Ventromedial prefrontal spectroscopic abnormalities over the course of depression: A comparison among first episode, remitted recurrent and chronic patients

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Abstract

Structural and neuropathological alterations in the ventromedial prefrontal cortex (vmPFC) described in depression (MDD) might become even more pronounced over the course of illness. Measurement of brain metabolites by means of Magnetic Resonance spectroscopy (MRS) can indirectly deliver information about glial and neuronal integrity or potential cellular loss. The aim of this study was to investigate whether Glutamate (Glu), Choline (Cho) and total N-acetylaspartate (total-NAA) levels in the vmPFC differed among MDD patients in distinct stages of illness and healthy controls. We hypothesized that high-past illness-burden would represent more metabolite abnormalities independently of mood state. A 3-Tesla MR facility was used to measure these metabolites in vmPFC of 45 depressive patients (10 first-episode-MDD, 16 remitted-recurrent-MDD and 19 chronic-MDD) and 15 healthy controls. Multivariate and correlation analyses were carried out to explore the influence of duration of illness, age at onset and mood-state. Levels of Glu were significantly decreased in remitted-recurrent and chronic patients compared with both first-episode and controls (up to 28% mean reduction; p < 0.001, Cohen’s d = 2.88) and were negatively correlated with illness duration (r = −0.56; p < 0.001). Cho levels showed an opposite pattern: highest values were detected in chronic patients, correlating positively with duration of illness (r = 0.32; p = 0.03). Total-NAA levels were significantly lowered in remitted-recurrent and chronic patients, which were associated with an earlier age at onset (r = 0.50; p = 0.001). Our data suggest that abnormalities in Glu, Cho and total-NAA levels are consistently related to the course of MDD, supporting the hypothesis that cellular changes would take place in vmPFC over time.

Introduction

Major depression (MDD) is a heterogeneous disorder with a high risk of relapse/recurrence, an inconsistent response to treatment, and no established mechanism. Given these characteristics, the nature of neural abnormality that precipitates or maintains MDD has yet to be described. Even more, the aberrant brain changes that could take place along the course of the illness are still little known. Numerous studies have sought to identify the key brain areas implied in the pathogenesis of depressive symptoms. The involvement of prefrontal cortex has been an important focus, particularly the ventromedial prefrontal cortex (vmPFC), including anterior cingulate cortex (ACC) (Drevets, 2000, Drevets et al., 2008a, Koenigs and Grafman, 2009). This area, densely connected with parahippocampus and subsequently with hippocampus, is a major target for glucocorticoids, being potentially exposed to the neurotoxic effects of a chronic sustained elevation over the illness course (Gold et al., 2002, Hercher et al., 2009). Despite the many studies reporting volumetric and functional neuroimaging abnormalities in this region in patients with MDD versus healthy comparison subjects (Drevets et al., 2008a, Mayberg et al., 1999, Liotti et al., 2002, Greicius et al., 2007), not so many have addressed the presence of deficiencies in prefrontal cellular neurochemistry in MDD. There is evidence that this brain region is affected by neuropathological processes that could be associated with altered availability of metabolites (Harrison, 2002) including amino acid neurotransmitters. Given the importance of glia in maintaining proper function of the glutamatergic system, the observation of abnormal reductions in prefrontal glial cell counts and density in postmortem studies of MDD (Rajkowska and Miguel-Hidalgo, 2007) is likely to have a strong link with the emerging line of research that highlights the contribution of glutamate and other amino acid neurotransmitters systems in the pathophysiology and treatment of mood disorders (Kugaya and Sanacora, 2005).

Magnetic resonance spectroscopy (MRS) provides a useful approach for quantization of in vivo amino acid neurotransmitters and other metabolites in brain (see Yildiz-Yesiloglu and Ankerst, 2006 for a review). Conventional MRS applications give only a snapshot of metabolite pool size rather than of pool kinetics, but they can indirectly provide in vivo helpful information about cellular integrity and potential cellular loss. Even though conflicting results have been reported, recent studies converge to suggest Glutamate/Glutamine/G-AminoButyric-Acid (Glu/Gln/GABA, respectively) as the most common metabolites to show abnormalities in prefrontal areas of MDD patients. Several previous works have reported lower Glu/Gln/GABA values in the frontal lobes of adult and pediatric patients with MDD compared to healthy controls (Auer et al., 2000, Michael et al., 2003a, Pfleiderer et al., 2003, Mirza et al., 2004, Rosenberg et al., 2005, Hasler et al., 2007, Ajilore et al., 2007, Walter et al., 2009). Glutamate serves as an important excitatory neurotransmitter that contributes to a wide array of normal brain functions, including regulation of neurotrophic factors and neuronal plasticity although excess levels of this metabolite have been involved in pathological conditions such as cerebral ischemia, traumatic brain injury or chronic neurodegenerative states among others (Lipton and Rosenberg, 1994). Based on the fact that glial cells, and particularly astrocytes, supply the primary source of energy to neurons and also furnish the major pathway for neuronal glutamate synthesis (Magistretti et al., 1999, Rajkowska and Miguel-Hidalgo, 2007), a provocative model proposed by Sanacora et al. (2003) suggests that the impaired glial cell function in amygdala and prefrontal cortex structures, observed in postmortem mood disorder samples, may result in decreased synaptic glutamate uptake with a resultant elevation of extracellular glutamate levels. The glial disruption and elevated extracellular glutamate may further accelerate neuronal and glial damage by its neurotoxic effect (Rothstein et al., 1993). These assumptions could seem contradictory with reductions of Glu/Gln/GABA levels found in prefrontal cortex of MDD patients by MRS studies. It should be mentioned that this MRS spectrum is overpoweringly composed by the intracellular pool contained in neurons and especially in glia. Therefore, decreased signal of these metabolites, instead of revealing potential abnormalities in extracellular concentrations or in glutamatergic neurotransmission per se, might account for the described anomalies of glial cells in prefrontal areas of depressed patients. Taking into account that further MRS techniques have been developed to overcome the Glu/Gln/GABA peak overlapping, specific Glu concentration at 3T field strength will better mirror the status of glia.

