Title

 

Authors

R. Crupi¹, M. Cambiaghi², R. Hen³, E. Spina¹ and F. Battaglia<sup>1,4

1</sup>Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Italy
²Experimental Neurophysiology Unit, Institute of Experimental Neurology - INSPE, University Scientific Institute Hospital San Raffaele, Milan, Italy
³Department of Neuroscience, Columbia University, NY, USA
⁴Division of Brain Stimulation and Therapeutic Modulation, Department of Psychiatry, Columbia University, New York, NY

 

Abstract

Major depressive disorders (MDD) are highly prevalent medical conditions (Kessler et al., 2003) that rank among the top ten causes of disability (Greenberg et al., 2003) and results in a tremendous burden on individual patients, health-care systems and society (Kessler et al., 2005). Although several pharmacotherapies are available to treat mood disorders, they are effective in only 50-60% of patients and have significant side effects (Fava, M. and K.G. Davidson 1996). These data boosted interest in non-pharmacological strategies to treat affective disorders. Until recently, the main treatment used in patients with drug-resistant depression was electroconvulsive treatment (ECT). Unfortunately ECT, although highly efficacious, is associated with significant cognitive side effects, and there concern regarding risks associated with repeated general anaesthesia (Lisanby et al., 2000). Recent advances in the field suggest that new neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), magnetic seizure therapy, direct current stimulation, vagus nerve stimulation, and deep brain stimulation, might be a reasonable alternative to ECT. Low-frequency repetitive transcranial magnetic stimulation (1 Hz rTMS) is a promising non-invasive tool for the treatment of depression. Studies in patients and in animal model of depression provided evidence for plastic changes in the hippocampus (Eisch et al., 2008). For instance, MDD have been associated with hippocampal atrophy and stress induces negative effects on hippocampal dendritic morphology and dentate gyrus (DG) neurogenesis. These morphological and functional hippocampal changes might contribute to key symptoms in MDD such us anhedonia, alteration of mood and cognition and might be useful biomarkers in the attempt to optimize brain stimulation interventions. Adult neurogenesis is modulated by ECT, vagal nerve stimulation, deep brain stimulation and chronic SSRI treatment. Hippocampal neuronal plasticity is thought to have a pivotal role in the pathophysiology of depressive disorders and the mechanism of action of antidepressant treatments. In this study, we investigated the consequences 1 Hz rTMS treatment on emotional behavior and hippocampal dentate gyrus structural plasticity. Adult male mice received either five days of 1 Hz rTMS or Sham stimulation. After stimulation mice underwent to a battery of anxiety-like and depression-like behaviors and we tested the effect of treatment on mature and newly generated granule cell dendritic morphology. Low-frequency rTMS induced antidepressant-like effects in the tail suspension test without affecting anxiety-like behaviors. No between groups differences in DG progenitor cell proliferation were found. However, 1 Hz rTMS stimulated mice showed increase dendritic complexity in newly generated neurons. The stimulation induced structural plasticity in mature granule cell as showed by increased dendritic spine density, dendritic lenght and number of intersections. This is the first study demonstrating that administration of 1 Hz rTMS for 5 days in normal mice can significantly induce antidepressant effects and modulate dentate gyrus mature and newly-generated neurons dendritic plasticity. This study showed that 1 Hz  these results provide critical evidence that supports the hypothesis that low frequency rTMS induces plastic changes in critical circuits. These changes can be used as biomarkers for the optimization of the treatment.

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