Promising new treatment of major depressive disorder by stimulation of the dorsolateral prefrontal cortex with Transcranial Direct Current Stimulation (tDCS)
Mini thesis – 1st version
Words: 3178
Tamara Vallina
10718044
11-1-2016 Supervisor: Mr L. C. Reteig MSc
Promising new treatment of major depressive disorder by stimulation of the dorsolateral prefrontal cortex with Transcranial Direct Current Stimulation (tDCS)
Introduction
Major depressive disorder (MDD) is a common psychiatric illness, that affects 6 to 12 percent of the world’s population. Neurobiological changes are considered fundamental to depressive symptoms , disabling nearly 300 million people (Vos et al. 2013). Current MDD treatments contain weighty side effects, that often result in early termination of the treatment (Brunoni et al., 2009) . New forms of treatment are therefore needed.
To this day, the treatment applied most for MDD is the administration of antidepressants. Brunoni et al. (2009) showed in their meta-analysis a relatively small effect of the antidepressants compared to placebo-treatment, revealing that antidepressants have less effect than is often claimed. No study provides robust evidence for superior efficacy of any antidepressant drug .
Repetitive transcranial magnitude stimulation (rTMS) is a technique that is considered to have a modulatory effect . It has been approved for the treatment of MDD and is being used worldwide . This technique demands a relatively expensive device an can be applied by trained physicians only. The device is non-portable, what obligates patients to visit clinics daily (Brunoni et al., 2012). A possible solution would be a device that combines the non-pharmalogical advantages of rTMS , convenience of use, portability and low-costs. All these aspects are present in tDCS devices.
Transcranial direct current stimulation (tDCS) is also considered to have a modulatory effect , influencing cortical excitability. It is a non-invasive technique that uses saline-soaked sponge electrodes placed directly on the scalp, delivering an electric current. It has shown to have effects on various functions of the brain. (Dayan et al., 2013) Animal studies have established that anodal direct current stimulation increases neuronal excitability and spontaneous firing rate, whereas chathodal stimulation leads to decreased neuronal firing rate and excitability . Similar changes in neuronal excitability due direct current stimulation have been observed in humans (Nitsche et al., 2000).
Right hemispheric hyper-activation and left hemispheric hypo-activation of the dorsolateral prefrontal cortex (DLPFC) are suggested to be a key aspect of depression. In addition, dysfunctional long-term potentiation (LTP) plasticity seems to play an important role. Therefore, therapeutic strategies of non-invasive brain stimulation techniques for the treatment of MDD, focus on enhancing left DLPFC activity and/or decreasing right DLPFC activity (Schonfeldt-Lecuona et al., 2010; Kuo et al., 2014).
The main modification demonstrated by MRI in MDD-patients are a reduction in gray- matter volume in the prefrontal cortex, hippocampus and striatum. This reduction is probably due to an excess of apoptosis, also known as neural loss. A deficit in the neurotrophic synthesis factor, called brain-derived neurotrophic factor (BDNF), may be responsible for this increased apoptosis. In parallel, the neural LTP plasticity (reductions of LTP?) is decreased (Fossati et al., 2004). Data concern the possible reversibility of these deficits with antidepressant treatment . Knowing the effects of tDCS, this technique seems really convincing for targeting BDNF-levels and/or plasticity defects , much more so than current treatments like anti-depressants.
The aim of this review is to debate evaluate the contribution of tDCS as a treatment for depression, as it seems promising and beneficial from health, ethical and economical perspectives. The main question is whether and how stimulation of the DLPFC with tDCS can contribute to the treatment of MDD. To answer this question, the influence of tDCS on mood during MDD will be examined. Furthermore, the effect of this technique on two considered neurobiological aspects of the disorder, BDNF level and neuroplasticity, will be looked at.
Effects of tDCS treatment in Major Depressive Disorder
This paragraph lends an overview of findings from recent studies that focussed on the efficacy of tDCS-treatment on the emotional condition of MDD patients . All patients recruited for these studies were MDD diagnosed following DSM-IV criteria. Depression severity was rated using the Montgomery–Äsberg Depression Rating Scale (MADRS)(Montgomery and Äsberg, 1979) or the Beck Depression Inventory (BDI)(Beck, 1988). When a patient is mentioned as responder to treatment, its HDRS score is reduced by at least 50% from baseline measurement. Remission is defined when the HDRS score decreases below 8.
