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October 1997, Vol 54, No. 10 >
Article | October 1997

Measurement of Glutamate and Glutamine in the Medial Prefrontal Cortex of Never-Treated Schizophrenic Patients and Healthy Controls by Proton Magnetic Resonance Spectroscopy

Robert Bartha, BSc; Peter C. Williamson, MD; Dick J. Drost, PhD; Ashok Malla, MB; Tom J. Carr, MD; Len Cortese, MD; Gita Canaran, MA; R. Jane Rylett, PhD; Richard W. J. Neufeld, PhD
Arch Gen Psychiatry. 1997;54(10):959-965. doi:10.1001/archpsyc.1997.01830220085012
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Background:  Positron emission tomographic and postmortem studies comparing schizophrenic patients with healthy control subjects have found medial prefrontal cortical and anterior cingulate abnormalities that suggest dysfunction in glutamatergic neurons. The glutamate used for nerve signal transduction is predominantly derived from glutamine. After signal transduction, glutamate released into the synapse is converted to glutamine in glial cells, transported back to the presynaptic neuron, and reconverted to glutamate for reuse. In this study, levels of glutamate and glutamine were examined by means of in vivo proton (1H) magnetic resonance spectroscopy.

Methods:  Localized in vivo1H spectra were acquired from a 4.5-cm3 volume in the left medial prefrontal cortex encompassing portions of Brodmann areas 24, 32, and 9 in 10 never-treated schizophrenic subjects and 10 healthy controls of comparable age, sex, handedness, education, and parental education. From each spectrum, metabolite levels were estimated for glutamate and glutamine, as well as 10 other metabolites and 3 macromolecules, by means of a noninteractive computer program that combined modeled in vitro spectra of every metabolite to reconstruct each in vivo spectrum.

Results:  A significant increase in glutamine level was found in the medial prefrontal cortex of the schizophrenic patients compared with controls. N-acetylaspartate and other measured metabolites and macromolecules were not significantly changed in schizophrenics.

Conclusion:  Increased glutamine levels in the medial prefrontal region most likely reflect decreased glutamatergic activity in this region in never-treated schizophrenic patients compared with healthy controls.

REFERENCES

1 +
Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT.  Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alternations with deficit syndrome . Arch Gen Psychiatry . 1992;;49:522-529.
2 +
Ebmeier KP, Blackwood DHR, Murray C, Souza V, Walker M, Dougall N, Moffoot APR, O'Carroll RE, Goodwin GM.  Single-photon emission computed tomography with 99mTc exametazime in unmedicated schizophrenic patients . Biol Psychiatry . 1993;;33:487-495.
3 +
Kawasaki Y, Maeda Y, Suzuki M, Urata K, Higaskima M, Kiba K, Yamaguchi N, Matsuda H, Hisada K.  SPECT analysis of regional cerebral blood flow changes in patients with schizophrenia during the Wisconsin Card Sorting Test . Schizophr Res . 1993;;10:109-116.
4 +
Siegel BV, Buchsbaum MS, Bunney WE, Gottschalk LA, Haier RJ, Lohr JB, Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG, Wu JC.  Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients . Am J Psychiatry . 1993;;150:1325-1336.
5 +
Ebmeier KP, Lawrie SM, Blackwood DHR, Johnstone EC, Goodwin GM.  Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia . J Neurol Neurosurg Psychiatry . 1995;;58:452-456.
6 +
Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RSJ, Grasby PM.  Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia . Nature . 1995;;378:180-194.
7 +
Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak SJ.  Patterns of cerebral blood flow in schizophrenia . Br J Psychiatry . 1992;;160:179-186.
8 +
Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, Cohen G, O'Leary DS.  Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia . Arch Gen Psychiatry . 1992;;49:943-958.
