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Eur Arch Psychiatry Clin Neurosci (2006) xx:1–4 Gabriele Ende Æ Traute Demirakca Æ Sigrid Walter Æ Tim Wokrina Æ Alexander SartoriusDirk Wildgruber Æ Fritz A. Henn Subcortical and medial temporal MR-detectable metaboliteabnormalities in unipolar major depression Received: 3 January 2006 / Accepted: 27 June 2006 / Published online: 16 August 2006 determine whether MR-detectable alterations of cho-line-containing compounds in two key neural systems Mood-congruent processing biases are amongst the involved in major depression disorder namely the most robust research findings in neuropsychological hippocampus and the basal ganglia can be detected.
studies of major depressive disorder (MDD). Func- Multislice proton magnetic resonance spectroscopic tional MR studies could demonstrate increased and imaging was applied in 11 patients with major decreased activity in depressed patients compared depressive disorder (MDD) and ten matched healthy to healthy controls as a response to emotional stim- subjects. Voxels were selected from the left and right side of the hippocampus and the putamen. Signifi- The hippocampus is the focus for hypotheses cantly lower choline-containing compounds in the related to stress and its effects. A reduced hippo- hippocampus and significantly higher choline-con- campal serotonergic neurotransmission and im- taining compounds in the putamen of patients with paired neurogenesis and synaptogenesis in this MDD compared to healthy subjects were found. No brain region have been reported for MDD [ significant differences were found for the other ]. We previously observed a decreased signal metabolites in the two regions evaluated. Abnormal of MR-detectable hippocampal choline-containing levels of choline-containing compounds most likely compounds in patients with medication refractory reflect altered membrane phospholipid metabolism.
A reduced level in the hippocampus and an increased The basal ganglia are a complex of deep nuclei level in the putamen suggest regionally opponent that consist of the corpus striatum, globus pallidus, and substantia nigra. The corpus striatum, whichincludes the caudate nucleus and the putamen, re- ceives input from the cerebral cortex and the thal- containing compounds Æ MR spectroscopic imaging Æ amus and, in turn, projects to the globus pallidus.
The basal ganglia are not only involved in motorfunctions but also have important cognitive, ocu-lomotor, and limbic processing functions. They Presented in part at the 13th annual meeting of the Society of form a part of the brain neuroanatomic circuits that Magnetic Resonance in Medicine, Miami 2005.
may be involved in mood regulation and have been PD Dr. G. Ende (&) Æ T. Demirakca Æ S. Walter Æ T. Wokrina increasingly implicated in the pathophysiology of MRI and PET studies found the hippocampi and Central Institute of Mental HealthJ5, 68159 Mannheim, Germany the basal ganglia morphologically and functionally altered in MDD compared to healthy subjects. For a review see Ende et al. []. In three previous MRS/ MRSI studies of the basal ganglia in MDD contro- EA versial results have been reported regarding the ratio PCN Department of Psychiatry and Psychotherapy of Cho to total creatine (tCr). While Renshaw et al.
] in a single voxel study and a fairly large patient Table 1 Summary of patient and control characteristics, mean MRSI metabolite values and standard deviations for the hippocampus and putamen hippocampus
basal ganglia
b Beck Depression Inventory at time of MRSI scan c Hamilton Depression Score (21 items) at time of admission group (n = 42) reported decreased Cho/tCr, Vythi-lingam et al. ] in a recent MRSI study of 17 MDDpatients and an early single voxel study by Charleset al. [reported increased Cho/tCr in a group of7 MDD patients compared to controls.
Our proton MRSI study aimed to corroborate reported alterations in MR-detectable choline-con-taining compounds in depressed patients compared Fig. 1 The location of the MRSI slices and the typical voxel position for the to healthy controls in these two neural key regions of evaluated subregions: (a) hippocampi and (b) putamen MDD. We hypothesized that Cho would be founddecreased in the hippocampus in MDD patients, whereas basal ganglia Cho would show an oppositealteration in comparison to healthy controls.
All MRSI studies were performed on a 1.5 T Siemens Vision system With the long echo multislice MR spectroscopic using a standard CP head coil (Magnetom VISION, Siemens,Erlangen, Germany). Three MRSI slices were acquired within one imaging method used, spectra with non-overlapping measurement. A selective lipid inversion pulse, TR = 1,500 ms, resonances of for N-acetylasparte (NAA), a marker TE = 135 ms, FOV = 300 mm, grid = 36 · 36, Slice thickness = of neuronal function, choline-containing compounds 15 mm, nominal voxel size = 1.04 cm3 (0.8 · 0.8 · 1.5 cm) were (Cho), possibly involved in membrane and myelin used. In addition, a 3D magnetization prepared rapid gradient echo(MPRAGE) data set was acquired.
sheath metabolism and creatine- and phosphocrea-tine (tCr) reflecting cerebral energy metabolism Postprocessing of the MRSI data included CSF correction of MRSIbrain data to increase sensitivity and decrease variance [ Voxels were selected from the left and right hippocampus and left and right putamen. In addition to the metabolite signals thevoxel composition for each subregion was evaluated for differences in GM, WM and CSF content. Per data set mean values of spectrafrom each subregion are reported.
