Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression

https://doi.org/10.1016/j.jpsychires.2006.02.003Get rights and content

Abstract

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20 Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.

Introduction

Besides pharmacotherapy and psychotherapy, antidepressant stimulation techniques like electroconvulsive therapy (ECT), vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) have been increasingly used and investigated as alternative treatments of major depression (Bajbouj and Heuser, 2005). High-frequency (5–20 Hz) repetitive transcranial magnetic stimulation over the left DLPFC is a relatively safe and non-invasive experimental method for the treatment of major depression. Several studies and meta-analyses (George et al., 1997, Martin et al., 2003) suggested a significant reduction of depressive symptoms among certain subgroups of patients. However, the clinical relevance has been described as little and the exact mechanism of action of rTMS still remains unclear. Various preclinical studies have investigated possible neurobiological effects related to the antidepressive properties of rTMS, like alteration of monoamine release patterns, β-adrenoreceptor downregulation or enhanced release of possible neuroprotective substances like BDNF (for review, see Post and Keck, 2001). Besides these preclinical data, rTMS is capable of modulating measures of motor cortex excitability which represent central inhibitory mechanisms related to the GABAergic system. In that context, high-frequency (20 Hz) rTMS has been shown to enhance cortical excitability in healthy volunteers (Maeda et al., 2000) and patients with major depression (Bajbouj et al., 2005a), whereas low-frequency stimulation reduces cortical excitability (Gerschlager et al., 2001). Furthermore, evidence from functional neuroimaging studies suggests that high-frequency (⩾1 Hz) rTMS increases cerebral blood flow and glucose metabolism in stimulated and remote brain regions (Kimbrell et al., 2002, Paus et al., 1997), whereas low-frequency (⩽1 Hz) rTMS seems to have opposite effects (Speer et al., 2000).

Proton magnetic resonance spectroscopy (MRS) provides a unique opportunity to measure brain metabolite levels in vivo. More specifically, metabolic changes of N-acetylaspartate (NAA, putative marker of neuronal functionality), creatine and creatine phosphate (tCr, involved in energy metabolism), choline containing compounds (tCho, involved in membrane synthesis and degradation) and glutamate (Glu, excitatory neurotransmitter) during a course of rTMS can be assessed (for review see Kato et al., 1998). Numerous data suggest the involvement of glutamate, the major excitatory transmitter in the human brain, and its related metabolite γ-aminobutyric acid (GABA) in the pathogenesis of major depression (e.g., Bajbouj et al., 2005b, Petty et al., 1992, Sanacora et al., 2003). Previous studies using magnetic resonance spectroscopy suggested a reduction of glutamate and GABA in different brain compartments of depressed patients (Auer et al., 2000, Sanacora et al., 1999). Conflicting results have been reported for tCho with some studies finding increases and others finding decreases in depressive patients (for review see Lyoo and Renshaw, 2002). In addition, an increase in glutamate/glutamine (Glx) and tCho levels by different antidepressant interventions like antidepressants (Renshaw et al., 1997), electroconvulsive therapy (Pfleiderer et al., 2003, Ende et al., 2000), and rTMS (Michael et al., 2003b) has been reported.

Glutamate, having a complex spin system, usually gives a poor resolution spectrum in conventional MR spectroscopy at 1.5 T, which often is due to a mixture of glutamate, glutamine and GABA, designated Glx. Recently, our group demonstrated a novel method for separate quantification of glutamate by single voxel proton MRS at high magnetic field strengths of 3 T (Schubert et al., 2004). The aim of the present study is to investigate the levels of glutamate, choline compounds, N-acetylaspartate and total creatine (creatine + creatine phosphate) in the left ACC and the left DLPFC in patients with major depression, before and after a series of 10 consecutive sessions of rTMS, and to investigate the relationship between metabolic changes and clinical features of these individuals.

Section snippets

Subjects

The study was carried out with a standardized protocol, in accordance with the latest version of the Declaration of Helsinki, and approved by the Ethics committee of the Free University of Berlin. All participants had given written informed consent. Seventeen patients (2 females, 15 males, aged 28–61 years, mean age 45 ± 11 years) were selected consecutively from the Department of Psychiatry, Charité – Universitätsmedizin Berlin (Campus Benjamin Franklin). All subjects met DSM IV criteria for a

Treatment response

Six out of seventeen patients responded to treatment, defined as a 50% reduction in the HAMD score. Individual results of all psychopathological rating scores in the responders compared to the non-responders are displayed in Table 2. None of the clinical variables at baseline showed statistically significant differences between responders and non-responders.

Metabolite concentrations

Metabolite DLPFC concentrations are summarized in Table 3. At baseline, significantly lower concentrations of glutamate (p = 0.035) and tCho (

Discussion

Metabolic alterations in the left DLPFC and ACC after rTMS treatment were measured by MRS in 17 patients with major depression. The aim of this study was to monitor possible changes in the concentrations of glutamate, but also N-acetylaspartate, total creatine and choline containing compounds over the left DLPFC and ACC after 10 sessions of high-frequency rTMS and to compare these results with the clinical outcome of these individuals. The major finding of this study is that patients who

Acknowledgements

We thank Charlotte Pütz and Katrin Niederhut for supporting us during our clinical work and data assessment for this study. Furthermore, support from the German Federal Ministry of Education and research (BMBF, Project Berlin Neuroimaging Center, No. 01G00208), is gratefully acknowledged.

References (50)

  • H.S. Mayberg et al.

    Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

    Biological Psychiatry

    (2000)
  • F. Padberg et al.

    Repetitive transcranial magnetic stimulation (rTMS) in major depression: relation between efficacy and stimulation intensity

    Neuropsychopharmacology

    (2002)
  • A. Pascual-Leone et al.

    Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression

    Lancet

    (1996)
  • F. Petty et al.

    Low plasma gamma-aminobutyric acid levels in male patients with depression

    Biological Psychiatry

    (1992)
  • B. Pfleiderer et al.

    Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients

    Psychiatry Research

    (2003)
  • A. Post et al.

    Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms?

    Journal of Psychiatric Research

    (2001)
  • P.F. Renshaw et al.

    Basal ganglia choline levels in depression and response to fluoxetine treatment: an in vivo proton magnetic resonance spectroscopy study

    Biological Psychiatry

    (1997)
  • F. Schubert et al.

    Glutamate concentrations in human brain using single voxel proton magnetic resonance spectroscopy at 3 Tesla

    Neuroimage

    (2004)
  • A.M. Speer et al.

    Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients

    Biological Psychiatry

    (2000)
  • C.A. Altamura et al.

    Plasma and platelet excitatory amino acids in psychiatric disorders

    American Journal of Psychiatry

    (1993)
  • M. Bajbouj et al.

    Vagus nerve stimulation, repetitive transcranial magnetic stimulation, and electroconvulsive therapy in the treatment of depressive disorders

    Nervenarzt

    (2005)
  • M. Bajbouj et al.

    Evidence for impaired cortical inhibition in patients with unipolar major depression

    Biological Psychiatry

    (2005)
  • A.T. Beck et al.

    An inventory for measuring depression

    Archives of General Psychiatry

    (1961)
  • C.J. Bench et al.

    Changes in regional cerebral blood flow on recovery from depression

    Psychological Medicine

    (1995)
  • E.R. Danielsen et al.

    Absolute quantitative proton NMR spectroscopy based on the amplitude of the local water suppression pulse. Quantification of brain water and metabolites

    NMR in Biomedicine

    (1994)
  • Cited by (115)

    View all citing articles on Scopus
    View full text