The number of magnetic resonance spectroscopy studies that assess the levels of different neurochemicals in bipolar disorder has increased considerably in recent years. Abnormalities were reported mainly in the brain regions implicated in the pathophysiology of BD: the dorsolateral prefrontal cortex, cingulated gyrus, hippocampus and basal ganglia. Although these findings are not diagnostic, future research in this area may help to elucidate the pathophysiology of BD and monitor treatment effects.
Magnetic resonance spectroscopy (MRS) is a useful, noninvasive method of examining alterations in brain neurochemistry that might be associated with the development of bipolar disorder (BD) and the effects of treatment (Soares et al., 1996). It uses the same technology as magnetic resonance imaging and provides a frequency signal intensity spectrum of multiple peaks that reflect the metabolite levels of a localized region in the brain. Magnetic resonance spectroscopy data are usually displayed in the frequency domain, and the area under a specific peak is proportional to the number of protons processing at that frequency (Stanley, 2002). It can assess chemicals containing phosphorus-31 (31P), carbon-13 (13C), lithium-7 and fluorine-19. The most commonly used, however, is proton magnetic resonance spectroscopy (1H-MRS).
N-acetylaspartate (NAA) is the predominant resonance in the 1H-MRS spectrum of the normal adult human brain. It is an amino acid found in high concentrations in mature neurons and considered to be a marker of neuronal integrity and viability. Reductions in NAA may also reflect impairment in the formation and maintenance of myelin and mitochondrial energy production (Baslow, 2002). In adults with BD, decreased NAA levels were reported in the dorsolateral prefrontal cortex (DLPFC) (Winsberg et al., 2000), orbital frontal gray matter (Cecil et al., 2002) and hippocampus (Bertolino et al., 2003; Deicken et al., 2002). Lower DLPFC NAA levels were also reported in children (Chang et al., 2003) and adolescents (Kusumakar et al., 2002) with BD. Investigating treatment-induced effects, the administration of lithium (Eskalith, Lithobid) during a four-week period was shown to increase brain NAA concentration as indirect evidence of its neurotrophic/neuroprotective effects (Moore et al., 2000; Silverstone et al., 2003). This increase has not been demonstrated with divalproex (Depakote) (Silverstone et al., 2003).
Lithium and divalproex were also recently shown to be protective against dextroamphetamine (a human model of mania)-induced choline decrease (Silverstone et al., 2004). The choline (Cho) peak in the 1H-MRS is considered a potential biomarker for the status of membrane phospholipid metabolism, and basal ganglia Cho/creatine (Cr) is elevated in the euthymic (Kato et al., 1996; Sharma et al., 1992) and depressive state (Hamakawa et al., 1998) in patients with BD. Lithium treatment did not appear to alter Cho resonance in the parietal lobes in seven male patients compared to healthy controls (Stoll et al., 1992) or in the temporal cortex of healthy volunteers (Silverstone et al., 1999). In a case series (n=6), Stoll et al. (1996) demonstrated that oral Cho in combination with lithium was an effective therapy for some patients with treatment-refractory rapid-cycling BD.
Glutamate, glutamine and γ-aminobutyric acid (GABA) are also of interest, as antiglutamatergic and GABAergic anticonvulsants appear useful in treating BD. In a majority of MRS reports, the Glx region refers to glutamate and glutamine. In a group of adolescents with bipolar depression, a bilateral increase in Glx in the frontal cortex and basal ganglia has been reported (Castillo et al., 2000). Glutamatergic abnormalities may be involved in neurotoxicity that is potentially responsible for specific brain insults in BD. Decreased GABA levels were reported in the occipital cortex in nonmedicated patients with unipolar depression (Sanacora et al., 1999). Occipital cortex GABA concentrations after selective serotonin reuptake inhibitor (Sanacora et al., 2002) and electroconvulsive therapy treatment (Sanacora et al., 2003) were significantly higher than pretreatment concentrations. Patients with BD appear not to have such reduction in GABA levels (Mason et al., 2000).
Another important metabolite in 1H-MRS is myo-inositol (mI), which is a substrate for the phosphoinositide cycle. At therapeutic levels, lithium inhibits inositol monophosphatase and polyphosphate-1-phosphatase, which are involved in recycling inositol mono- and polyphosphates to mI (Berridge and Irvine, 1989). Divalproex also decreases the concentration of mI and increases the concentration of inositol monophosphate in rat brains (O'Donnell et al., 2003).
Moore et al. (1999) found decreased mI in the right frontal lobe of depressed patients with BD following acute (five to seven days) lithium administration, which persisted through one month of treatment. However, the patients' clinical state was clearly unchanged at this time, supporting the hypothesis that the initial actions of lithium may occur with a reduction of mI and that this reduction initiates a cascade of secondary changes that are ultimately responsible for lithium's therapeutic efficacy. Consistent with this, Davanzo et al. (2001) observed a significant decrease in anterior cingulate mI/Cr ratios following seven days of lithium therapy in children and adolescents with early-onset BD. Children in a manic phase demonstrated elevated mI/Cr levels within the anterior cingulate cortex.
