Commentary 1 Toward New Therapeutics in Depression: tdcs s Secrets

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1 Commentary 1 Toward New Therapeutics in Depression: tdcs s Secrets Adeline Etiévant 1,2* and Julie Monnin 1,2,3 1 Laboratoire de Neurosciences intégratives et cliniques, EA 481, Université Bourgogne Franche-Comté, France 2 Service de Psychiatrie, CHRU Besançon, France 3 Centre d Investigation Clinique CIC1431, Inserm, CHRU Besançon, France * Corresponding Author: Adeline Etiévant, Laboratoire de Neurosciences intégratives et cliniques, EA 481, Université Bourgogne Franche-Comté, Besançon, France, Tel: ; adeline.etievant@gmail.com First Published October 16, 2017 Copyright: 2017 Adeline Etiévant and Julie Monnin. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2

2 There is an urgent need for effective, safe and affordable therapies for major depressive disorder considering the partial and delayed therapeutics activity of available pharmacological treatments [1,2]. Faced with these therapeutic limits, novel nonphamacological options based on brain stimulation are of great interest to the scientific community. Initially, there was a simple idea behind the use of brain stimulation: depressed patients have a functional asymmetry in cortical activity between the left and right hemispheres; the first is hypofunctional whereas the second is hyperfunctional [3,4]. If the former could be stimulated and the last inhibited, the asymmetry would disappear as well as depression. This assumption, more or less hazardous and today called into question, encouraged the use of an old and simple neuromodulatory technique, the transcranial direct current stimulation (tdcs). A weak, direct electrical current was applied to the brain through two large and external electrodes placed over the scalp and connected to a stimulator. This technique has the advantage of being non-invasive and well tolerated by patients. Unlike electroconvulsive therapy, which is very controversial, tdcs is less frightening and one could even imagine that it could be used at home; some of them having even made up their minds to make some handcrafted devices in their garage. In addition to its technical strengths, first clinical trials in depressed subjects showed that the antidepressant effects were there. Indeed, tdcs seemed to alleviate symptoms in depressed patients through anodal 3

3 stimulation over the left dorsolateral prefrontal cortex, via the induced-increase of cortical excitability [5 8]. However, other trials report some discrepancies: its beneficial effect was not systematic and its duration was limited. Given that observations, it could be assumed that the tool is far from being mastered. The technique and its outcomes seem therefore more subtle than it appeared at the beginning and researches aiming at elucidating its mechanisms of action are multiplying. In the 60 s, first data from animal researches have shown the basic effects of polarized current on neuronal excitability: anodal stimulation enhanced neural excitability by modulating membrane potential (depolarization) and increasing neuronal firing rate, while cathodal stimulation hyperpolarized neuron membrane inducing a decrease of neuronal activity [9,10]. This non-synaptic modulation would be responsible of the immediate effects of tdcs whereas synaptic strength alteration would be involved in its after-effects. Indeed, other cellular modifications, involved in cortical plastic changes observed after anodal polarization, were identified in the 90 s: direct current stimulation induced the modulation of Ca 2+ in the cerebral cortex, hippocampus and thalamus and the overexpression of protein kinase Cγ and cfos protein in several areas of the rat brain [11 13]. This theory was strengthened by the findings of Nitsche and his collaborators. They performed several studies on the pharmacological modulation of after-effects of tdcs in humans. They highlight- 4

4 ed that the modulation of the dopaminergic, serotoninergic, glutamatergic and GABAergic systems through the administration of pharmacological agents could modify the cortical excitability induced during and a few hours after a tdcs stimulation [14 18]. These observations were considered to be related to deep and lasting changes of synaptic plasticity and long-term potentiation (LTP) mechanism. Today, more and more researches use animal models to explore the neurobiological mechanisms of tdcs and open up an unlimited range of investigative paths due to genetic and environmental control, the wide choice of biological analyzes and the possibility of multiplying experiments. It has been clearly demonstrated that antidepressant-like behavioral effects can be observed after tdcs in healthy rodents as well as in animal model of depression. Our lab, and others, developed a device which permits to mimic some behavioral effect of tdcs in mice [19 21]. We demonstrated that a single stimulation over the left frontal cortex of healthy mice (20 min, 200 µa) was able to decrease the immobility duration in the forced-swim test (FST) three and twenty-one days after the stimulation. Repetition of stimulation (ten sessions) enhanced the duration of the behavioral outcomes of tdcs which lasted at least 60 days. This behavioral response was dependent of stimulation parameters such as the current intensity and polarity, the duration and the vigilance state during stimulation. We also found that fifteen sessions of anodal 5

5 tdcs significantly reversed depressive-like behaviors in the FST observed in mice exposed to long-term oral corticosterone, a validated mouse model of depression [21]. These behavioral effects could be due to an enhancement of neural activity since tdcs results in a rapid and wide neuronal activation, characterized by a c-fos over expression, in the ventromedial prefrontal cortex (vmp- FC, i.e. IL and PL PFC), its associated subcortical limbic circuitry and the reward circuitry [21]. The repetition of stimuli promoted the duration of the behavioral outcomes and likely engaged neurons towards plasticity phenomena. This hypothesis is supported by recent data. In rats and mice, tdcs was able to increase the number of endogeneous neural stem cells in the hippocampal SVZ [22,23], enhance LTP in hippocampal slice and expression of BDNF and pcreb levels [24]. Anodal tdcs also upregulated the transcription of several plasticity related gene (BDNF, CREB, synapsin I, CaMKII, Arc and c-fos ) within rat cortex and hippocampus [25]. Many other pathways and hypothesis remain to be studied: for example, what about the inflammatory pathway, today strongly associated with depression and other psychiatric pathologies? Few studies have been performed on this topic lately and suggested that tdcs could act on the activation of microglial cells, a key player of cerebral inflammation. However, these interesting results are not homogeneous and suggest that different parameters could act on this effect, such as animal species, 6

6 stimulation polarity and the existing level of inflammation [23]. Moreover, besides its activation of microglial cells, tdcs seems to modulate neuro-inflammatory response by promoting stem cells migration to support brain lesion regeneration [22]. tdcs has not yet revealed all its mysteries! References 1. Nemeroff CB. Prevalence and management of treatment-resistant depression. J Clin Psychiatry. 2007; 68: Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006; 354: Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997; 9: Kennedy SH, Evans KR, Kruger S, Mayberg HS, Meyer JH, et al. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry. 2001; 158: Mondino M, Bennabi D, Poulet E, Galvao F, Brunelin J, et al. Can transcranial direct current stimulation (tdcs) alleviate symptoms and im- 7

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10 22. Rueger MA, Keuters MH, Walberer M, Braun R, Klein R, et al. Multi-session transcranial direct current stimulation (tdcs) elicits inflammatory and regenerative processes in the rat brain. PLoS One. 2012; 7: e Pikhovych A, Stolberg NP, Jessica Flitsch L, Walter HL, Graf R, et al. Transcranial Direct Current Stimulation Modulates Neurogenesis and Microglia Activation in the Mouse Brain. Stem Cells Int. 2016; 2016: Podda MV, Cocco S, Mastrodonato A, Fusco S, Leone L, et al. Anodal transcranial direct current stimulation boosts synaptic plasticity and memory in mice via epigenetic regulation of Bdnf expression. Sci Rep. 2016; 6: Kim MS, Koo H, Han SW, Paulus W, Nitsche MA, et al. Repeated anodal transcranial direct current stimulation induces neural plasticity-associated gene expression in the rat cortex and hippocampus. Restor Neu 11