, Volume 8, Issue 1, pp 19–33 | Cite as

Brain lipid changes after repetitive transcranial magnetic stimulation: potential links to therapeutic effects?

  • Lynette Hui-Wen Lee
  • Chay-Hoon Tan
  • Yew-Long Lo
  • Akhlaq A. Farooqui
  • Guanghou Shui
  • Markus R. Wenk
  • Wei-Yi Ong
Original Article


Repetitive transcranial magnetic stimulation (rTMS) is increasingly used in the management of neurologic disorders such as depression and chronic pain, but little is known about how it could affect brain lipids, which play important roles in membrane structure and cellular functions. The present study was carried out to examine the effects of rTMS on brain lipids at the individual molecular species level using the novel technique of lipidomics. Rats were subjected to high frequency (15 Hz) stimulation of the left hemisphere with different intensities and pulses of rTMS. The prefrontal cortex, hippocampus and striatum were harvested 1 week after rTMS and lipid profiles analyzed by tandem mass spectrometry. rTMS resulted in changes mainly in the prefrontal cortex. There were significant alterations in plasmalogen phosphatidylethanolamines, phosphatidylcholines, and increases in sulfated galactosylceramides or sulfatides. Plasmalogen species with long chain polyunsaturated fatty acids (PUFAs) showed decrease in abundance together with corresponding increase in lysophospholipid species suggesting endogenous release of long chain fatty acids such as docosahexaenoic acid (DHA) in brain tissue. The hippocampus showed no significant changes, whilst changes in the striatum were often opposite to that of the prefrontal cortex. It is postulated that changes in brain lipids may underlie some of the clinical effects of rTMS.


Transcranial magnetic stimulation Sulfatide Plasmalogens Lipids Polyunsaturated fatty acids Depression Pain Alzheimer’s disease Frontal cortex 



This work was supported by the National Medical Research Council (R-181-000-125-275 and R-183-000-224-213), National Research Foundation (CRP Award No. 2007-04), Biomedical Research Council (R-183-000-211-305) and the Academic Research Fund (R-183-000-160-112). There are no conflicts of interest.