9 +
Gur RE, Mozley D, Resnick SM, Harper Mozley L, Shtasl DL, Gallacher F, Arnold SE, Karp JS, Alavi A, Reivich M, Gur RC.  Resting cerebral glucose metabolism in first-episode and previously treated patients with schizophrenia relates to clinical features . Arch Gen Psychiatry . 1995;;52:657-667.
10 +
Frith CD, Friston KJ, Herold S, Silbersweig D, Fletcher P, Cahill C, Dolan RJ, Frackowiak RSJ, Liddle PF.  Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task . Br J Psychiatry . 1995;;167:343-349.
11 +
Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, Jones T, Frackowiak RSJ.  A functional neuroanatomy of hallucinations in schizophrenia . Nature . 1995;;378:176-179.
12 +
Benes FM, Sorensen I, Vincent SL, Bird ED.  Increased density of glutamate-immunoreactive vertical process in superficial laminae in cingulate cortex of schizophrenic brain . Cerebral Cortex . 1992;;2:503-512.
13 +
Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL.  Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients . Arch Gen Psychiatry . 1991;;48:996-1001.
14 +
Nishikawa T, Takashima M, Toru M.  Increased [3H] kainic acid binding in the prefrontal cortex in schizophrenia . Neurosci Lett . 1983;;40:245-250.
15 +
Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT.  Abnormal excitatory neurotransmitter metabolism in schizophrenic brains . Arch Gen Psychiatry . 1995;;52:829-836.
16 +
Deakin JFW, Slater P, Simpson MDC, Gilchrist AC, Skan WJ, Royston MC, Reynolds GP, Cross AJ.  Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia . J Neurochem . 1989;;52:1781-1786.
17 +
Vogt BA.  Structural organization of cingulate cortex: areas, neurons, and somatodendritic transmitter receptors . In: Vogt BA, Gabriel M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus . Boston, Mass: Birkhauser; 1993;:19-70.
18 +
Stanley JA, Drost DJ, Williamson PC, Thompson RT.  The use of a priori knowledge to quantify short echo in vivo 1H MR spectra . Magn Reson Med . 1995;;34:17-24.
19 +
Provencher SW.  Estimation of metabolite concentrations from localized in-vivo proton NMR spectra . Magn Reson Med . 1994;;30:672-679.
20 +
Michaelis T, Merboldt K, Bruhn H, Hanicke W, Frahm J.  Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra . Radiology . 1993;;187:219-227.
21 +
Ernst T, Ross BD, Flores R.  Cerebral MRS in infants with suspected Reye's syndrome . Lancet . 1992;;340:486.
22 +
Kreis R, Ross BD. Farrow NA, Ackerman Z.  Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy . Neuroradiology . 1992;;182:19-27.
23 +
Stanley JA, Williamson PC, Drost DJ, Rylett J, Carr T, Malla A, Thompson RT.  An in vivo proton magnetic resonance spectroscopy study of schizophrenic patients . Schizophr Bull . 1996;;22:597-609.
24 +
Spitzer R, Williams J. Structured Clinical Interview for DSM-III-R . New York, NY: New York Psychiatric Institute; 1985;.
25 +
Andreasen N. Scale for the Assessment of Negative Symptoms (SANS) . Iowa City, Iowa: University of Iowa; 1994;.
26 +
Andreasen N. Scale for the Assessment of Positive Symptoms (SAPS) . Iowa City, Iowa: University of Iowa; 1994;.
27 +
Bryden P.  Measuring handedness with questionnaires . Neuropsychologia . 1977;;15:617-624.
28 +
Liu Z, Javaid T, Hu J, Brown TR. CSI—autoshim procedures for body and surface coil. In: Proceedings of the Society of Magnetic Resonance 2nd Annual Meeting; August 6-12, 1994; San Francisco, Calif; Page 1174. Abstract.
29 +
Tailairach J, Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain . New York, NY: Thieme Medical Publishers Inc; 1988;.
30 +
Frahm J, Merboldt KD, Hanicke W.  Localized proton spectroscopy using stimulated echoes . J Magn Reson . 1987;;72:502-508.
