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Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder

Molecular Psychiatry volume 20, pages 1079–1084 (2015)Cite this article

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Abstract

Converging evidence suggests bioenergetic abnormalities in bipolar disorder (BD). In the brain, phosphocreatine (PCr) acts a reservoir of high-energy phosphate (HEP) bonds, and creatine kinases (CK) catalyze the transfer of HEP from adenosine triphosphate (ATP) to PCr and from PCr back to ATP, at times of increased need. This study examined the activity of this mechanism in BD by measuring the levels of HEP molecules during a stimulus paradigm that increased local energy demand. Twenty-three patients diagnosed with BD-I and 22 healthy controls (HC) were included. Levels of phosphorus metabolites were measured at baseline and during visual stimulation in the occipital lobe using 31P magnetic resonance spectroscopy at 4T. Changes in metabolite levels showed different patterns between the groups. During stimulation, HC had significant reductions in PCr but not in ATP, as expected. In contrast, BD patients had significant reductions in ATP but not in PCr. In addition, PCr/ATP ratio was lower at baseline in patients, and there was a higher change in this measure during stimulation. This pattern suggests a disease-related failure to replenish ATP from PCr through CK enzyme catalysis during tissue activation. Further studies measuring the CK flux in BD are required to confirm and extend this finding.

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References

  1. MacDonald ML, Naydenov A, Chu M, Matzilevich D, Konradi C . Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar disorders 2006; 8: 255–264.

    Article  CAS  Google Scholar 

  2. Naydenov AV, MacDonald ML, Ongur D, Konradi C . Differences in lymphocyte electron transport gene expression levels between subjects with bipolar disorder and normal controls in response to glucose deprivation stress. Arch Gen Psychiatry 2007; 64: 555–564.

    Article  Google Scholar 

  3. Baxter LR Jr., Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE et al. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 1985; 42: 441–447.

    Article  Google Scholar 

  4. Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 2004; 61: 450–458.

    Article  CAS  Google Scholar 

  5. Kim DJ, Lyoo IK, Yoon SJ, Choi T, Lee B, Kim JE et al. Clinical response of quetiapine in rapid cycling manic bipolar patients and lactate level changes in proton magnetic resonance spectroscopy. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 1182–1188.

    Article  CAS  Google Scholar 

  6. Brady RO Jr., Cooper A, Jensen JE, Tandon N, Cohen B, Renshaw P et al. A longitudinal pilot proton MRS investigation of the manic and euthymic states of bipolar disorder. Transl Psychiatry 2012; 2: e160.

    Article  Google Scholar 

  7. Kato T, Takahashi S, Shioiri T, Inubushi T . Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo 31P and 7Li magnetic resonance spectroscopy. J Affect Disord 1993; 27: 53–59.

    Article  CAS  Google Scholar 

  8. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S . Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 1994; 55: 41–50.

    Article  CAS  Google Scholar 

  9. Kato T, Murashita J, Kamiya A, Shioiri T, Kato N, Inubushi T . Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity. Eur Arch Psychiatry Clin Neurosci 1998; 248: 301–306.

    Article  CAS  Google Scholar 

  10. Stork C, Renshaw PF . Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 2005; 10: 900–919.

    Article  CAS  Google Scholar 

  11. Cataldo AM, McPhie DL, Lange NT, Punzell S, Elmiligy S, Ye NZ et al. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. Am J Pathol 2010; 177: 575–585.

    Article  Google Scholar 

  12. Kato T, Stine OC, McMahon FJ, Crowe RR . Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry 1997; 42: 871–875.

    Article  CAS  Google Scholar 

  13. Quiroz JA, Gray NA, Kato T, Manji HK . Mitochondrially mediated plasticity in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 2008; 33: 2551–2565.

    Article  CAS  Google Scholar 

  14. Boyer PD . What makes ATP synthase spin? Nature 1999; 402: 247–249.

    Article  CAS  Google Scholar 

  15. Beard E, Braissant O . Synthesis and transport of creatine in the CNS: importance for cerebral functions. J Neurochemistry 2010; 115: 297–313.

    Article  CAS  Google Scholar 

  16. Saks VA, Ventura-Clapier R, Aliev MK . Metabolic control and metabolic capacity: two aspects of creatine kinase functioning in the cells. Biochim Biophys Acta 1996; 1274: 81–88.