The 31P-MRS allows in vivo examination of the changes in phosphorus-based membrane metabolism and the effects of medication. In a comprehensive series of studies, one group measured frontal lobe phosphomonoesters (PMEs; precursors of membrane phospholipid metabolism) and demonstrated that frontal lobe PME levels vary with mood state (Deicken et al., 1995a; Kato et al., 1994, 1993). Deicken et al. (1995b) also reported significantly reduced PME in both the right and left temporal lobes in unmedicated euthymic patients compared with healthy controls. An increase in PME concentration with seven and 14 days of lithium administration in the human brain was observed (Yildiz et al., 2001). As patients in the previously mentioned studies were mostly on lithium or off lithium for short periods of time, increased levels of PME could reflect medication effects. This is significant, as lithium inhibits inositol monophosphatase, producing increased levels of PME that would be consistent with increased membrane anabolism.
Bipolar disorder is associated with altered brain chemistry in a number of regions, mainly the DLPFC, basal ganglia, hippocampus and anterior cingulate. The NAA levels in the DLPFC are decreased in patients with BD. It is not clear whether such an abnormality may precede illness onset, or to what extent it may reflect aberrant neurodevelopmental mechanisms, or whether it is related to progressive neuronal loss during the disease process.
Decreased NAA levels may reduce the transfer of acetyl groups required for myelin formation and/or maintenance (Chakraborty et al., 2001). Moreno et al. (2001) demonstrated that NAA synthesis is coupled to energetic (glucose) metabolism using in vivo 13C-MRS and [1-13C] glucose infusion. Abnormal brain energy metabolism is also suggested by 31P-MRS findings, such as decreased phosphocreatine (PCr) and intracellular pH (Kato et al., 1994, 1993). A mitochondrial dysfunction hypothesis for the pathophysiology of BD has also been proposed (Konradi et al., 2004).
Studying treatment effects on the neurochemistry of BD is an intriguing area of research (Soares, 2002). The findings of the studies reviewed here show that lithium increases total brain NAA and decreases mI in the anterior cingulate and right frontal lobe, whereas it does not affect the Cho resonance in the parietal lobes. Divalproex also appears to have an effect on the activity of the intracellular phosphoinositol cycle similar to lithium.
Treatment with GABAergic medications increases prefrontal GABA, while treatment with SSRIs is possibly associated with increased occipital cortex GABA concentrations and with a decrease in Cho in the anterior cingulate cortex.
These findings are preliminary and need replication, but they are important. They reflect cellular metabolism and membrane turnover, upon which many essential neuronal functions, such as neurotransmission and second- messenger cascades, are dependent. The application of in vivo MRS technology to the study of the pathophysiology of BD and the mechanisms of action of mood stabilizers is a new field of research. Currently, this is primarily a research tool, but as research evolves and the mechanisms involved are elucidated, it is expected that such tools will be of relevance for diagnosing and monitoring the effects of various treatments.
Our work on this field has been partly supported by MH 01736, the National Alliance for Research on Schizophrenia and Depression, Dana Foundation, the American Foundation for Suicide Prevention, the U.S. Department of Veterans Affairs, the Krus Endowed Chair in Psychiatry (UTHSCSA), and the UTHSCSA GCRC and its imaging core (M01-RR-01346).
Dr. Monkup is a postdoctoral fellow in the division of mood and anxiety disorders in the department of psychiatry at the University of Texas Health Sciences Center at San Antonio.
Dr. Soares is chief of the division of mood and anxiety disorders in the department of psychiatry at the University of Texas Health Sciences Center at San Antonio.
Baslow MH (2002), Evidence supporting a role for N-acetyl-L-aspartate as a molecular water pump in myelinated neurons in the central nervous system. An analytical review. Neurochem Int 40(4):295-300.
Berridge MJ, Irvine RF (1989), Inositol phophates and cell signalling. Nature 341(6239):197-205.
Bertolino A, Frye M, Callicott JH et al. (2003), Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 53(10):906-913.
Castillo M, Kwock L, Courvoisie H, Hooper SR (2000), Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations. AJNR Am J Neuroradiol 21(5):832-838.
Cecil KM, DelBello MP, Morey R, Strakowsky SM (2002), Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy. Bipolar Disord 4(6):357-365.
Chakraborty G, Mekala P, Yahya D et al. (2001), Intraneuronal N-acetylaspartate supplies acetyl groups for myelin lipid synthesis: evidence for myelin-associated aspartoacylase. J Neurochem 78(4):736-745.
Chang K, Adleman N, Dienes K et al. (2003), Decreased N-acetylaspartate in children with familial bipolar disorder. Biol Psychiatry 53(11):1059-1065.
Davanzo P, Thomas MA, Yue K et al. (2001), Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology 24(4):359-369.
Deicken RF, Fein G, Weiner MW (1995a), Abnormal frontal lobe phosphorous metabolism in bipolar disorder. Am J Psychiatry 152(6):915-918.