31 +
Frahm J, Michaelis T, Merboldt KD, Bruhn H, Gyngell ML, Hanicke W.  Improvements in localized proton NMR spectroscopy of human brain: water suppression, short echo times, and 1 ml resolution . J Magn Reson . 1990;;90:464-473.
32 +
Bartha R, Drost DJ, Stanley J, Williamson PC. A comparison between time and frequency domain quantification of short echo 1H MR spectra. In: Proceedings of the 3rd Society of Magnetic Resonance Meeting; August 19-25, 1995; Nice, France. Page 1946. Abstract.
33 +
Klose U.  In vivo proton spectroscopy in presence of eddy currents . Magn Reson Med . 1990;;14:26-30.
34 +
De Beer R, van Ormondt D.  Analysis of data using time domain fitting procedures . NMR Basic Principles Prog . 1992;;26:201-248.
35 +
Van den Boogaart A, Ala-Korpela M, Jokisaari J, Griffiths JR.  Time and frequency domain analysis of NMR data compared: an application to 1D1H spectra of lipoproteins . Magn Reson Med . 1994;;31:347-358.
36 +
Marquardt DW.  An algorithm for least-squares estimations of non-linear parameters . J Soc Indust Appl Math . 1963;;11:431-441.
37 +
Behar KL, Rothman DL, Spencer DD, Petroff OAC.  Analysis of macromolecule resonances in 1H NMR spectra of human brain . Magn Reson Med . 1994;;32:294-302.
38 +
Ross B, Michaelis T.  Clinical applications of magnetic resonance spectroscopy . Magn Reson Q . 1994;;10:191-247.
39 +
Christiansen P, Henriksen O, Stubgaard M, Gideon P, Larsson HBW.  In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard . Magn Reson Imag . 1993;;11:107-118.
40 +
SPSS for Windows: Release 6.0. Chicago, Ill: SPSS Inc; 1993.
41 +
Cochran WG.  Analysis of covariance: its nature and uses . Biometrics . 1957;;13:261-281.
42 +
Lees MC, Neufeld RWJ.  Matching the limits of clinical inference to the limits of quantitative methods: a formal appeal to practice what we persistently preach . Can Psychol . 1994;;35:268-282.
43 +
Larzelere RE, Mulaik SA.  Single sample tests for many comparisons . Psychol Bull . 1977;;4:557-569.
44 +
Bradford HF, Ward HK, Thomas AJ.  Glutamine: a major substrate for nerve endings . J Neurochem . 1978;;30:1453-1459.
45 +
Erecinska M, Silver IA.  Metabolism and role of glutamate in mammalian brain . Prog Neurobiol . 1990;;35:245-296.
46 +
Ross B.  Biochemical considerations in 1H spectroscopy: glutamate and glutamine; myo-inositol and related metabolites . NMR Biomed . 1991;;4:59-63.
47 +
Hamberger AC, Chiang GH, Nylen ES, Scheff SW, Cotman CW.  Glutamate as a CNS transmitter, I: evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate . Brain Res . 1979;;168:513-530.
48 +
Urenjak J, Williams SR, Gadian DG, Noble M.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types . J Neurosci . 1993;;13:981-989.
49 +
Selemon LD, Rajkowska G, Goldman-Rakic PS.  Abnormally high neuronal density in the schizophrenic cortex . Arch Gen Psychiatry . 1995;;53:805-818.
50 +
Olney JW, Farber NB.  Glutamate receptor dysfunction in schizophrenia . Arch Gen Psychiatry . 1995;;52:998-1007.
51 +
Javitt DC, Zukin SR.  Recent advances in the phencyclidine model of schizophrenia . Am J Psychiatry . 1991;;148:1301-1308.
52 +
Nasrallah PM.  In vivo proton magnetic resonance spectroscopy of the hippocampal amygdala region in schizophrenics . Schizophr Res . 1992;;6:150.
