1H magnetic resonance spectroscopy study of ...

Neuroscience Letters 425 (2007) 49–52

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H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients Jun Mu a , Peng Xie a,∗ , Ze-Song Yang d , De-Lan Yang b , Fa-Jin Lv c , Tian-You Luo c , Yong Li a

a

Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, The Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing, 400016, China b Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China c MRI Center, Chongqing Medical University, Chongqing, 400016, China d Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China Received 4 March 2007; received in revised form 4 August 2007; accepted 7 August 2007

Abstract Treatment-resistant depression (TRD) is a common clinical problem, and represents a considerable challenge to treatment, however, the pathogenesis of this disease is poorly understood. Thalamus is generally believed to have a role in the pathophysiology of depression. In this study, we adopted 1.5 T 1 H magnetic resonance spectroscopy (1 H MRS) to examine possible alterations of thalamus metabolism in 20 adult TRD patients. Our results suggested there might be damage and loss of neurons, as well as membrane phospholipids associated metabolism abnormality in the TRD thalamus. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Magnetic resonance spectroscopy; Treatment resistant depression; Thalamus; Neuroimaging

Major depression disorder (MDD) is considered to be a chronic and relapsing illness, with gradually increasing prevalence worldwide [24]. The fact that one third of depressive patients fail to experience sufficient symptom improvement despite adequate treatment [16,17,19], enables the introduction of diagnosis criteria for treatment-resistant depression (TRD) [19,16,20], in which TRD was defined as failure to respond to two different antidepressants in adequate dosage for a period of 6–8 weeks. Although TRD affects millions of adults each year worldwide, no objective evaluation markers are currently available for both diagnosis and prognosis. The pathogenesis of this disease is complicated and involves multiple genetic, psychological, and environmental factors. Although recent studies have identified several anatomical abnormalities in the brain regions associated with major depression [11,23,25], the roles of regional metabolism remain largely unknown. The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders.

∗

Corresponding author. Tel.: +86 23 68485490; fax: +86 23 68485111. E-mail address: Xie peng [email protected] (P. Xie).

0304-3940/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2007.08.004

Increasing evidences indicate that thalamus has a role in the pathogenesis of MDD. A reversible depressive syndrome is found to be a very frequent side effect after stereotaxic thalamotomy in patients with abnormal movements, although no abnormalities in thalamic size are detected by magnetic resonance imaging (MRI) in bipolar and unipolar individuals [1,4]. Although decreased thalamic cerebral blood flow (CBF) in the right hemisphere was observed after mood-induction procedures [6], other Imaging studies consistently demonstrate hyperactivity in the midline thalamic regions during episodes of MDD [22]. This hyperactivity decreases with efficient control of MDD by medical treatment, indicating midline thalamic overactivity is related to the depressive condition. Furthermore, electrical stimulation of the inferior thalamic peduncle, may improve TRD [8]. Studies of thalamic neuroanatomy and neurochemistry in mood disorders are rare. Data from postmortem studies suggest there is an elevation in the total number of neurons in the limbic thalamus [26]. However, neurochemical changes of the thalamus in vivo remain largely unexplored. We therefore hypothesized that there might be corresponding increased N-acetyl-aspartate (NAA) level in TRD thalamus. To identify metabolism changes

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J. Mu et al. / Neuroscience Letters 425 (2007) 49–52