Boggio et al. (2008) were the first to demonstrate significant improvement in mood and lasting effects in the long term due tDCS in a relatively large study. They also indicated that the therapeutic effect of tDCS is most targeting when stimulation is applied anodal at the left DLPFC. In their study, forty patients were randomly divided into three groups: one group receiving active treatment with anodal tDCS over the left DLPFC, one active control group with anodal tDCS on the occipital cortex, and one sham control group with sham tDCS over the left DLPFC. All groups received cathodal tDCS over the right supraorbital region. Patients received 10 sessions of tDCS over a period of two weeks. The active current was set at 2 mA for 20 minutes each session. HDRS scores and BDI measurements were rated at baseline, at the end of treatment and till one month after treatment. There were significant differences of the HDRS scores between the active treatment group, the active control group and the sham control group, but the control groups did not separate differ from each other. BDI outcomes showed a similar pattern. Results counted 8 responders in the active treatment group, compared with 2 responders in the active control group and none in the sham control group. There were 5 patients in remission in the active treatment group, but none in the control groups.
The study of Loo et al. (2012) confirmed that active tDCS has significantly greater antidepressant effects than sham TDCS. This trial included more participants and applied more robust treatment . 64 patients were randomised to receive either active tDCS at 2 mA for 20 min or sham tDCS. The anode was placed over left DLPFC, the cathode lateral to the right orbit. The treatment was delivered in 15 tDCS sessions, over a period of 3 weeks. More sessions were offered to those who were responding to the treatment. MADRS scores were measured at baseline, during sessions and till 4 weeks after trial completion. Results showed a significant interaction between time and group MADRS scores, where active tDCS group had lower scores than the sham-controlled group . At 1-week follow-up , 16 out of 26 patients in the active tDCS group met criteria for response compared to 6 out of 26 in the sham tDCS group.wat is er opeens met de andere 10 gebeurd?
What had not been investigated in these studies, was the efficacy of tDCS in combination with antidepressants . The study of Brunoni et al. (2013) is the largest randomized controlled trial to date of tDCS treatment in MDD, where efficacy of tDCS combined with the antidepressant sertraline is analysed. They showed a significant better mood when sertraline and tDCS were initiated simultaneously than other groups in the trial. In this study, 120 Patients were randomised to one of four groups: Active tDCS with sertraline, active tDCS with placebo medication, sham tDCS with sertraline and sham tDCS with placebo medication. The anode was placed over the Left DLPFC, and the cathode over the Right DLPFC . 12 tDCS sessions were delivered over a period of 14 days. Active tDCS was delivered using a current setting of 2 mA, for 30 min per session. Sertraline was administered at a fixed dose of 50 mg per day. MADRS scores were measured after 6 weeks. Active tDCS was significantly superior over sham tDCS for all outcomes. there was a significantly better improvement in MADRS scores in the combined treatment group receiving sertraline with active tDCS compared to the group receiving sertraline with sham tDCS.
However, it was not yet clear whether tDCS is effective in treatment resistant depressive disorder patients . Bennabi et al (2015) studied the efficacy of tDCS in 24 patients, that met stage II criteria for treatment resistance. All patients received a constant dose of escitalopram over 4 weeks before the trial started. Patients were randomised to receive active or sham TDCS. 10 sessions were delivered over 5 days, from which active tDCS used a 2mA current for 30 minutes per session. HDRS scores and BDI measurements were rated at baseline and at the end of treatment. There was no significant difference between active and sham tDCS in the change in HDRS score. However, in the active tDCS group there were 3 subjects who responded and 2 who met criteria for remission. In the sham tDCS group there was 1 responder and no remitters.
Above studies suggest that tDCS has powerful anti-depressant effects when applied as treatment. All trials found significant improvement in mood at the end of treatment. Treatment seems even more effective when tDCS is combined with the antidepressant Sertraline. These effects are less clear in treatment-resistant patients, implying less efficacy of tDCS when classic antidepressants do not work. This study (Bennabi, 2015) however, is limited by a small number of subjects.