53 +
Renshaw PF, Yurgelum-Todd DA, Tohen M, Gruber S, Cohen BM.  Temporal lobe proton magnetic resonance spectroscopy of patients with first-episode psychosis . Am J Psychiatry . 1995;;152:444-446.
54 +
Alexander GE, De Long MR, Strick PL.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex . Annu Rev Neurosci . 1986;;9:357-381.
55 +
Alexander EA, Crutcher MD, De Long MR.  Basal ganglia-thalamocortical cricuits: parallel substrates for motor, oculomotor, 'prefrontal' and 'limbic' functions . Prog Brain Res . 1990;;85:119-146.
56 +
Rajakumar N, Williamson P, Stoessl J, Flumerfelt B. Neurodevelopmental pathogenesis of schizophrenia. In: Proceedings of the Society of Neuroscience Meeting; 1996; Washington, DC. Vol 2, p 1187.
57 +
Lipska BK, Jaskiw GE, Chrapasta S, Karoum F, Weinberger DR.  Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens in prefrontal cortex . Brain Res . 1992;;585( (1-2) ):1-6.
58 +
Miller BL.  A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine, and choline . NMR Biomed . 1991;;4:47-52.
59 +
Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M.  Alternations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy . Arch Gen Psychiatry . 1991;;48:563-568.
60 +
Potwarka J, Drost DJ, Williamson PC. A study of schizophrenia using 2D 31P chemical shift imaging with 1H decoupling. In: Proceedings of the Society of Magnetic Resonance Meeting; April 27-May 3, 1996; New York, NY. Page 998. Abstract.
61 +
Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett RJ, Malla A, Thompson RT.  An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy . Arch Gen Psychiatry . 1995;;52:399-406.
62 +
Buckley PF, Moore C, Long H, Larkin C, Thompson P, Mulvany F, Redmond O, Stack JP, Ennis JT, Waddington JL.  1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: clinical, neurodevelopmental, and cognitive correlates . Biol Psychiatry . 1994;;36:792-800.
63 +
Benes FM.  Relationship of cingulate cortex to schizophrenia and other psychiatric disorders . In: Vogt BA, Gabriel M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus . Boston, Mass: Birkhauser; 1993;:581-605.

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Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Tamminga CA, Thaker GK, Buchanan R, Kirkpatrick B, Alphs LD, Chase TN, Carpenter WT.  Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alternations with deficit syndrome . Arch Gen Psychiatry . 1992;;49:522-529.
2 +
Ebmeier KP, Blackwood DHR, Murray C, Souza V, Walker M, Dougall N, Moffoot APR, O'Carroll RE, Goodwin GM.  Single-photon emission computed tomography with 99mTc exametazime in unmedicated schizophrenic patients . Biol Psychiatry . 1993;;33:487-495.
3 +
Kawasaki Y, Maeda Y, Suzuki M, Urata K, Higaskima M, Kiba K, Yamaguchi N, Matsuda H, Hisada K.  SPECT analysis of regional cerebral blood flow changes in patients with schizophrenia during the Wisconsin Card Sorting Test . Schizophr Res . 1993;;10:109-116.
4 +
Siegel BV, Buchsbaum MS, Bunney WE, Gottschalk LA, Haier RJ, Lohr JB, Lottenberg S, Najafi A, Nuechterlein KH, Potkin SG, Wu JC.  Cortical-striatal-thalamic circuits and brain glucose metabolic activity in 70 unmedicated male schizophrenic patients . Am J Psychiatry . 1993;;150:1325-1336.
5 +
Ebmeier KP, Lawrie SM, Blackwood DHR, Johnstone EC, Goodwin GM.  Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia . J Neurol Neurosurg Psychiatry . 1995;;58:452-456.
6 +
Dolan RJ, Fletcher P, Frith CD, Friston KJ, Frackowiak RSJ, Grasby PM.  Dopaminergic modulation of impaired cognitive activation in the anterior cingulate cortex in schizophrenia . Nature . 1995;;378:180-194.
