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