assistance

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Authors and Affiliations

  1. Medical Image Processing Laboratory, Department of Imaging Sciences and Interventional Radiology (IS & IR), Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, 695 011, India

    Anupa A. Vijayakumari, Bejoy Thomas, Thumboli Muyyayil Arun & Chandrasekharan Kesavadas

  2. Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology (SCTIMST), Trivandrum, Kerala, India

    Ramshekhar N. Menon & Mohanan Nandini

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  1. Anupa A. Vijayakumari
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Vijayakumari, A.A., Menon, R.N., Thomas, B. et al. Glutamatergic response to a low load working memory paradigm in the left dorsolateral prefrontal cortex in patients with mild cognitive impairment: a functional magnetic resonance spectroscopy study. Brain Imaging and Behavior 14, 451–459 (2020). https://doi.org/10.1007/s11682-019-00122-7

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