    Article  Google Scholar 

  17. Kemp GJ . Non-invasive methods for studying brain energy metabolism: what they show and what it means. Dev Neurosci 2000; 22: 418–428.

    Article  CAS  Google Scholar 

  18. Sappey-Marinier D, Calabrese G, Fein G, Hugg JW, Biggins C, Weiner MW . Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy. J Cereb Blood Flow Metab 1992; 12: 584–592.

    Article  CAS  Google Scholar 

  19. Rango M, Castelli A, Scarlato G . Energetics of 3.5s neural activation in humans: a 31P MR spectroscopy study. Magn Reson Med 1997; 38: 878–883.

    Article  CAS  Google Scholar 

  20. Kato T, Takahashi S, Shioiri T, Murashita J, Hamakawa H, Inubushi T . Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1994; 31: 125–133.

    Article  CAS  Google Scholar 

  21. Deicken RF, Weiner MW, Fein G . Decreased temporal lobe phosphomonoesters in bipolar disorder. J Affect Disord 1995; 33: 195–199.

    Article  CAS  Google Scholar 

  22. Hamakawa H, Murashita J, Yamada N, Inubushi T, Kato N, Kato T . Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder. Psychiatry Clin Neurosci 2004; 58: 82–88.

    Article  CAS  Google Scholar 

  23. Deicken RF, Fein G, Weiner MW . Abnormal frontal lobe phosphorous metabolism in bipolar disorder. Am J Psychiatry 1995; 152: 915–918.

    Article  CAS  Google Scholar 

  24. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S . Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia. Psychiatry Res 1995; 61: 151–160.

    Article  CAS  Google Scholar 

  25. Murashita J, Kato T, Shioiri T, Inubushi T, Kato N . Altered brain energy metabolism in lithium-resistant bipolar disorder detected by photic stimulated 31P-MR spectroscopy. Psychol Med 2000; 30: 107–115.

    Article  CAS  Google Scholar 

  26. Wandell BA, Brewer AA, Dougherty RF . Visual field map clusters in human cortex. Philos Trans R Soc Lond B Biol Sci 2005; 360: 693–707.

    Article  Google Scholar 

  27. Du F, Cooper AJ, Thida T, Sehovic S, Lukas SE, Cohen BM et al. In vivo evidence for cerebral bioenergetic abnormalities in schizophrenia measured using 31P magnetization transfer spectroscopy. JAMA Psychiatry 2014; 71: 19–27.

    Article  CAS  Google Scholar 

  28. Lin Y, Stephenson MC, Xin L, Napolitano A, Morris PG . Investigating the metabolic changes due to visual stimulation using functional proton magnetic resonance spectroscopy at 7T. J Cereb Blood Flow Metab 2012; 32: 1484–1495.

    Article  CAS  Google Scholar 

  29. MRUI: a graphical user interface for accurate routine MRS data analysis. Proceedings of the 13th Annual Meeting of ESMRMB 1996; Prague.

  30. Du F, Cooper A, Lukas SE, Cohen BM, Ongur D . Creatine kinase and ATP synthase reaction rates in human frontal lobe measured by (3) (1)P magnetization transfer spectroscopy at 4T. Magn Reson Imaging 2013; 31: 102–108.

    Article  CAS  Google Scholar 

  31. Petroff OA, Prichard JW, Behar KL, Alger JR, den Hollander JA, Shulman RG . Cerebral intracellular pH by 31P nuclear magnetic resonance spectroscopy. Neurology 1985; 35: 781–788.

    Article  CAS  Google Scholar 

  32. Sahlin K, Harris RC . The creatine kinase reaction: a simple reaction with functional complexity. Amino Acids 2011; 40: 1363–1367.

    Article  CAS  Google Scholar 

  33. Kato T, Murashita J, Shioiri T, Hamakawa H, Inubushi T . Effect of photic stimulation on energy metabolism in the human brain measured by 31P-MR spectroscopy. J Neuropsychiatry Clin Neurosci 1996; 8: 417–422.

    Article  CAS  Google Scholar 

  34. Murashita J, Kato T, Shioiri T, Inubushi T, Kato N . Age-dependent alteration of metabolic response to photic stimulation in the human brain measured by 31P MR-spectroscopy. Brain Res 1999; 818: 72–76.

    Article  CAS  Google Scholar 

  35. Chen W, Zhu XH, Adriany G, Ugurbil K . Increase of creatine kinase activity in the visual cortex of human brain during visual stimulation: a 31P magnetization transfer study. Magn Reson Med 1997; 38: 551–557.

