Advertisement

Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging

      Abstract

      Background

      The brain regions involved in the pathophysiology of bipolar disorder have not been definitively determined. Previous studies have suggested possible involvement of the hippocampus and of prefrontal regions. Proton magnetic resonance spectroscopic imaging (1H-MRSI) allows measurement of N-acetylaspartate (NAA, marker of neuronal integrity), choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in multiple brain regions. The objective of this study was to assess possible NAA reductions in hippocampus and prefrontal regions in patients with bipolar disorder.

      Methods

      We studied 17 patients with bipolar disorder and 17 age- and gender-matched healthy subjects on a 1.5-T nuclear magnetic resonance (NMR) machine. With 1H-MRSI we measured ratios of areas under the metabolite peaks of the proton spectra (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions.

      Results

      Patients showed significant reductions of NAA/CRE bilaterally in the hippocampus. There were no significant changes in CHO/CRE or in NAA ratios in any other area sampled.

      Conclusions

      This study shows that patients with bipolar disorder have a regional reduction of NAA relative signals, suggesting neuronal damage or malfunction of the hippocampus. As suggested by other studies, neuronal pathology in the hippocampus may be involved in the pathophysiology of bipolar disorder and in susceptibility to psychosis.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ali S.O.
        • Denicoff K.D.
        • Altshuler L.L.
        • Hauser P.
        • Li X.
        • Conrad A.J.
        • et al.
        A preliminary study of the relation of neuropsychological performance to neuroanatomic structures in bipolar disorder.
        Neuropsychiatry Neuropsychol Behav Neurol. 2000; 13: 20-28
        • Altshuler L.L.
        • Conrad A.
        • Hauser P.
        • Li X.M.
        • Guze B.H.
        • Denikoff K.
        • et al.
        Reduction of temporal lobe volume in bipolar disorder.
        Arch Gen Psychiatry. 1991; 48: 482-483
        • Benes F.M.
        • Berretta S.
        GABAergic interneurons.
        Neuropsychopharmacology. 2001; 25: 1-27
        • Bertolino A.
        • Callicott J.H.
        • Elman I.
        • Mattay V.S.
        • Tedeschi G.
        • Frank J.A.
        • et al.
        Regionally specific neuronal pathology in untreated patients with schizophrenia.
        Biol Psychiatry. 1998; 43: 641-648
        • Bertolino A.
        • Callicott J.H.
        • Mattay V.S.
        • Weidenhammer K.M.
        • Rakow R.
        • Egan M.F.
        • Weinberger D.R.
        The effect of treatment with antipsychotic drugs on brain N- acetylaspartate measures in patients with schizophrenia.
        Biol Psychiatry. 2001; 49: 39-46
        • Bertolino A.
        • Kumra S.
        • Callicott J.H.
        • Mattay V.S.
        • Lestz R.M.
        • Jacobsen L.
        • et al.
        Common pattern of cortical pathology in childhood-onset and adult-onset schizophrenia as identified by proton magnetic resonance spectroscopic imaging.
        Am J Psychiatry. 1998; 155: 1376-1383
        • Bertolino A.
        • Nawroz S.
        • Mattay V.S.
        • Barnett A.S.
        • Duyn J.H.
        • Moonen C.T.
        • et al.
        Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging.
        Am J Psychiatry. 1996; 153: 1554-1563
        • Cendes F.
        • Andermann F.
        • Dubeau F.
        • Matthews P.M.
        • Arnold D.L.
        Normalization of neuronal metabolic dysfunction after surgery for temporal lobe epilepsy. Evidence from proton MR spectroscopic imaging.
        Neurology. 1997; 49: 1525-1533
        • Coffey C.E.
        • Wilkinson W.E.
        • Weiner R.D.
        • Parashos I.A.
        • Djang W.T.
        • Webb M.C.
        • et al.
        Quantitative cerebral anatomy in depression. A controlled magnetic resonance imaging study.
        Arch Gen Psychiatry. 1993; 50: 7-16
        • Coffman J.A.
        • Bornstein R.A.
        • Olson S.C.
        • Schwarzkopf S.B.
        • Nasrallah H.A.
        Cognitive impairment and cerebral structure by MRI in bipolar disorder.
        Biol Psychiatry. 1990; 27: 1188-1196
        • Deicken R.F.
        • Eliaz Y.
        • Feiwell R.
        • Schuff N.
        Increased thalamic N-acetylaspartate in male patients with familial bipolar I disorder.
        Psychiatry Res. 2001; 106: 35-45
        • De Stefano N.
        • Matthews P.
        • Antel J.P.
        • Preul M.
        • Francis G.
        • Arnold D.L.
        Chemical pathology of acute demyelinating lesions and its correlations with disability.
        Ann Neurol. 1995; 38: 901-909
        • Duvernoy H.M.
        • Cabanis E.A.
        The Human Brain: Surface, Three-Dimensional Sectional Anatomy, and MRI. Springer-Verlag, New York1991
        • Duyn H.
        • Gillen J.
        • Sobering G.
        • van Zijl P.C.
        • Moonen C.T.W.
        Multisection proton MR spectroscopic imaging of the brain.
        Radiology. 1993; 188: 277-282
        • Eastwood S.L.
        • Harrison P.J.
        Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression.
        Mol Psychiatry. 2000; 5: 425-432
      1. First MB, Gibbon M, Spitzer RL, Williams JBW (1996): Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders—Research Version. Washington, DC: American Psychiatric Association

