Normal metabolite levels in the left dorsolateral prefrontal cortex of unmedicated major depressive disorder patients: A single voxel 1H spectroscopy study

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Abstract

Few proton magnetic resonance spectroscopy (1H spectroscopy) studies have investigated the dorsolateral prefrontal cortex (DLPFC), a key region in the pathophysiology of major depressive disorder (MDD). We used 1H spectroscopy to verify whether MDD patients differ from healthy controls (HC) in metabolite levels in this brain area. Thirty-seven unmedicated DSM-IV MDD patients were compared with 40 HC. Subjects underwent a short echo-time 1H spectroscopy examination at 1.5 T, with an 8-cm3 single voxel placed in the left DLPFC. Reliable absolute metabolite levels of N-acetyl aspartate (NAA), phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol, glutamate plus glutamine (Glu + Gln), and glutamate were obtained using the unsuppressed water signal as an internal reference. Metabolite levels in the left DLPFC did not statistically differ between MDD patients and HC. We found an interaction between gender and diagnosis on PCr+Cr levels. Male MDD patients presented lower levels of PCr+Cr than male HC, and female MDD patients presented higher levels of PCr+Cr than female HC. Moreover, length of illness was inversely correlated with NAA levels. These findings suggest that there is not an effect of diagnosis on the left DLPFC neurochemistry. Possible effects of gender on PCr+Cr levels of MDD patients need to be further investigated.

Introduction

Despite being one of the most prevalent psychiatric disorders and a leading cause of disability and suicide, major depressive disorder (MDD) has a poorly understood pathophysiology. Several lines of evidence suggest that MDD patients present structural and functional abnormalities in fronto-limbic brain areas that participate in neuroanatomical circuits involved in mood regulation (Soares and Mann, 1997, Drevets, 2000, Sheline, 2003). One key region in this neurocircuitry is the dorsolateral prefrontal cortex (DLPFC). This brain area corresponds to the middle frontal gyrus (Brodmann areas 9 and 46) and is functionally responsible for high cognitive functions, such as working memory, language, attention, judgment and behavior planning (D'Esposito, 2003). Evidence that the DLPFC is involved in the pathophysiology of MDD comes from reports of pathological changes in this brain area of MDD patients, including reduced density and size of neurons and glial cells (Rajkowska et al., 1999, Cotter et al., 2002) and lower glucose metabolism (Baxter et al., 1989, Biver et al., 1994, Mayberg et al., 1999). Moreover, repetitive transcranial magnetic stimulation (rTMS) of the DLPFC improves depressive symptoms in MDD patients (Eschweiler et al., 2000, Avery et al., 2006).

Proton magnetic resonance spectroscopy (1H spectroscopy) permits the quantification of neurometabolites in vivo that may be involved in the pathophysiology and clinical features of mood disorders, such as N-acetyl aspartate (NAA), choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), myo-inositol (myo-Ins), and glutamate plus glutamine (Glu + Gln) (Kato et al., 1998, Stanley et al., 2000, Stanley, 2002). Although these metabolites may be involved in the pathophysiology and clinical features of mood disorders, few controlled studies have used 1H spectroscopy to investigate neurochemical abnormalities in the DLPFC of MDD patients. For instance, higher ratios of GPC+PC/PCr+Cr and myo-Ins/PCr+Cr ratios were found in the dorsolateral white matter of late-onset MDD patients (Kumar et al., 2002). PC is a precursor of membrane phospholipids and GPC is a breakdown product of membrane phospholipids (Stanley et al., 2000), which suggests an alteration in the membrane phospholipid metabolism. Myo-Ins abnormalities may suggest disturbances in the second messenger system or imbalances in the neuronal signaling network, or a glial pathology, as Myo-Ins is almost exclusively located in astrocytes (Kim et al., 2005, Coupland et al., 2005). Absolute levels of Glx, a term that is most commonly defined as the sum of glutamate plus glutamine levels (i.e., Glu plusGln), were reported to be lower in the DLPFC (Michael et al., 2003) and in the dorsomedial/dorsal anterolateral and ventromedial prefrontal region of MDD patients (Hasler et al., 2007). Physiologically, glutamate and glutamine are highly coupled through the removal of glutamate from the synapses and conversion of glutamate to glutamine by the glia cells (Magistretti and Pellerin, 1999, Rothman et al., 1999), and alterations in the concentration of glutamate and/or glutamine may correspond to a disturbance in the glutamatergic neurotransmitter system. Additionally, other investigators have suggested that a glutamatergic neurotransmitter dysfunction may play a role in the pathophysiology of mood disorders (Krystal et al., 2002, Zarate et al., 2003, Kugaya and Sanacora, 2005). On the other hand, two other studies failed to show differences in absolute levels of metabolites between adult MDD patients and healthy controls (HC) (Brambilla et al., 2005, Hasler et al., 2005).

The full meaning of these preliminary findings, vis-a-vis the pathophysiology of MDD, is still unknown. They might represent the neurochemical counterpart of postmortem and functional abnormalities previously reported in MDD patients. In this study, we investigated metabolite levels in the left DLPFC of MDD patients and well-matched HC, using 1H spectroscopy. Secondarily, we studied the association of metabolite levels with possible markers of severity or chronicity of MDD, including mood state, age at disease onset, length of illness, and severity of depressive symptoms. Based on previous reports, we hypothesized that MDD patients would present lower Glu + Gln and higher GPC+PC and myo-Ins levels in the left DLPFC in comparison to HC. Such abnormalities, if present in the left DLPFC of MDD patients, would provide evidence for the existence of disturbances in the glutamatergic neurotransmitter system and intracellular signaling pathways that ultimately cause a possible disruption in prefrontal circuits and are associated with the clinical symptoms and response to treatment in MDD.

Section snippets

Subjects

The sample comprised 37 unmedicated MDD patients (mean age ± S.D.: 36.6 ± 13.7 years; range: 18–60 years; males: 35.1%) matched by age and gender to 40 HC (mean age ± S.D.: 40.0 ± 12.3 years; range: 20–60 years; males: 35%). All of the patients and HC were residents of the San Antonio metropolitan area or surrounding cities. The subjects were recruited from the community through local media advertisements and flyers posted in the medical center. Inclusion criteria for the MDD patients were a diagnosis

Results

The MDD and HC groups did not differ significantly on mean age (Mann–Whitney U test, P = 0.22) or gender (χ2 test, P = 0.99). Twenty-six (70.3%) of the MDD patients were currently in a major depressive episode, and of those, eight (30.8%) were classified as mild, 16 (61.5%) as moderate, and two (7.7%) as severe according to SCID criteria. No patient presented a severe episode with psychotic features. Major depression was present in first-degree relatives of 12 patients. Bipolar disorder was present

Discussion

In this 1H spectroscopy study unmedicated MDD patients presented no statistical differences in levels of NAA, GPC+PC, PCr+Cr, myo-Ins, Glu + Gln, and glutamate, in the left DLPFC compared with age- and gender-matched HC. Exploratory post hoc analyses showed a statistically significant interaction between gender and diagnosis on PCr+Cr levels, i.e., male MDD patients presented statistically lower PCr+Cr levels than male HC, and female MDD patients presented non-statistically higher PCr+Cr levels

Acknowledgments

This research was partly supported by grants MH 01736, MH 068662, RR 020571, UTHSCSA GCRC (M01-RR-01346), the Krus Endowed Chair in Psychiatry (UTHSCSA), the Veterans Administration (VA Merit Review), the CAPES Foundation (Brazil) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil — grant # 200006/04-5).

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