By contrast, though Choline-containing compounds (Cho) seem to be clearly increased in the basal ganglia of patients with MDD, the presence of abnormalities in the Cho peak in prefrontal areas is somewhat more controversial (Yildiz-Yesiloglu and Ankerst, 2006, Nery et al., 2009, Kaymak et al., 2009, Milne et al., 2009). Since Cho is hugely present in oligodendrocytes (Urenjak et al., 1993), observed increases of Cho levels in MDD could also reflect abnormalities in glial function and/or myelinization (Yildiz-Yesiloglu and Ankerst, 2006). Moreover, Cho is over-released from membrane stores normally under pathological conditions and could be therefore conceived as a marker of cellular membrane turnover and active neurodegeneration (Malhi et al., 2002).

N-acetylaspartate (NAA), that is considered to be a marker of neuronal density or integrity, has also been investigated in MDD patients in prefrontal regions yielding inconclusive findings to date (Yildiz-Yesiloglu and Ankerst, 2006, Gonul et al., 2006, Ajilore et al., 2007, Walter et al., 2009, Nery et al., 2009, Kaymak et al., 2009). Although pathology of neurons in depression seems to be less prominent than that of glial cells (Rajkowska and Miguel-Hidalgo, 2007), both cellular lines are closely related, since the latter is known to be crucial for the efficient development and functioning of neurons (Magistretti et al., 1999). Therefore, one could expect to find alterations in prefrontal NAA peak in MDD, which would reflect a primary neuronal damage or, at least, the downstream effects on neuronal structures caused by defects in glia.

So far, most spectroscopic studies in MDD have focused on the differences between patients and healthy controls, and on the potential influence of illness severity, acute effects of therapeutic strategies or treatment resistance (see for example Walter et al., 2009, Block et al., 2009, Price et al., 2009). Nevertheless, the relationship between metabolic changes in vmPFC and other relevant clinical variables, including length of depressive disorder, age at onset or illness subtype, has not received nearly the attention it deserves (Nery et al., 2009, Milne et al., 2009, Hasler et al., 2005).

The aim of this study was to investigate whether Glu levels in the vmPFC differed between MDD patients in distinct stages of the illness and healthy controls. In addition, we also investigated differences of Cho and total NAA concentrations among these groups of patients. We hypothesized that high-past illness burden would imply more metabolite abnormalities independently of mood state.

Section snippets

Subjects

Sixty right-handed patients with MDD (DSM-IV-TR) aged between 20 and 60 years old entered the study to undergo a specifically designed MR protocol. Patients were split into three different groups. One group of depressed participants was comprised of individuals who were presenting for a first depressive episode (n = 20, first-episode). The second group of patients included individuals who had experienced three or more previous episodes of MDD and were currently euthymic –for at least six

Results

After visual assessment of the spectra, 70% of cases resulted good/acceptable for analyses. Included spectra had SD% less than 22% for Glu and Glx, 16% for total NAA, 6% for Cr and 12% for Cho. An exploratory analysis showed that the assumption of homoscedasticity among study groups was satisfied for all metabolites, except for total NAA (Levene’s test was not significant for Glu, Glx, Cho and Cr; and for total NAA, F = 4.09, p = 0.01). Sample sizes were as follows: first-episode patients: n

Discussion

To our knowledge, these exploratory results constitute the first comparison of prefrontal brain metabolite concentrations among different stages of MDD. The observation in our sample of higher values of Glu at the beginning of the disorder and its progressive decrement extends previous MRS studies, which had reported reductions in Glu levels in the ACC and prefrontal brain cortex when comparing depressive patients to healthy controls. The decrease was of a relevant magnitude, reaching up to 25%

Conclusions

In summary, we found decreased Glu and total NAA concentrations and increased Cho levels in the vmPFC of long-standing MDD patients. Abnormalities in Glu and Cho resonances were more pronounced in patients with chronic or remitted-recurrent depression and consistently related to illness duration, suggesting that the course of the illness may be an important factor to explain such metabolite abnormalities, rather than mood state. These results would provide support for the hypothesis that there

Role of funding source

This work was supported by Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Ministerio de Ciencia e Innovación, and co-funded by Fondo Europeo de Desarrollo Regional (FEDER). In addition, it was partly supported by grant FIS 07/770, and by research funding from Boehringer-Ingelheim, Spain.

Contributors

MJP, VP, EA and BGA designed the study and wrote the protocol. MJP and JDA managed the literature searches and analyses. BGA, RMF and YV performed and analyzed the NMR spectroscopy. JDA, DP, RP, EA and VP performed the recruitment and psychopathological assessment of the patients. MJP and JDA undertook the statistical analysis, and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

Dr. Víctor Pérez declares having received educational honoraria from: Sanofi-Aventis, Lundbeck, Pfizer, AstraZenecaand Eli Lilly, and research funding from Boehringer-Ingelheim for this work. Dr. Enric Alvarez has received consulting and educational honoraria from several pharmaceutical companies including Eli Lilly, Sanofi-Aventis, Lundbeck and Pfizer, and he has participated as main local investigator in clinical trials from Eli Lilly, Bristol-Myers and Sanofi-Aventis and also as national

Acknowledgements

We thank the staff of the Deparment of Psychiatry and the Department of Neuroradiology of Hospital de la Santa Creu i Sant Pau for their assistance with the study. We also give thanks to the patients who participated in the current study for their kindly co-operation.

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