7 +
Liddle PF, Friston KJ, Frith CD, Hirsch SR, Jones T, Frackowiak SJ.  Patterns of cerebral blood flow in schizophrenia . Br J Psychiatry . 1992;;160:179-186.
8 +
Andreasen NC, Rezai K, Alliger R, Swayze VW, Flaum M, Kirchner P, Cohen G, O'Leary DS.  Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia . Arch Gen Psychiatry . 1992;;49:943-958.
9 +
Gur RE, Mozley D, Resnick SM, Harper Mozley L, Shtasl DL, Gallacher F, Arnold SE, Karp JS, Alavi A, Reivich M, Gur RC.  Resting cerebral glucose metabolism in first-episode and previously treated patients with schizophrenia relates to clinical features . Arch Gen Psychiatry . 1995;;52:657-667.
10 +
Frith CD, Friston KJ, Herold S, Silbersweig D, Fletcher P, Cahill C, Dolan RJ, Frackowiak RSJ, Liddle PF.  Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task . Br J Psychiatry . 1995;;167:343-349.
11 +
Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, Jones T, Frackowiak RSJ.  A functional neuroanatomy of hallucinations in schizophrenia . Nature . 1995;;378:176-179.
12 +
Benes FM, Sorensen I, Vincent SL, Bird ED.  Increased density of glutamate-immunoreactive vertical process in superficial laminae in cingulate cortex of schizophrenic brain . Cerebral Cortex . 1992;;2:503-512.
13 +
Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL.  Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients . Arch Gen Psychiatry . 1991;;48:996-1001.
14 +
Nishikawa T, Takashima M, Toru M.  Increased [3H] kainic acid binding in the prefrontal cortex in schizophrenia . Neurosci Lett . 1983;;40:245-250.
15 +
Tsai G, Passani LA, Slusher BS, Carter R, Baer L, Kleinman JE, Coyle JT.  Abnormal excitatory neurotransmitter metabolism in schizophrenic brains . Arch Gen Psychiatry . 1995;;52:829-836.
16 +
Deakin JFW, Slater P, Simpson MDC, Gilchrist AC, Skan WJ, Royston MC, Reynolds GP, Cross AJ.  Frontal cortical and left temporal glutamatergic dysfunction in schizophrenia . J Neurochem . 1989;;52:1781-1786.
17 +
Vogt BA.  Structural organization of cingulate cortex: areas, neurons, and somatodendritic transmitter receptors . In: Vogt BA, Gabriel M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus . Boston, Mass: Birkhauser; 1993;:19-70.
18 +
Stanley JA, Drost DJ, Williamson PC, Thompson RT.  The use of a priori knowledge to quantify short echo in vivo 1H MR spectra . Magn Reson Med . 1995;;34:17-24.
19 +
Provencher SW.  Estimation of metabolite concentrations from localized in-vivo proton NMR spectra . Magn Reson Med . 1994;;30:672-679.
20 +
Michaelis T, Merboldt K, Bruhn H, Hanicke W, Frahm J.  Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra . Radiology . 1993;;187:219-227.
21 +
Ernst T, Ross BD, Flores R.  Cerebral MRS in infants with suspected Reye's syndrome . Lancet . 1992;;340:486.
22 +
Kreis R, Ross BD. Farrow NA, Ackerman Z.  Metabolic disorders of the brain in chronic hepatic encephalopathy detected with H-1 MR spectroscopy . Neuroradiology . 1992;;182:19-27.
23 +
Stanley JA, Williamson PC, Drost DJ, Rylett J, Carr T, Malla A, Thompson RT.  An in vivo proton magnetic resonance spectroscopy study of schizophrenic patients . Schizophr Bull . 1996;;22:597-609.
24 +
Spitzer R, Williams J. Structured Clinical Interview for DSM-III-R . New York, NY: New York Psychiatric Institute; 1985;.
