Elsevier

Biological Psychiatry

Volume 52, Issue 11, 1 December 2002, Pages 1057-1065
Biological Psychiatry

Original article
Chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation: effects on stress hormone levels and adult hippocampal neurogenesis

https://doi.org/10.1016/S0006-3223(02)01457-9Get rights and content

Abstract

Background

Repetitive transcranial magnetic stimulation is increasingly used as a therapeutic tool in psychiatry and has been demonstrated to attenuate the activity of the stress hormone system. Stress-induced structural remodeling in the adult hippocampus may provide a cellular basis for understanding the impairment of neural plasticity in depressive illness. Accordingly, reversal of structural remodeling might be a desirable goal for antidepressant therapy. The present study investigated the effect of chronic psychosocial stress and concomitant repetitive transcranial magnetic stimulation treatment on stress hormone regulation and hippocampal neurogenesis.

Methods

Adult male rats were submitted to daily psychosocial stress and repetitive transcranial magnetic stimulation (20 Hz) for 18 days. Cell proliferation in the dentate gyrus was quantified by using BrdU immunohistochemistry, and both the proliferation rate of progenitors and the survival rate of BrdU-labeled cells were evaluated. To characterize the activity of the hypothalamic-pituitary-adrenocortical system, plasma corticotropin and corticosterone concentrations were measured.

Results

Chronic psychosocial stress resulted in a significant increase of stress hormone levels and potently suppressed the proliferation rate and survival of the newly generated hippocampal granule cells. Concomitant repetitive transcranial magnetic stimulation treatment normalized the stress-induced elevation of stress hormones; however, despite the normalized activity of the hypothalamic-pituitary-adrenocortical system, the decrement of hippocampal cell proliferation was only mildly attenuated by repetitive transcranial magnetic stimulation, while the survival rate of BrdU-labeled cells was further suppressed by the treatment.

Conclusions

These results support the notion that attenuation of the hypothalamic-pituitary-adrenocortical system is an important mechanism underlying the clinically observed antidepressant effect of repetitive transcranial magnetic stimulation, whereas this experimental design did not reveal beneficial effects of repetitive transcranial magnetic stimulation on adult hippocampal neurogenesis.

Introduction

Repetitive transcranial magnetic stimulation (rTMS) is currently being evaluated in the treatment of major depression in various clinical trials. Indeed, several lines of evidence resulting from both preclinical Fleischmann et al 1995, Zyss et al 1997, Keck et al 2001 and clinical Padberg et al 1999, Berman et al 2000, George et al 1999 studies support the notion that rTMS may have antidepressant properties; however, there is still a profound lack of knowledge concerning the putative effects at the molecular and cellular level underlying the observed clinical effects (Post and Keck 2001). Previously, we demonstrated that in certain conditions, long-term rTMS of left frontal brain regions may induce neuroprotective-like effects both in vitro and in vivo (Post et al 1999). In addition, we could show that long-term rTMS induces changes in the expression of brain-derived neurotrophic factor (BDNF) and cholecystokinin, which are similar to those reported after antidepressant drug treatment and electroconvulsive seizures (Müller et al 2000). These data support the hypothesis that a common molecular mechanism may underlie different antidepressant treatment strategies and emphasize the importance of animal experiments in understanding the neurobiological changes induced by rTMS.

It is widely accepted that chronic stress increases the risk of developing and is associated with affective disorders (Kendler et al 1999). Therefore, a hypothesis relating stress hormone dysregulation to causality of depression was proposed suggesting that antidepressants may act through normalization of the hypothalamic-pituitary-adrenocortical (HPA) changes (Holsboer 2000). In line with the above are the findings on chronic rTMS-induced changes in stress-induced corticotropin (ACTH) and corticosterone plasma levels in rats Keck et al 2000a, Keck et al 2001 providing evidence that rTMS of frontal brain regions attenuates the stress-induced activity of the HPA system. Moreover, basal corticosterone plasma concentrations were reported to be lowered after a single rTMS application (Hedges et al 2002).

Proliferation and maturation of functional neurons have been demonstrated to occur at a significant rate in the adult hippocampus in many different mammalian species including humans Eriksson et al 1998, Gross 2000, Van Praag et al 2002. Moreover, adult neurogenesis is an extremely dynamic process that is regulated in both a positive and negative manner by neuronal activity and environmental factors (Gould et al 2000). In addition, exposure to psychotropic drugs or stress regulates the rate of neurogenesis in adult brain, suggesting a possible role for neurogenesis in the pathophysiology and treatment of neurobiological illnesses such as depression and posttraumatic stress disorder Duman et al 1999, Duman et al 2001.

The aim of the present study was to determine whether a concomitant rTMS treatment might exert a beneficial effect on the psychosocial stress-induced decrease in adult neuron production and/or survival of the newly generated cells in the hippocampal dentate gyrus. As granule neuron production and survival is highly dependent on circulating levels of glucocorticoid hormones, we additionally monitored the effects of rTMS on plasma ACTH and corticosterone levels.

Section snippets

Animals

The animal studies were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the Government of Bavaria, and NIH guidelines. Three-month-old male Wistar rats (n = 48) were used. Animals were housed in groups of six under standard laboratory conditions in the breeding unit of the Max Planck Institute of Psychiatry under standard laboratory conditions (12/12 hours light/dark cycle, food and water ad libitum). Two weeks before the experiment, all rats were housed

Stress-induced elevation of ACTH and corticosterone is normalized by rTMS treatment

To characterize the basal activity of the HPA system, blood samples were taken for hormone concentration measurements at the end of the 18 days of treatment. The mean values of ACTH and corticosterone (cort) levels in each group are displayed in Figure 1. Basal plasma ACTH and cort levels were comparable in the control and control + rTMS rats. Exposure to chronic psychosocial stress induced a substantial elevation both in plasma ACTH (+94%) and corticosterone (+97%) levels. Two-way ANOVA

Discussion

The present study was designed to examine the effects of concomitant rTMS treatment on plasma stress hormone levels and on neurogenesis in the hippocampal dentate gyrus of the adult rat during chronic psychosocial stress. Repetitive transcranial magnetic stimulation (20 Hz) of frontal brain regions normalized the stress-induced elevation of plasma ACTH and corticosterone, herewith confirming our previous results Keck et al 2000a, Keck et al 2001. An important finding of this study is that the

Acknowledgements

The authors would like to thank Monika Rücker for skillful technical assistance. The magnetic stimulation device was kindly provided by DANTEC/Medtronic, Skovlunde, Denmark.

This project was supported by the German Federal Research Ministry within the promotional emphasis “Competence Nets in Medicine” Kompetenznetz Depression & Suizidalität; subproject 4.5 (MEK), and the network “Gepulste Magnet-Stimulation des Gehirns in der Therapie Neuropsychologischer Erkankungen” (0311467B) (EF). AKF was

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