linked with TRD pathogenesis, in the present study we set up to examine possible alteration thalamus metabolism in TRD patients. A total of 20 severely depressed patients (35.5 ± 7.8 years old; 10 females) with a diagnosis of major depressive episode, unipolar with melancholic features due to treatment resistance, were recruited. The diagnosis was made independently by two experienced psychiatrists employing the Munich Checklist for Diagnostic and Statistical Manual of Mental Diseases, fourth edition (DSM-IV) diagnoses. The treatment resistance was defined as failure to respond to two different antidepressants in adequate dosage for at least a period of 8 weeks. At study entry, 6/20 were on Fluoxetine (40 mg/day), 4/20 on Seroxat (40 mg/day), 2/20 on Sertraline (200 mg/day), 3/20 on Venlafaxine (200 mg/day), 1/20 on Amitriptyline (300 mg/day), 2/20 on Citalopram (40 mg/day) and 2/20 on Escitalopram (20 mg/day). Patients with a medical history of alcohol, drug abuse, head injury or dementia were excluded. All patients had been off psychotropic medication for more than a week (only Lorazepam at maximum 2 mg/day and psychotherapy allowed) and had not been on any electroconvulsive therapy. Duration of current episode was averaged 9.6 ± 1.5 weeks. The evolution time of depression symptoms lasted 27.5 ± 7.7 weeks. The Hamilton Depression Rating Scale (HAMD)-24 items was utilized to rate the severity of clinical symptoms. Compared with the controls (5.2 ± 1.0), the HAMD score was significantly increased in the TRD patients (27.5 ± 3.8) (P < 0.01). Written informed consent was obtained. The protocol was approved by ethics committee of the Chonqing Medical University and the studies were carried out in accordance with the Declaration of Helsinki. Twenty ageand gender-matched healthy controls (36.8 ± 5.6 years old; 10 females) were enrolled. In vivo 1 H MRS was conducted on a 1.5 T GE Signa Highspeed Superconductive Imaging System (General Electric Medical Systems) using the standard head coil. A set of sagittal scout images was first obtained to verify patient position and image quality, to locate a midline sagittal image, and to position the MRS voxel. Sagittal slices covering the entire brain were obtained using a fast spin echo (FSE) sequence (TR = 25 ms, TE = 17 ms, flip angle = 90, FOV = 24 cm, slice thickness = 3 mm, NEX = 2, matrix size = 256 × 192) for tissue segmentation of the 1 H MRS spectroscopy voxels. The single-voxel Point-Resolved Echo Spin Spectroscopy (PRESS) sequence was performed with a chemical shift selective presequence for water suppression (TE = 144 ms, TR = 2500 ms, bandwidth = 2500 Hz, number of points = 2048, NEX = 1, voxel dimension 2.0 cm × 2.0 cm × 2.0 cm). This 8-cm3 voxel was placed in both the left and right thalami (Fig. 1). Acquisition was repeated 2–4 times with the voxel sitting in place, to reduce the errors resulted from partial volume effect or post-processing procedures. Each spectrum was evaluated for the presence of choline (Cho)-containing compounds, creatine (Cr), N-acetylaspartate (NAA) and glutamate/glutamine (Glx). And the ratios of Cho/Cr, NAA/Cr and Glx/Cr were then calculated. The postprocessing and quantification steps were automatically done using the Functool Spectroscopy-2D Brain image software GE Signa LX Release version 9. [1]. Spectral post-processing com-

Fig. 1. 1 H MRS volume of interest in the left and right thalami. The white box represents the location of the volume of interest (2 cm × 2 cm × 2 cm).

prised line broadening, reducing the residual water resonance, linear baseline correction, and peak integration. All analyses were performed using SPSS for Windows software, version 11.0, and the significance level was set at P < 0.05. A t-paired test was performed to compare 1 H metabolite levels between TRD patients and healthy individuals. The measured 1 H MRS metabolites as well as the CSF, gray matter, and white matter voxel contents did not differ significantly between the left and right thalami in both TRD patients and healthy controls (paired t-test, P > 0.05). Table 1 shows the metabolite ratios between TRD patients and the age-matched controls. NAA/Cr in both thalamus was decreased in TRD patients compared with controls (P < 0.05) suggesting there might be damage and loss of neurons. 17/20 TRD patients had below-normal NAA/Cr in the left thalamus and 16/20 in the right. Cho/Cr was increased bilaterally in TRD patients, while only that in left thalamus showed significance (P < 0.05), showing that membrane phospholipids associated metabolism abnormality was suspected. There was no difference between the groups in Glx/Cr (P > 0.05). 1 H MRS is noted for its non-invasive nature and ability to measure levels of important metabolites in vivo. This can be done in well-defined brain areas involved in critical physiological brain processes and possibly implicated in the pathophysiology of depression. Although the abnormality of serotonin system was long thought to play a critical role in the pathogenesis of major depression, and also the inter-synapse neurotransmitter serotonin receptors were the target of several antidepressants, serotonin cannot be detected by MRS due to the extremely low concentration. However, some very important metabolites could still be measured to reflect the metabolism of neurons and neuroglia cells.


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Table 1 MRS metabolite measures for bilateral thalamus in TRD patients and matched healthy subjects (mean ± S.D.)

1H

Group

TRD Control a

N

20 20

NAA/Cr

Cho/Cr

Glx/Cr

Left

Right

Left

Right

Left

Right

1.261 ± 0.227a

1.244 ± 0.227a

1.494 ± 0.257a

1.418 ± 0.209 1.252 ± 0.177

0.236 ± 0.053 0.248 ± 0.041

0.231 ± 0.057 0.240 ± 0.033

1.600 ± 0.266

1.745 ± 0.376

1.192 ± 0.175

There is statistically significant difference between groups (P < 0.05).