25 +
Andreasen N. Scale for the Assessment of Negative Symptoms (SANS) . Iowa City, Iowa: University of Iowa; 1994;.
26 +
Andreasen N. Scale for the Assessment of Positive Symptoms (SAPS) . Iowa City, Iowa: University of Iowa; 1994;.
27 +
Bryden P.  Measuring handedness with questionnaires . Neuropsychologia . 1977;;15:617-624.
28 +
Liu Z, Javaid T, Hu J, Brown TR. CSI—autoshim procedures for body and surface coil. In: Proceedings of the Society of Magnetic Resonance 2nd Annual Meeting; August 6-12, 1994; San Francisco, Calif; Page 1174. Abstract.
29 +
Tailairach J, Tournoux P. Co-Planar Stereotaxic Atlas of the Human Brain . New York, NY: Thieme Medical Publishers Inc; 1988;.
30 +
Frahm J, Merboldt KD, Hanicke W.  Localized proton spectroscopy using stimulated echoes . J Magn Reson . 1987;;72:502-508.
31 +
Frahm J, Michaelis T, Merboldt KD, Bruhn H, Gyngell ML, Hanicke W.  Improvements in localized proton NMR spectroscopy of human brain: water suppression, short echo times, and 1 ml resolution . J Magn Reson . 1990;;90:464-473.
32 +
Bartha R, Drost DJ, Stanley J, Williamson PC. A comparison between time and frequency domain quantification of short echo 1H MR spectra. In: Proceedings of the 3rd Society of Magnetic Resonance Meeting; August 19-25, 1995; Nice, France. Page 1946. Abstract.
33 +
Klose U.  In vivo proton spectroscopy in presence of eddy currents . Magn Reson Med . 1990;;14:26-30.
34 +
De Beer R, van Ormondt D.  Analysis of data using time domain fitting procedures . NMR Basic Principles Prog . 1992;;26:201-248.
35 +
Van den Boogaart A, Ala-Korpela M, Jokisaari J, Griffiths JR.  Time and frequency domain analysis of NMR data compared: an application to 1D1H spectra of lipoproteins . Magn Reson Med . 1994;;31:347-358.
36 +
Marquardt DW.  An algorithm for least-squares estimations of non-linear parameters . J Soc Indust Appl Math . 1963;;11:431-441.
37 +
Behar KL, Rothman DL, Spencer DD, Petroff OAC.  Analysis of macromolecule resonances in 1H NMR spectra of human brain . Magn Reson Med . 1994;;32:294-302.
38 +
Ross B, Michaelis T.  Clinical applications of magnetic resonance spectroscopy . Magn Reson Q . 1994;;10:191-247.
39 +
Christiansen P, Henriksen O, Stubgaard M, Gideon P, Larsson HBW.  In vivo quantification of brain metabolites by 1H-MRS using water as an internal standard . Magn Reson Imag . 1993;;11:107-118.
40 +
SPSS for Windows: Release 6.0. Chicago, Ill: SPSS Inc; 1993.
41 +
Cochran WG.  Analysis of covariance: its nature and uses . Biometrics . 1957;;13:261-281.
42 +
Lees MC, Neufeld RWJ.  Matching the limits of clinical inference to the limits of quantitative methods: a formal appeal to practice what we persistently preach . Can Psychol . 1994;;35:268-282.
43 +
Larzelere RE, Mulaik SA.  Single sample tests for many comparisons . Psychol Bull . 1977;;4:557-569.
44 +
Bradford HF, Ward HK, Thomas AJ.  Glutamine: a major substrate for nerve endings . J Neurochem . 1978;;30:1453-1459.
45 +
Erecinska M, Silver IA.  Metabolism and role of glutamate in mammalian brain . Prog Neurobiol . 1990;;35:245-296.
46 +
Ross B.  Biochemical considerations in 1H spectroscopy: glutamate and glutamine; myo-inositol and related metabolites . NMR Biomed . 1991;;4:59-63.