        • Guidotti A.
        • Auta J.
        • Davis J.M.
        • Di-Giorgi-Gerevini V.
        • Dwivedi Y.
        • Grayson D.R.
        • et al.
        Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder.
        Arch Gen Psychiatry. 2000; 57: 1061-1069
        • Hamilton M.
        Development of a rating scale for primary depressive illness.
        Br J Soc Clin Psychol. 1994; 6: 278-296
        • Harvey I.
        • Persaud R.
        • Ron M.A.
        • Baker G.
        • Murray R.M.
        Volumetric MRI measurements in bipolars compared with schizophrenics and healthy controls.
        Psychol Med. 1994; 24: 689-699
        • Hauser P.
        • Altshuler L.L.
        • Berrettini W.
        • Dauphinais I.D.
        • Gelernter J.
        • Post R.M.
        Temporal lobe measurement in primary affective disorder by magnetic resonance imaging.
        J Neuropsychiatry Clin Neurosci. 1989; 1: 128-134
        • Heckers S.
        • Stone D.
        • Walsh J.
        • Shick J.
        • Koul P.
        • Benes F.M.
        Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia.
        Arch Gen Psychiatry. 2002; 59: 521-529
        • Jenkins B.G.
        • Klivenyi P.
        • Kustermann E.
        • Andreassen O.A.
        • Ferrante R.J.
        • Rosen B.R.
        • Beal M.F.
        Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington’s disease mice.
        J Neurochem. 2000; 74: 2108-2119
        • Kato T.
        • Inubushi T.
        • Kato N.
        Magnetic resonance spectroscopy in affective disorders.
        J Neuropsychiatry Clin Neurosci. 1998; 10: 133-147
        • Kemmerer M.
        • Nasrallah H.
        • Sharma S.
        • Olson S.
        • Martin R.
        • Lynn M.
        Increased hippocampal volume in bipolar disorder.
        Biol Psychiatry. 1994; 35: 626
        • Ketter T.A.
        • George M.S.
        • Kimbrell T.A.
        • Benson B.A.
        • Post R.M.
        Functional brain imaging, limbic function, and affective disorders.
        Neuroscientist. 1996; 2: 55-65
        • Krishnan K.R.
        • Doraiswamy P.M.
        • Figiel G.S.
        • Husain M.M.
        • Shah S.A.
        • Na C.
        • et al.
        Hippocampal abnormalities in depression.
        J Neuropsychiatry Clin Neurosci. 1991; 3: 387-391
        • Leverich G.S.
        • Nolen W.A.
        • Rush A.J.
        • Nolen W.A.
        • Denicoff K.D.
        • Altshuler L.L.
        • et al.
        The Stanley Foundation Bipolar Treatment Outcome Network. I. Longitudinal methodology.
        J Affect Disord. 2001; 67: 33-44
        • Lim K.O.
        • Adalsteinsson E.
        • Spielman D.
        • Sullivan E.V.
        • Rosenbloom M.J.
        • Pfefferbaum A.
        Proton magnetic resonance spectroscopic imaging of cortical gray and white matter in schizophrenia.
        Arch Gen Psychiatry. 1998; 55: 346-352
        • Mayberg H.S.
        Frontal lobe dysfunction in secondary depression.
        J Neuropsychiatry Clin Neurosci. 1994; 6: 428-442
        • Mayberg H.S.
        • Liotti M.
        • Brannan S.K.
        • McGinnis S.
        • Mahurin R.K.
        • Jerabek P.A.
        • et al.
        Reciprocal limbic-cortical function and negative mood.
        Am J Psychiatry. 1999; 156: 675-682
        • Moffett J.R.
        • Namboodiri M.A.
        Differential distribution of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat forebrain.
        J Neurocytol. 1995; 24: 409-433
        • Moore G.J.
        • Bebchuk J.M.
        • Hasanat K.
        • Chen G.
        • Seraji-Bozorgzad N.
        • Wilds I.B.
        • et al.
        Lithium increases N-acetyl-aspartate in the human brain.