  1. Adibhatla, R. M., & Hatcher, J. F. (2007). Role of lipids in brain injury and diseases. Future Lipidology, 2, 403–422.PubMedCrossRefGoogle Scholar
  2. Adibhatla, R. M., Hatcher, J. F., & Dempsey, R. J. (2006). Lipids and lipidomics in brain injury and diseases. AAPS Journal, 8, E314–E321.PubMedGoogle Scholar
  3. Aizenstein, H. J., Butters, M. A., Figurski, J. L., Stenger, V. A., Reynolds, C. F., I. I. I., & Carter, C. S. (2005). Prefrontal and striatal activation during sequence learning in geriatric depression. Biological Psychiatry, 58, 290–296.PubMedCrossRefGoogle Scholar
  4. Avery, D. H., Isenberg, K. E., Sampson, S. M., et al. (2008). Transcranial magnetic stimulation in the acute treatment of major depressive disorder: Clinical response in an open-label extension trial. Journal of Clinical Psychiatry, 69, 441–451.PubMedCrossRefGoogle Scholar
  5. Bazan, N. G. (2009). Cellular and molecular events mediated by docosahexaenoic acid-derived neuroprotectin D1 signaling in photoreceptor cell survival and brain protection. Prostaglandins Leukotrienes and Essential Fatty Acids, 81, 205–211.CrossRefGoogle Scholar
  6. Bestmann, S. (2008). The physiological basis of transcranial magnetic stimulation. Trends in Cognitive Sciences, 12, 81–83.PubMedCrossRefGoogle Scholar
  7. Bligh, E. G., & Dyer, W. J. (1959). A rapid method of total lipid extraction and purification. Canadian Journal of Biochemistry and Physiology, 37, 911–917.PubMedCrossRefGoogle Scholar
  8. Bloch, Y., Grisaru, N., Harel, E. V., et al. (2008). Repetitive transcranial magnetic stimulation in the treatment of depression in adolescents: An open-label study. Journal of ECT, 24, 156–159.PubMedCrossRefGoogle Scholar
  9. Celada, P., Puig, M. V., Casanovas, J. M., Guillazo, G., & Artigas, F. (2001). Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. Journal of Neuroscience, 21, 9917–9929.PubMedGoogle Scholar
  10. Cotelli, M., Manenti, R., Cappa, S. F., et al. (2006). Effect of transcranial magnetic stimulation on action naming in patients with Alzheimer disease. Archives of Neurology, 63, 1602–1604.PubMedCrossRefGoogle Scholar
  11. DeMar, J. C., Jr., Ma, K., Bell, J. M., Igarashi, M., Greenstein, D., & Rapoport, S. I. (2006). One generation of n-3 polyunsaturated fatty acid deprivation increases depression and aggression test scores in rats. Journal of Lipid Research, 47, 172–180.PubMedCrossRefGoogle Scholar
  12. Drevets, W. C. (2000). Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Progress in Brain Research, 126, 413–431.PubMedCrossRefGoogle Scholar
  13. Eckhardt, M. (2008). The role and metabolism of sulfatide in the nervous system. Molecular Neurobiology, 37, 93–103.PubMedCrossRefGoogle Scholar
  14. Eschweiler, G. W., Wegerer, C., Schlotter, W., et al. (2000). Left prefrontal activation predicts therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in major depression. Psychiatry Research, 99, 161–172.PubMedCrossRefGoogle Scholar
  15. Farooqui, A. A. (1981). Metabolism of sulfolipids in mammalian tissues. Advances in Lipid Research, 18, 159–202.PubMedGoogle Scholar
  16. Farooqui, A. A. (2009). Lipid mediators in the neural cell nucleus: Their metabolism, signaling, and association with neurological disorders. Neuroscientist, 15, 392–407.PubMedCrossRefGoogle Scholar
  17. Farooqui, A. A., & Horrocks, L. A. (2001). Plasmalogens, phospholipase A2, and docosahexaenoic acid turnover in brain tissue. Journal of Molecular Neuroscience, 16, 263–272. (discussion 279–284).CrossRefGoogle Scholar
  18. Feng, H. L., Yan, L., & Cui, L. Y. (2008). Effects of repetitive transcranial magnetic stimulation on adenosine triphosphate content and microtubule associated protein-2 expression after cerebral ischemia-reperfusion injury in rat brain. Chinese Medical Journal (English), 121, 1307–1312.Google Scholar
  19. Fitzgerald, P. (2008). Brain stimulation techniques for the treatment of depression and other psychiatric disorders. Australas Psychiatry, 16, 183–190.PubMedCrossRefGoogle Scholar
