Regular ArticleRepetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder
Introduction
A number of findings indicate that changes in central cortical inhibitory pathways, especially associated with gamma-aminobutyric acid (GABA) neurotransmission, may be involved in the pathogenesis of major depressive disorder. Animal studies report decreased GABA concentration and receptor function after both acute and chronic stress (Acosta et al., 1993, Acosta and Rubio, 1994). In depressive patients with melancholic subtype, GABA levels have been reported to be decreased in cerebrospinal fluid in some but not in all studies (Gold et al., 1980, Roy et al., 1991). Finally, in accordance with these findings, proton magnetic resonance spectroscopy studies demonstrated lower GABA concentrations in depressed patients than in healthy subjects (Sanacora et al., 1999).
Furthermore, a number of studies support the view that improvement in depressive symptomatology is accompanied by an increase in GABAergic neurotransmission. It has been reported that GABA-agonists prevent and reverse learned helplessness in rodent models of depression (Petty and Sherman, 1981). This has been supported by therapeutic studies indicating that anticonvulsants that elevate GABA have antidepressant properties as well as mood stabilizing and anxiolytic ones (Calabrese et al., 1999). In addition, antiepileptic vagus nerve stimulation (VNS) seems to have both anticonvulsant and antidepressant effects (Rush et al., 2000). Finally, changes in TMS measures pointing towards an increase in GABAergic activity have been demonstrated after electroconvulsive therapy in patients with major depression (Bajbouj et al., 2003a).
Transcranial magnetic stimulation (TMS) is a non-invasive investigational tool which has been extensively used over recent years to assess human motor cortex excitability (Maeda and Pascual-Leone, 2003, Siebner and Rothwell, 2003). A number of different TMS measures are available, each with a distinct anatomy and neurophysiological underpinning. Resting motor threshold (RMT), or the lowest intensity required to elicit a motor evoked potential of a designated amplitude in 5/10 trials, has been associated with membrane excitability of cortical motor neurons. Cortical silent period (CSP) succeeds the contralateral motor evoked potential (MEP) and refers to a silence in the EMG following the MEP. It depends, at least in part, on GABAergic neurotransmission (Reis et al., 2002). Intracortical inhibition (ICI) and facilitation (ICF) as measured by the paired pulse technique have been associated with the balance of GABAergic, dopaminergic, and glutamatergic tone. Therefore, these parameters are of special interest in the context of our study as potential markers of central GABAergic system activity (for review: (Daskalakis et al., 2002)).
An increasing number of clinical studies demonstrate therapeutic effects of repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex in patients with major depressive disorder (for review: see Schlaepfer et al., 2003). However, limited data are available so far concerning the effects on central nervous inhibitory pathways.
Since other antidepressant stimulation techniques like vagus nerve stimulation and electroconvulsive therapy, involve the GABAergic system, the aim of the present study was to address the question whether rTMS works via an analogous pattern. Therefore, we investigated all mentioned parameters of motor cortical excitability in 30 patients with major depressive disorder. It was hypothesized that patients responding to rTMS would show neurophysiological changes consistent with enhanced GABAergic activity.
Section snippets
Patients
Thirty right handed patients from the Department of Psychiatry, Charité University Medicine Berlin, Campus Benjamin Franklin, participated in this study. All patients provided their written informed consent for this study after the procedure had been fully explained. The ethics of the study were approved by the local institutional review board, and the study was carried out in accordance with the Declaration of Helsinki 1975. Cut of for inclusion was a Hamilton Depression Rating Scale score
Results
After 2 weeks of rTMS 10 out of 30 patients had an antidepressant response defined as a 50% reduction in the Hamilton Rating Scale (HAMD). Eight out of these 10 patients showed a response defined as a 50% reduction in the Beck Depression Inventory (BDI) score, one patient achieved remission.
At baseline (T1) none of the neurophysiological variables showed statistically significant differences between responders and non-responders, respectively (see Table 2). Since no differences were observed
Discussion
Using single and paired pulse TMS we investigated effects of high frequency rTMS of the left dorsolateral, prefrontal cortex on the function of excitatory and inhibitory neuronal structures in the motor cortex of patients with major depressive disorder. The main finding of our study is that ICI is significantly enhanced after ten sessions of rTMS in depressive patients responding to rTMS. This finding indicates an involvement of certain GABAergic pathways in the antidepressant mode of action of
Acknowledgments
The authors are grateful to Florence Hellen and Agnieszka Slezah for technical assistance.
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