Eleven inpatients diagnosed for MDD and ten healthy comparison Absolute integral values for NAA, tCr, and Cho were evaluated subjects were studied with 1H MRSI. All patients satisfied DSM IV [, ]. In a first analysis all spectra indicated in Fig. were curve criteria for MDD and were inpatients of the Department of Psy- fitted. The operator was blinded to the subject’s status (patient or chiatry and Psychotherapy at the time of the examination. All control) but not to the research question. The operator chose patients were on antidepressive medication and no restrictions spectra by anatomical location, at this step blinded to spectral were made regarding antidepressive co-medication like lorazepam.
appearance. Spectra were then filtered for further evaluation by A summary of patient and control characteristics is given in the objective quality criteria In a next step these criteria were applied in an automated exclusion routine: linewidth had to be less After complete description of the study to the subjects, written than 10 Hz, voxel CSF content had to be less than 25%, for hip- informed consent was obtained. The study was approved by the pocampal voxels GM voxel content had to be higher than WM Cho hippocampi
Cho putamen
GM voxel content hippocampi
GM voxel content putamen
Fig. 2 Scatter plots of the Cho signal in patients (gray circles) and healthy controls (black circles) as a function of voxel GM content A voxel-based-morphometry (VBM) analysis was performed correlation analyses revealed a significant negative with SPM2 using the 3D mprage data sets in order to detect mor- correlation between hippocampal GM and the Cho phometrical changes in those brain areas where metabolic changeswere hypothesized.
signal in the patient group (R = )0.81, P = 0.02).
In concordance with our previous results we could corroborate a decreased Cho value in the hippocam-pus of patients with major depression (F = 5.73, Hypothesis driven univariate as well as multivariate analyses based on a general linear model were used for data analysis by the use of In the spectra from the putamen we see a signifi- SPSS for windows release 12.0. For the univariate analyses thedependent variable was the concentration estimates for Cho in cant above normal Cho value in the patients com- the two subregions (hippocampus, putamen) with group as the pared to controls (F = 5.66, df = 1, 10, P = 0.039).
between-subject factor and with age and voxel GM content as Statistics on the remaining metabolite signal values in co-variates. Additionally, according multivariate analyses were these two regions were above the P = 0.05 level (tCr, conducted with the remaining metabolite measures (NAA, tCr) as hippocampus: F = 3.10, df = 1, 12, P = 0.1; tCr, pu- dependent variables. We used a paired t-test to determine intra-individual left–right metabolite differences. Correlations were tamen: F = 3.11, df = 1, 10, P = 0.11; NAA, hippo- assessed with the Spearman’s test. The criterion of significance level campus: F = 1.35, df = 1, 12, P = 0.27 and NAA, putamen: F = 2.73, df = 1, 10, P = 0.13). Meanmetabolite values, GM and CSF voxel contents are VBM analysis did not reveal any significant dif- ferences in neither hippocampal nor striatal volumina The quality criteria based on spectral resolution (spectral linewidth and voxel CSF content) were not Due to the small sample size a co-analysis of met by all spectra from all subjects. Therefore, the medication effects (e.g. dosage or medication type) group sizes for each evaluated region are less than the total group of acquired data sets (see Table Wecould not detect a significant left–right hemispheredifference, neither for the hippocampi nor the putamen in both groups (paired t-test P > 0.16, t < 1.5). GM,WM and CSF voxel contents were not significantly The hippocampus is the focus for hypotheses related different between patients and controls. A Spearman to stress and its effects. A reduced hippocampal Cho signal is in good accordance to reduced serotonergicneurotransmission and impaired neurogenesis/syna- ptogenesis in this brain region, respectively [We 1. Charles HC, Lazeyras F, Krishnan KR, Boyko OB, Payne M, previously observed a decreased Cho signal in the Moore D (1994) Brain choline in depression: in vivo detection hippocampus in MDD patients []. Additionally, two of potential pharmacodynamic effects of antidepressant ther-apy using hydrogen localized spectroscopy. Prog Neuropsy- previous MRSI studies of the basal ganglia in major chopharmacol Biol Psychiatry 18:1121–1127 depression reported increased Cho/tCr in the puta- 2. Davidson RJ, Irwin W, Anderle MJ, Kalin NH (2003) The neural men. This is in concordance with our finding of substrates of affective processing in depressed patients treated an increased striatal Cho signal with the tCr signal with venlafaxine. Am J Psychiatry 160:64–75 3. Drevets WC (2000) Neuroimaging studies of mood disorders.