  20. Fujiki, M., & Steward, O. (1997). High frequency transcranial magnetic stimulation mimics the effects of ECS in upregulating astroglial gene expression in the murine CNS. Brain Research Molecular Brain Research, 44, 301–308.PubMedCrossRefGoogle Scholar
  21. George, M. S., Lisanby, S. H., Avery, D., et al. (2010). Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial. Archives of General Psychiatry, 67, 507–516.PubMedCrossRefGoogle Scholar
  22. Guan, X. L., He, X., Ong, W. Y., Yeo, W. K., Shui, G., & Wenk, M. R. (2006). Non-targeted profiling of lipids during kainate-induced neuronal injury. FASEB Journal, 20, 1152–1161.PubMedCrossRefGoogle Scholar
  23. Han, X., Cheng, H., Fryer, J. D., Fagan, A. M., & Holtzman, D. M. (2003). Novel role for apolipoprotein E in the central nervous system. Modulation of sulfatide content. The Journal of Biological Chemistry, 278, 8043–8051.PubMedCrossRefGoogle Scholar
  24. Han, X., Holtzman, D. M., McKeel, D. W., Jr., Kelley, J., & Morris, J. C. (2002). Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: Potential role in disease pathogenesis. Journal of Neurochemistry, 82, 809–818.PubMedCrossRefGoogle Scholar
  25. Honke, K., Zhang, Y., Cheng, X., Kotani, N., & Taniguchi, N. (2004). Biological roles of sulfoglycolipids and pathophysiology of their deficiency. Glycoconjugate Journal, 21, 59–62.PubMedCrossRefGoogle Scholar
  26. Ishizuka, I. (1997). Chemistry and functional distribution of sulfoglycolipids. Progress in Lipid Research, 36, 245–319.PubMedCrossRefGoogle Scholar
  27. Ji, R. R., Schlaepfer, T. E., Aizenman, C. D., et al. (1998). Repetitive transcranial magnetic stimulation activates specific regions in rat brain. Proceedings of the National Academy of Sciences of the United States of America, 95, 15635–15640.PubMedCrossRefGoogle Scholar
  28. Kapogiannis, D., & Wassermann, E. M. (2008). Transcranial magnetic stimulation in clinical pharmacology. Central Nervous System Agents in Medicinal Chemistry, 8, 234–240.PubMedGoogle Scholar
  29. Kim, E. J., Kim, W. R., Chi, S. E., et al. (2006). Repetitive transcranial magnetic stimulation protects hippocampal plasticity in an animal model of depression. Neuroscience Letters, 405, 79–83.PubMedCrossRefGoogle Scholar
  30. Koch, G., & Rothwell, J. C. (2009). TMS investigations into the task-dependent functional interplay between human posterior parietal and motor cortex. Behavioural Brain Research, 202, 147–152.PubMedCrossRefGoogle Scholar
  31. Koos, T., & Tepper, J. M. (1999). Inhibitory control of neostriatal projection neurons by GABAergic interneurons. Nature Neuroscience, 2, 467–472.PubMedCrossRefGoogle Scholar
  32. Lee, L. H., Shui, G., Farooqui, A. A., Wenk, M. R., Tan, C. H., & Ong, W. Y. (2009). Lipidomic analyses of the mouse brain after antidepressant treatment: Evidence for endogenous release of long-chain fatty acids? The International Journal of Neuropsychopharmacology, 10, 1–12.Google Scholar
  33. Lefaucheur, J. P. (2009). Methods of therapeutic cortical stimulation. Neurophysiologie Clinique, 39, 1–14.PubMedCrossRefGoogle Scholar
  34. Lefaucheur, J. P., Hatem, S., Nineb, A., et al. (2006). Somatotopic organization of the analgesic effects of motor cortex rTMS in neuropathic pain. Neurology, 67, 1998–2004.PubMedCrossRefGoogle Scholar
  35. Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods, 25, 402–408.PubMedCrossRefGoogle Scholar
  36. Mozzi, R., & Buratta, S. (2010). Brain phosphatidylserine: Metabolism and functions. In A. Lajtha, G. Tettamanti, & G. Goracci (Eds.), Handbook of neurochemistry and molecular neurobiology: Neural lipids (pp. 39–59). New York: Springer.Google Scholar
  37. Muller, M. B., Toschi, N., Kresse, A. E., Post, A., & Keck, M. E. (2000). Long-term repetitive transcranial magnetic stimulation increases the expression of brain-derived neurotrophic factor and cholecystokinin mRNA, but not neuropeptide tyrosine mRNA in specific areas of rat brain. Neuropsychopharmacology, 23, 205–215.PubMedCrossRefGoogle Scholar
  38. O’Reardon, J. P., Solvason, H. B., Janicak, P. G., et al. (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: A multisite randomized controlled trial. Biological Psychiatry, 62, 1208–1216.PubMedCrossRefGoogle Scholar