    Article  CAS  Google Scholar 

  36. Vidyasagar R, Kauppinen RA . 31P magnetic resonance spectroscopy study of the human visual cortex during stimulation in mild hypoxic hypoxia. Exp Brain Res 2008; 187: 229–235.

    Article  Google Scholar 

  37. Brewer GJ, Wallimann TW . Protective effect of the energy precursor creatine against toxicity of glutamate and beta-amyloid in rat hippocampal neurons. J Neurochemistry 2000; 74: 1968–1978.

    Article  CAS  Google Scholar 

  38. Menon RS, Hendrich K, Hu X, Ugurbil K . 31P NMR spectroscopy of the human heart at 4T: detection of substantially uncontaminated cardiac spectra and differentiation of subepicardium and subendocardium. Magn Reson Med 1992; 26: 368–376.

    Article  CAS  Google Scholar 

  39. Hochachka PW, Clark CM, Holden JE, Stanley C, Ugurbil K, Menon RS . 31P magnetic resonance spectroscopy of the Sherpa heart: a phosphocreatine/adenosine triphosphate signature of metabolic defense against hypobaric hypoxia. Proc Natl Acad Sci USA 1996; 93: 1215–1220.

    Article  CAS  Google Scholar 

  40. in 't Zandt HJ, de Groof AJ, Renema WK, Oerlemans FT, Klomp DW, Wieringa B et al. Presence of (phospho)creatine in developing and adult skeletal muscle of mice without mitochondrial and cytosolic muscle creatine kinase isoforms. J Physiol 2003; 548: 847–858.

    Article  CAS  Google Scholar 

  41. Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 2001; 24: 420–429.

    Article  CAS  Google Scholar 

  42. Rezin GT, Cardoso MR, Goncalves CL, Scaini G, Fraga DB, Riegel RE et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int 2008; 53: 395–400.

    Article  CAS  Google Scholar 

  43. Zhuravliova E, Barbakadze T, Zaalishvili E, Chipashvili M, Koshoridze N, Mikeladze D . Social isolation in rats inhibits oxidative metabolism, decreases the content of mitochondrial K-Ras and activates mitochondrial hexokinase. Behav Brain Res 2009; 205: 377–383.

    Article  CAS  Google Scholar 

  44. Dworak M, McCarley RW, Kim T, Kalinchuk AV, Basheer R . Sleep and brain energy levels: ATP changes during sleep. J Neuroscience 2010; 30: 9007–9016.

    Article  CAS  Google Scholar 

  45. Wisor JP, Rempe MJ, Schmidt MA, Moore ME, Clegern WC . Sleep slow-wave activity regulates cerebral glycolytic metabolism. Cereb Cortex 2013; 23: 1978–1987.

    Article  Google Scholar 

  46. Yuksel C, Ongur D . Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 2010; 68: 785–794.

    Article  Google Scholar 

  47. Feier G, Valvassori SS, Varela RB, Resende WR, Bavaresco DV, Morais MO et al. Lithium and valproate modulate energy metabolism in an animal model of mania induced by methamphetamine. Pharmacol Biochem Behav 2013; 103: 589–596.

    Article  CAS  Google Scholar 

  48. Streck EL, Amboni G, Scaini G, Di-Pietro PB, Rezin GT, Valvassori SS et al. Brain creatine kinase activity in an animal model of mania. Life Sci 2008; 82: 424–429.

    Article  CAS  Google Scholar 

  49. Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S et al. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol 2009; 12: 805–822.

    Article  CAS  Google Scholar 

  50. Repetto G, del Peso A, Sanz P, Repetto M . In vitro effects of lithium and nickel at different levels on Neuro-2a mouse neuroblastoma cells. Toxicology In Vitro 2001; 15: 363–368.

    Article  CAS  Google Scholar 

  51. Maurer IC, Schippel P, Volz HP . Lithium-induced enhancement of mitochondrial oxidative phosphorylation in human brain tissue. Bipolar Disord 2009; 11: 515–522.

    Article  CAS  Google Scholar 

  52. Valvassori SS, Rezin GT, Ferreira CL, Moretti M, Goncalves CL, Cardoso MR et al. Effects of mood stabilizers on mitochondrial respiratory chain activity in brain of rats treated with d-amphetamine. J Psychiatric Res 2010; 44: 903–909.