Deicken RF, Pegues MP, Anzalone S et al. (2002), Proton MRSI evidence for hippocampal neuronal pathology in familial bipolar I disorder. Biol Psychiatry 51:84S-85S.
Deicken RF, Weiner MW, Fein G (1995b), Decreased temporal lobe phosphomonoesters in bipolar disorder. J Affect Disord 33(3):195-199.
Hamakawa H, Kato T, Murashita J, Kato N (1998), Quantitative proton magnetic resonance spectroscopy of the basal ganglia in patients with affective disorders. Eur Arch Psychiatry Clin Neurosci 248(1):53-58.
Kato T, Hamakawa H, Shioiri T et al. (1996), Choline-containing compounds detected by proton magnetic resonance spectroscopy in the basal ganglia in bipolar disorder. J Psychiatry Neurosci 21(4):248-254.
Kato T, Shioiri T, Murashita J et al. (1994), Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 55(1):41-50.
Kato T, Takahashi S, Shioiri T, Inubushi T (1993), Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo 31P and 7Li magnetic resonance spectroscopy. J Affect Disord 27(1):53-59.
Konradi C, Eaton M, MacDonald ML et al. (2004), Molecular evidence for mitochondrial dysfunction in bipolar disorder. [Published erratum Arch Gen Psychiatry 61(6):538.] Arch Gen Psychiatry 61(3):300-308.
Kusumakar V, MacMaster FP, Sparkes S (2002), Dorsolateral prefrontal cortex N-acetyl-aspartate in treatment naive adolescent mood disorders. Biol Psychiatry 51:12S-13S.
Mason GF, Sanacora G, Anand A et al. (2000), Cortical GABA reduced in unipolar but not bipolar depression. Biol Psychiatry 47:92S.
Moore GJ, Bebchuk JM, Hasanat K et al. (2000), Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects? Biol Psychiatry 48(1):1-8.
Moore GJ, Bebchuk JM, Parrish JK et al. (1999), Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness. Am J Psychiatry 156(12):1902-1908.
Moreno A, Ross BD, Bluml S (2001), Direct determination of the N-acetyl-L-aspartate synthesis rate in the human brain by (13)C MRS and [1-(13)C]glucose infusion. J Neurochem 77(1):347-350.
O'Donnell T, Rotzinger S, Nakashima TT et al. (2003), Chronic lithium and sodium valproate both decrease the concentration of myoinositol and increase the concentration of inositol monophosphates in rat brain. Eur Neuropsychopharmacol 13(3):199-207.
Sanacora G, Mason GF, Rothman DL et al. (1999), Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 56(11):1043-1047.
Sanacora G, Mason GF, Rothman DL, Krystal JH (2002), Increased occipital cortex GABA concentrations in depressed patients after therapy with selective serotonin reuptake inhibitors. Am J Psychiatry 159(4):663-665.
Sanacora G, Mason GF, Rothman DL et al. (2003), Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 160(3):577-579.
Sharma R, Venkatasubramanian PN, Barany M, Davis JM (1992), Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients. Schizophr Res 8(1):43-49.
Silverstone PH, Asghar SJ, O'Donnell T et al. (2004), Lithium and valproate protect against dextroamphetamine induced brain choline concentration changes in bipolar disorder patients. World J Biol Psychiatry 5(1):38-44.
Silverstone PH, Rotzinger S, Pukhovsky A, Hanstock CC (1999), Effects of lithium and amphetamine on inositol metabolism in the human brain as measured by 1H and 31P MRS. Biol Psychiatry 46(12):1634-1641.
Silverstone PH, Wu RH, O'Donnell T et al. (2003), Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. Int Clin Psychopharmacol 18(2):73-79.
Soares JC (2002), Can brain-imaging studies provide a 'mood stabilizer signature?' Mol Psychiatry 7(suppl 1):S64-S70.
Soares JC, Krishnan KR, Keshavan MS (1996), Nuclear magnetic resonance spectroscopy: new insights into the pathophysiology of mood disorders. Depression 4(1):14-30.
Stanley JA (2002), In vivo magnetic resonance spectroscopy and its application to neuropsychiatric disorders. Can J Psychiatry 47(4):315-326 [see comment].
Stoll AL, Renshaw PF, Sachs GS et al. (1992), The human brain resonance of choline-containing compounds is similar in patients receiving lithium treatment and controls: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 32(10):944-949.
Stoll AL, Sachs GS, Cohen BM et al. (1996) Choline in the treatment of rapid-cycling bipolar disorder: clinical and neurochemical findings in lithium-treated patients. Biol Psychiatry 40(5):382-388.
Winsberg ME, Sachs N, Tate DL et al. (2000), Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry 47(6):475-481.
Yildiz A, Demopulos CM, Moore CM et al. (2001), Effect of lithium on phosphoinositide metabolism in human brain: a proton decoupled (31)P magnetic resonance spectroscopy study. Biol Psychiatry 50(1):3-7.