  39. Padberg, F., Zwanzger, P., Keck, M. E., et al. (2002). Repetitive transcranial magnetic stimulation (rTMS) in major depression: Relation between efficacy and stimulation intensity. Neuropsychopharmacology, 27, 638–645.PubMedCrossRefGoogle Scholar
  40. Pascual-Leone, A., Rubio, B., Pallardo, F., & Catala, M. D. (1996). Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet, 348, 233–237.PubMedCrossRefGoogle Scholar
  41. Paxinos, G., & Watson, C. (1986). The rat brain in stereotaxic coodinates. Sydney: Academic Press.Google Scholar
  42. Ramakrishnan, H., Hedayati, K. K., Lullmann-Rauch, R., et al. (2007). Increasing sulfatide synthesis in myelin-forming cells of arylsulfatase A-deficient mice causes demyelination and neurological symptoms reminiscent of human metachromatic leukodystrophy. Journal of Neuroscience, 27, 9482–9490.PubMedCrossRefGoogle Scholar
  43. Rao, J. S., Ertley, R. N., Lee, H. J., et al. (2007). n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Molecular Psychiatry, 12, 36–46.PubMedCrossRefGoogle Scholar
  44. Rossi, S., Pasqualetti, P., Rossini, P. M., et al. (2000). Effects of repetitive transcranial magnetic stimulation on movement-related cortical activity in humans. Cerebral Cortex, 10, 802–808.PubMedCrossRefGoogle Scholar
  45. Sachdev, P. S., Loo, C. K., Mitchell, P. B., McFarquhar, T. F., & Malhi, G. S. (2007). Repetitive transcranial magnetic stimulation for the treatment of obsessive compulsive disorder: A double-blind controlled investigation. Psychological Medicine, 37, 1645–1649.PubMedCrossRefGoogle Scholar
  46. Sapolsky, R. M. (2001). Depression, antidepressants, and the shrinking hippocampus. Proceedings of the National Academy of Sciences of the United States of America, 98, 12320–12322.PubMedCrossRefGoogle Scholar
  47. Schutter, D. J. (2009). Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: A meta-analysis. Psychological Medicine, 39, 65–75.PubMedCrossRefGoogle Scholar
  48. Shui, G., Bendt, A. K., Pethe, K., Dick, T., & Wenk, M. R. (2007). Sensitive profiling of chemically diverse bioactive lipids. Journal of Lipid Research, 48, 1976–1984.PubMedCrossRefGoogle Scholar
  49. van Zyl, R., Gieselmann, V., & Eckhardt, M. (2010). Elevated sulfatide levels in neurons cause lethal audiogenic seizures in mice. Journal of Neurochemistry, 112, 282–295.PubMedCrossRefGoogle Scholar
  50. Vance, J. E. (2008). Phosphatidylserine and phosphatidylethanolamine in mammalian cells: Two metabolically related aminophospholipids. Journal of Lipid Research, 49, 1377–1387.PubMedCrossRefGoogle Scholar
  51. Watson, A. D. (2006). Thematic review series: Systems biology approaches to metabolic and cardiovascular disorders. Lipidomics: A global approach to lipid analysis in biological systems. Journal of Lipid Research, 47, 2101–2111.PubMedCrossRefGoogle Scholar
  52. Wenk, M. R. (2005). The emerging field of lipidomics. Nature Reviews Drug Discovery, 4, 594–610.PubMedCrossRefGoogle Scholar
  53. Ziemann, U. (2004). TMS induced plasticity in human cortex. Reviews in the Neurosciences, 15, 253–266.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lynette Hui-Wen Lee
    • 1
  • Chay-Hoon Tan
    • 1
  • Yew-Long Lo
    • 2
  • Akhlaq A. Farooqui
    • 3
  • Guanghou Shui
    • 4
  • Markus R. Wenk
    • 4
    • 5
    • 7
  • Wei-Yi Ong
    • 6
    • 7
  1. 1.Department of PharmacologyNational University of SingaporeSingaporeSingapore
  2. 2.Department of NeurologyNational Neuroscience InstituteSingaporeSingapore
  3. 3.Department of Molecular and Cellular BiochemistryThe Ohio State UniversityColumbusUSA
  4. 4.Department of BiochemistryNational University of SingaporeSingaporeSingapore
  5. 5.Department of Biological SciencesNational University of SingaporeSingaporeSingapore
  6. 6.Department of AnatomyNational University of SingaporeSingaporeSingapore
  7. 7.Ageing/Neurobiology Research ProgrammeNational University of SingaporeSingaporeSingapore

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