Patients of our earlier study were medication 4. Duman RS (2004) Depression: a case of neuronal life and death? resistant and more severely ill. Their hippocampal Cho levels increased to normal levels with electro- 5. Ende G, Braus DF, Walter S, Weber-Fahr W, Henn FA (2000) convulsive therapy. Normal choline levels were also The hippocampus in patients treated with electroconvulsivetherapy: a proton magnetic resonance spectroscopic imaging observed in remitted patients treated with amitrip- tyline Cho decreased again in our 12-month 6. Ende G, Braus DF, Walter S, Weber-Fahr W, Henn FA (2003) follow-up study without patients necessarily relaps- Multiregional 1H-MRSI of the hippocampus, thalamus, and basal ganglia in schizophrenia. Eur Arch Psychiatry Clin Neurosci253:9–15 Structural or functional abnormalities of the 7. Ende G, Demirakca T, Tost H (2006) The biochemistry of dys- limbic-cortical-striatal-pallidal-thalamic functional emotions: proton MR spectroscopic findings in major circuit have been reported and are associated with depressive disorder. Progr Brain Res Volume 156, Chapter 27 an increased risk for major depression [Smaller 8. Henn F, Vollmayr B, Sartorius A (2004) Mechanisms of hippocampal, caudate and putamen volumes have depression: the role of neurogenesis. Drug Discov Today DisMech 1:407–411 been reported in several MRI studies of major 9. Henn FA, Vollmayr B (2004) Neurogenesis and depression: depression []. Functional investigations stated uni- etiology or epiphenomenon? Biol Psychiatry 56:146–150 directional alterations in striato-limbic areas. The 10. Husain MM, McDonald WM, Doraiswamy PM, Figiel GS, Na C, Danish/PET depression project observed an in- Escalona PR, Boyko OB, Nemeroff CB, Krishnan KR (1991) Amagnetic resonance imaging study of putamen nuclei in major creased CBF (right sided) in MDD patients in hip- pocampal and striatal regions []. Presentation of 11. Obergriesser T, Ende G, Braus DF, Henn FA (2001) Hippo- sad and happy facial expressions showed fMRI campal 1H-MRSI in ecstasy users. Eur Arch Psychiatry Clin alterations of the same sign in parahippocampal and 12. Obergriesser T, Ende G, Braus DF, Henn FA (2003) Long-term putaminal regions. A differential pattern of neural follow-up of magnetic resonance-detectable choline signal response toward sad versus happy facial expressions changes in the hippocampus of patients treated with electro- in MDD was observed by Surguladze et al. [ convulsive therapy. J Clin Psychiatry 64:775–780 These results do not necessarily contradict MRSI 13. Renshaw PF, Lafer B, Babb SM, Fava M, Stoll AL, Christensen findings of regionally opposed cholinergic changes.
JD, Moore CM, Yurgelun-Todd DA, Bonello CM, Pillay SS,Rothschild AJ, Nierenberg AA, Rosenbaum JF, Cohen BM It can be speculated, that deficits in hippocampal (1997) Basal ganglia choline levels in depression and response synaptogenesis as predicted by the neurotrophin to fluoxetine treatment: an in vivo proton magnetic resonance hypothesis lead to compensatory functional altera- spectroscopy study. Biol Psychiatry 41:837–843 tions in other regions within the LCSPT circuit.
14. Sapolsky RM (2004) Is impaired neurogenesis relevant to the affective symptoms of depression. Biol Psychiatry 56:137–139 Striatal synaptic and/or membrane alterations (here: 15. Surguladze S, Brammer MJ, Keedwell P, Giampietro V, Young AW, possibly an increased membrane turnover) are then Travis MJ, Williams SC, Phillips ML (2005) A differential pattern of neural response toward sad versus happy facial expressions inmajor depressive disorder. Biol Psychiatry 57:201–209 16. Videbech P, Ravnkilde B, Pedersen TH, Hartvig H, Egander A, Clemmensen K, Rasmussen NA, Andersen F, Gjedde A, Rosenberg R (2002) The Danish PET/depression project: clin-ical symptoms and cerebral blood flow. A regions-of-interestanalysis. Acta Psychiatr Scand 106:35–44 Overall, abnormal Cho signals most likely reflect al- 17. Vythilingam M, Charles HC, Tupler LA, Blitchington T, Kelly L, tered membrane phospholipid metabolism. A reduced Krishnan KR (2003) Focal and lateralized subcortical abnor- level in the hippocampus and an increased level in the malities in unipolar major depressive disorder: an automated putamen suggest regionally opponent membrane multivoxel proton magnetic resonance spectroscopy study. BiolPsychiatry 54:744–750 18. Weber-Fahr W, Ende G, Braus DF, Bachert P, Soher BJ, Henn FA, Buchel C (2002) A fully automated method for tissue seg-mentation and CSF-correction of proton MRSI metabolites We thank Dr. Norbert Schuff for providing corroborates abnormal hippocampal NAA in schizophrenia.
the multislice spherical k-space sampling MRSI sequence and Drs. Andrew Maudsley and Brian Soher (NIH/NIA Grant # 19. Wokrina T, Ende G (2004) Quality maps facilitate MRSI eval- R01AG12119) for providing the automated spectral fitting routine.
uation with automated spectral analysis. Proceedings of the This study was supported by a grant from the Heidelberg Academy European Society for Magnetic Resonance in Medicine and

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