        Biol Psychiatry. 2000; 48: 1-8
        • Ongur D.
        • Drevets W.C.
        • Price J.L.
        Glial reduction in the subgenual prefrontal cortex in mood disorders.
        Proc Natl Acad Sci U S A. 1998; 95: 13290-13295
        • Gorham D.R.
        • Overall J.E.
        The brief psychiatric rating scale.
        Psychol Rep. 1962; 10: 799-812
        • Rajkowska G.
        Cell pathology in bipolar disorder.
        Bipolar Disord. 2002; 4: 105-116
        • Renshaw P.F.
        • Lafer B.
        • Babb S.M.
        • Fava M.
        • Stoll A.L.
        • Christensen J.D.
        • et al.
        Basal ganglia choline levels in depression and response to fluoxetine treatment.
        Biol Psychiatry. 1997; 41: 837-843
        • Richards T.L.
        Proton MR spectroscopy in multiple sclerosis.
        AJR Am J Roentgenol. 1991; 157: 1073-1078
        • Rubin E.
        • Sackeim H.A.
        • Prohovnik I.
        • Moeller J.R.
        • Schnur D.B.
        • Mukherjee S.
        Regional cerebral blood flow in mood disorders.
        Psychiatry Res. 1995; 61: 1-10
        • Sackeim H.A.
        • Prohovnik I.
        • Moeller J.R.
        • Mayeux R.
        • Stern Y.
        • Devanand D.P.
        Regional cerebral blood flow in mood disorders. I. Comparison of major depressives and normal controls at rest.
        Arch Gen Psychiatry. 1990; 47: 60-70
        • Schlaepfer T.E.
        • Harris G.J.
        • Tien A.Y.
        • Peng L.W.
        • Lee S.
        • Federman E.B.
        • et al.
        Decreased regional cortical gray matter volume in schizophrenia.
        Am J Psychiatry. 1994; 151: 842-848
        • Sharma R.
        • Venkatasubramanian P.N.
        • Barany M.
        • Davis J.M.
        Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients.
        Schizophr Res. 1992; 8: 43-49
        • Soares J.C.
        • Mann J.J.
        The functional neuroanatomy of mood disorders.
        J Psychiat Res. 1997; 31: 393-432
        • Stoll A.
        • Renshaw P.F.
        • De Micheli E.
        • Wurtmann R.
        • Pillay S.S.
        • Cohen B.
        Choline ingestion increases the resonance of choline-containing compounds in human brain.
        Biol Psychiatry. 1995; 37: 170-174
        • Swayze II, V.W.
        • Andreasen N.C.
        • Alliger R.J.
        • Yuh W.T.
        • Ehrhardt J.C.
        Subcortical and temporal structures in affective disorder and schizophrenia.
        Biol Psychiatry. 1992; 31: 221-240
        • Talairach J.
        • Tournoux P.
        Coplanar Stereotaxic atlas of the Human Brain. Thieme Medical Publishers, New York1998
        • Urenjak J.
        • Williams S.R.
        • Gadian D.G.
        • Noble M.
        Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types.
        J Neurosci. 1993; 13: 981-989
        • Vawter M.P.
        • Freed W.J.
        • Kleinman J.E.
        Neuropathology of bipolar disorder.
        Biol Psychiatry. 2000; 48: 486-504
        • Vion-Dury J.
        • Salvan A.M.
        • Confort-Gouny S.
        • Dhiver C.
        • Cozzone P.
        Reversal of brain metabolic alterations with zidovudine detected by proton localised magnetic resonance spectroscopy.
        Lancet. 1995; 345: 60-61
        • Winsberg M.E.
        • Sachs N.
        • Tate D.L.
        • Adalsteinsson E.
        • Spielman D.
        • Ketter T.A.
        Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder.
        Biol Psychiatry. 2000; 47: 475-481
        • Young R.C.
        • Biggs J.T.
        • Ziegler V.E.
        A rating scale for mania: Reliability, validity and sensitivity.
        Br J Psychiatry. 2000; 133: 429-435