    Article  Google Scholar 

  53. Correa C, Amboni G, Assis LC, Martins MR, Kapczinski F, Streck EL et al. Effects of lithium and valproate on hippocampus citrate synthase activity in an animal model of mania. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 887–891.

    Article  CAS  Google Scholar 

  54. Assis LC, Scaini G, Di-Pietro PB, Castro AA, Comim CM, Streck EL et al. Effect of antipsychotics on creatine kinase activity in rat brain. Basic Clin Pharmacol Toxicol 2007; 101: 315–319.

    Article  CAS  Google Scholar 

  55. Agostinho FR, Scaini G, Ferreira GK, Jeremias IC, Reus GZ, Rezin GT et al. Effects of olanzapine, fluoxetine and olanzapine/fluoxetine on creatine kinase activity in rat brain. Brain Res Bull 2009; 80: 337–340.

    Article  CAS  Google Scholar 

  56. Ma D, Chan MK, Lockstone HE, Pietsch SR, Jones DN, Cilia J et al. Antipsychotic treatment alters protein expression associated with presynaptic function and nervous system development in rat frontal cortex. J Proteome Res 2009; 8: 3284–3297.

    Article  CAS  Google Scholar 

  57. Rosenfeld M, Brenner-Lavie H, Ari SG, Kavushansky A, Ben-Shachar D . Perturbation in mitochondrial network dynamics and in complex I dependent cellular respiration in schizophrenia. Biol Psychiatry 2011; 69: 980–988.

    Article  CAS  Google Scholar 

  58. Brenner-Lavie H, Klein E, Ben-Shachar D . Mitochondrial complex I as a novel target for intraneuronal DA: modulation of respiration in intact cells. Biochem Pharmacol 2009; 78: 85–95.

    Article  CAS  Google Scholar 

  59. Burkhardt C, Kelly JP, Lim YH, Filley CM, Parker WD Jr . Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol 1993; 33: 512–517.

    Article  CAS  Google Scholar 

  60. Prince JA, Yassin MS, Oreland L . Neuroleptic-induced mitochondrial enzyme alterations in the rat brain. J Pharmacol Exp Ther 1997; 280: 261–267.

    CAS  PubMed  Google Scholar 

  61. Prince JA, Yassin MS, Oreland L . Normalization of cytochrome-c oxidase activity in the rat brain by neuroleptics after chronic treatment with PCP or methamphetamine. Neuropharmacology 1997; 36: 1665–1678.

    Article  CAS  Google Scholar 

  62. Prince JA, Yassin MS, Oreland L . A histochemical demonstration of altered cytochrome oxidase activity in the rat brain by neuroleptics. Eur Neuropsychopharmacol 1998; 8: 1–6.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by funding from John Kaneb fellowship to CY, NARSAD Young Investigator Award to FD, NIMH grant R01MH094594 to DO and Shervert Frazier Research Institute to BC. We thank our patients that participated in this study.

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Author notes

  1. C Yuksel and F Du: These authors contributed equally to this work.

Authors and Affiliations

  1. McLean Hospital, Belmont, MA, USA

    C Yuksel, F Du, C Ravichandran, J R Goldbach, T Thida, P Lin, B Dora, J Gelda, L O'Connor, S Sehovic, S Gruber, D Ongur & B M Cohen

  2. Harvard Medical School, Boston, MA, USA

    C Yuksel, F Du, C Ravichandran, P Lin, S Gruber, D Ongur & B M Cohen

  3. Geisel School of Medicine, Dartmouth, NH, USA

    T Thida

  4. Key Laboratory of Biomedical Information Engineering of Education Ministry, Institute of Biomedical Engineering, Xi`an Jiaotong University, Xi`an, China

    P Lin

  5. Department of Psychology, Koc University, Istanbul, Turkey

    B Dora

  6. George Washington University Medical School, Washington, DC, USA

    J Gelda

  7. Bryn Mawr College, Bryn Mawr, PA

    S Sehovic

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Correspondence to C Yuksel.

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Dr Ongur served in a scientific advisory board for Lilly in 2013. The authors declare no conflict of interest.

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Yuksel, C., Du, F., Ravichandran, C. et al. Abnormal high-energy phosphate molecule metabolism during regional brain activation in patients with bipolar disorder. Mol Psychiatry 20, 1079–1084 (2015). https://doi.org/10.1038/mp.2015.13

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