47 +
Hamberger AC, Chiang GH, Nylen ES, Scheff SW, Cotman CW.  Glutamate as a CNS transmitter, I: evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate . Brain Res . 1979;;168:513-530.
48 +
Urenjak J, Williams SR, Gadian DG, Noble M.  Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types . J Neurosci . 1993;;13:981-989.
49 +
Selemon LD, Rajkowska G, Goldman-Rakic PS.  Abnormally high neuronal density in the schizophrenic cortex . Arch Gen Psychiatry . 1995;;53:805-818.
50 +
Olney JW, Farber NB.  Glutamate receptor dysfunction in schizophrenia . Arch Gen Psychiatry . 1995;;52:998-1007.
51 +
Javitt DC, Zukin SR.  Recent advances in the phencyclidine model of schizophrenia . Am J Psychiatry . 1991;;148:1301-1308.
52 +
Nasrallah PM.  In vivo proton magnetic resonance spectroscopy of the hippocampal amygdala region in schizophrenics . Schizophr Res . 1992;;6:150.
53 +
Renshaw PF, Yurgelum-Todd DA, Tohen M, Gruber S, Cohen BM.  Temporal lobe proton magnetic resonance spectroscopy of patients with first-episode psychosis . Am J Psychiatry . 1995;;152:444-446.
54 +
Alexander GE, De Long MR, Strick PL.  Parallel organization of functionally segregated circuits linking basal ganglia and cortex . Annu Rev Neurosci . 1986;;9:357-381.
55 +
Alexander EA, Crutcher MD, De Long MR.  Basal ganglia-thalamocortical cricuits: parallel substrates for motor, oculomotor, 'prefrontal' and 'limbic' functions . Prog Brain Res . 1990;;85:119-146.
56 +
Rajakumar N, Williamson P, Stoessl J, Flumerfelt B. Neurodevelopmental pathogenesis of schizophrenia. In: Proceedings of the Society of Neuroscience Meeting; 1996; Washington, DC. Vol 2, p 1187.
57 +
Lipska BK, Jaskiw GE, Chrapasta S, Karoum F, Weinberger DR.  Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens in prefrontal cortex . Brain Res . 1992;;585( (1-2) ):1-6.
58 +
Miller BL.  A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine, and choline . NMR Biomed . 1991;;4:47-52.
59 +
Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG, Allen M.  Alternations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics: a pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy . Arch Gen Psychiatry . 1991;;48:563-568.
60 +
Potwarka J, Drost DJ, Williamson PC. A study of schizophrenia using 2D 31P chemical shift imaging with 1H decoupling. In: Proceedings of the Society of Magnetic Resonance Meeting; April 27-May 3, 1996; New York, NY. Page 998. Abstract.
61 +
Stanley JA, Williamson PC, Drost DJ, Carr TJ, Rylett RJ, Malla A, Thompson RT.  An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy . Arch Gen Psychiatry . 1995;;52:399-406.
62 +
Buckley PF, Moore C, Long H, Larkin C, Thompson P, Mulvany F, Redmond O, Stack JP, Ennis JT, Waddington JL.  1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: clinical, neurodevelopmental, and cognitive correlates . Biol Psychiatry . 1994;;36:792-800.
63 +
Benes FM.  Relationship of cingulate cortex to schizophrenia and other psychiatric disorders . In: Vogt BA, Gabriel M, eds. Neurobiology of Cingulate Cortex and Limbic Thalamus . Boston, Mass: Birkhauser; 1993;:581-605.

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To understand the clinical management of acute heart failure syndromes.
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The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Note: You must get at least of the answers correct to pass this quiz.
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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
To view and print your certificate and access a summary of your CME courses go to My CME.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s “Cited By” API will populate this tab (http://www.crossref.org/citedby.html).
Compression-Only CPR: Pushing the Science Forward
Cone
AAM 2010;304:1493-1495.
All you need to read in the other general journals
BMJ 2010;341:c5893-c1494.
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