In the present study, a significant NAA/Cr decrease in both thalami of TRD patients, suggesting there might be damage and loss of neurons. NAA is a neuronal compound exclusively found in mature neurons and neuronal processes and therefore is thought to be a marker of neuronal integrity, viability, and activity [18,21]. Although its specific neuronal function is still unclear, the neurodevelopmental or neurodegenerative processes could possibly explain our findings. Recently, a postmortem study [26] suggested an elevation in total number of thalamic neurons, which at first glance, might be contradictory to ours. The significant decreased NAA level indicated by our research, seemed contrary to our previous hypothesis. However, increased number of thalamic neurons may not necessarily lead to higher than normal thalamic NAA level. Aside from the differences in the patient cohort examined, possible confounds from psychotropic medication use, age, gender, disease course, complications, cause of death and TRD status, the abnormal neuronal developmental or neurodegenerative process might be the underlying causes. That was why the underdeveloped thalamic neurons from TRD patient would present a lower NAA content per neuron. Besides, abnormally low NAA concentrations have been reported in various neurodegenerative disorders by several in vivo 1 H MRS studies (i.e. Alzheimer’s Disease, lateral amyotrophic sclerosis, multiple sclerosis) [5,9,10], schizophrenia [2] and also in other brain regions in major depression (i.e. dorsolateral prefrontal cortex, hippocampus) [3,15]. Thus decreased NAA levels may be possibly a reflection of underlying neurodegenerative process and shared by several chronic neuropsychiatric diseases. The augmented thalamic neurons might be due to the neuroprotective process against abnormal neurodevelopment or neurodegeneration. Previously preclinical and clinical studies demonstrate that depression leads to loss of neurons in the adult hippocampus, which can be reversed partly by antidepressants [7]. In the case of depression, the antidepressant induced neurogenesis [12–14] might not be so effective to improve symptoms of TRD patients, because the augmented neurons may not function properly. However, further studies are needed to answer the questions that our findings may predate (neurodevelopment) or follow (neurodegeneration) the onset of disease or may be the result of pharmacologic treatment. Some potential limitations of the present study should be taken into consideration. Firstly, the relatively small sample size may have limited our ability to detect minor changes in metabolite concentrations. Nonetheless, as suggested by the reported effect sizes from studies that examined the brain 1 H MRS metabolites, our study with 20 subjects had adequate statistical power. Once the sample size has been enlarged, some factors

influencing the NAA and Cho levels, for example, psychotic features, age and duration of illness, might be further compared between the TRD patients and normal controls. Secondly, only the thalamus was investigated in this study. Therefore, even though neurodegenerative process was suggested in TRD, caution should be taken when findings are extrapolated to other brain areas. Thirdly, it might be better if a treatment-responsive depression comparison group could be added in further longitudinal study. In conclusion, our study reported reduced 1 H MRS NAA in both thalami of TRD patients compared with age-and gendermatched healthy individuals. Although these results must be considered preliminary, to our best knowledge, this is the first in vivo MRS study investigating NAA levels in the thalamus of TRD patients. Future longitudinal studies will be needed to investigate the role of neurodegenerative or neurodevelopment process which might provide a clue for novel antidepressant exploration and check point for eventual fail in conventional treatment in order to avoid insufficient and extended treatment. Acknowledgments This work is supported by a grant from National Nature Science Foundation of China (no. 30570657). We are grateful to Shuo Luo for editing the manuscript. References [1] L. Angelini, N. Nardocci, R. Bono, G. Broggi, Depression after stereotactic thalamotomy in patients with abnormal movements, Ital. J. Neurol. Sci. 3 (4) (1982) 301–310. [2] A. Bertolino, J.H. Callicott, I. Elman, V.S. Mattay, G. Tedeschi, J.A. Frank, A. Breier, D.R. Weinberger, Regionally specific neuronal pathology in untreated patients with schizophrenia: a proton magnetic resonance spectroscopic imaging study, Biol. Psychiatry 43 (9) (1998) 641–648. [3] P. Brambilla, J.A. Stanley, M.A. Nicoletti, R.B. Sassi, A.G. Mallinger, E. Frank, D.J. Kupfer, M.S. Keshavan, J.C. Soares, 1H magnetic resonance spectroscopy study of dorsolateral prefrontal cortex in unipolar mood disorder patients, Psychiatry Res. 138 (2) (2005) 131–139. [4] S.C. Caetano, R. Sassi, P. Brambilla, K. Harenski, M. Nicoletti, A.G. Mallinger, E. Frank, D.J. Kupfer, M.S. Keshavan, J.C. Soares, MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals, Psychiatry Res. 108 (3) (2001) 161–168. [5] C.A. Davie, C.P. Hawkins, G.J. Barker, A. Brennan, P.S. Tofts, D.H. Miller, W.I. McDonald, Serial proton magnetic resonance spectroscopy in acute multiple sclerosis lesions, Brain 117 (Pt 1) (1994) 49–58. [6] R. De Raedt, H. D’haenen, H. Everaert, R. Cluydts, A. Bossuyt, Cerebral blood flow related to induction of a depressed mood within and out of the realm of attention in normal volunteers, Psychiatry Res. 74 (3) (1997) 159–171. [7] R.S. Duman, J. Malberg, S. Nakagawa, C. D’Sa, Neuronal plasticity and survival in mood disorders, Biol. Psychiatry 48 (2001) 732–739.

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