Effects of tDCS on Brain derived neurotrophic factors and neuroplasticity
Despite the fact that tDCS has been increasingly used in experimental and clinical settings, the exact molecular and cellular mechanism of tDCS remains unknown. This paragraph provides an overview of findings from recent studies, that focussed on the effects of tDCS on brain derived neurotrophic factors (BDNF) and neuroplasticity. BDNF is a neurotrophin related to neuronal survive, synaptic signalling and synaptic consolidation . BDNF levels are often used to index neuroplasticity. Again, patients included in these studies were MDD diagnosed following DSM-IV criteria.
Several studies on MDD have shown that BDNF is associated with depression response. Brunoni et al. (2008) showed that BDNF levels are correlated with clinical changes in depression, supporting the conception that depression improvement is associated with neuroplastic changes. They performed a meta-analysis on MDD and BDNF levels including 20 studies, totalling to 1504 patients and control subjects. The results showed that BDNF levels increased significantly after antidepressant treatment. In addition, there was a significant correlation between changes in BDNF level and depression scores changes. Finally, there was a difference between patients before treatment and healthy controls and a small but significant difference between treated patients and healthy controls.
tDCS may improve neuroplasticity trough augmentation of BDNF secretion . Fritsch et al. (2010) proposed that DCS could serve as a tool to induce synaptic plasticity in regions that do not respond to conventional protocols. They also implied that tDCS might serve as treatment for conditions marked by impaired plasticity and/or reduced cortical BDNF levels. Their study was designed to study the cellular and molecular mechanisms underlying the effect on motor skill learning in a mouse brain slice. Effects of DCS were investigated using fEPSPs to monitor synaptic efficacy. Results showed that anodal DCS induces a long-lasting synaptic potention, that requires activity-dependent BDNF secretion.
It was yet unknown if neuroplasticity changed in depressed patients before and after a treatment course of tDCS. Player et al. (2014) were the first to demonstrate a significant improvement in cortical plasticity after following a treatment course of tDCS in depressed patients. The study included 18 patients, who were randomised to receive a course of active anodal tDCS or double-blind, sham-controlled tDCS. Between 13 and 21 sessions were given on consecutive weekdays, with a 2mA current for 20-30 minutes in the active tDCS treatment. The anode was placed over the left DLPFC. Neuroplasticity (with the PAS protocol) , MADRS scores and BDNF levels were measured at baseline and after tDCS treatment. Results showed that tDCS treatment led to significant improvement in mood and cortical plasticity, although no significant correlation was found in the percentage changes. There were no significant changes in BDNF levels, and there was no relationship between BDNF levels and changes in measured neuroplasticity.
Since The authors/you/earlier findings predicted that increased BDNF levels were expectedwould increase after tDCS treatment, so these results above seem a bit converselywere unexpected. However, these findings got confirmed when Palm et al. (2013) demonstrated unchanged BDNF levels after tDCS in treatment-resistant depressed patients. This study was the first to investigate the effect of tDCS on BDNF serum levels in depression specifically. 22 patients were included, which had undergone at least two antidepressant treatment trials without effect. All patients received 10 sessions of active and 10 sessions of sham tDCS for 2 weeks, with half the group in opposite order. Active and sham tDCS were each applied over the dorsolateral prefrontal cortex (DLPFC) for 20 min on 10 days, at a current between 1 and 2 mA. The anode was placed over the left DLPFC and the cathode over the right supraorbital region. BDNF levels were measured at baseline, at end of treatment and during a 2-week follow-up phase. The results showed no significant effect of active tDCS on BDNF serum levels in therapy-resistant depressed patients compared to sham tDCS.
It is hypothesized that this is because BDNF serum levels were already raised to their limited potential due treatment with antidepressants before these trials started, since 13 patients were on antidepressants . Later research of Brunoni et al. (2015) showed that BDNF levels did not change after tDCS treatment, regardless treatment with antidepressants or not. They stated that BDNF are not surrogate markers of treatment response or even involved in the antidepressant mechanisms of tDCS. In this study, 103 patients were randomised to receive active or sham tDCS, combined with Sertraline or placebo medicine. The tDCS sessions were delivered 30 minutes per day, for 10 days consecutively, using a current of 2 mA for the active condition. The anode was placed over the left DLPFC and the cathode on the right DLPFC. Sertraline was simultaneously administered in a fixed dose of 50 mg/day. MADRS scores were measured at baseline till 6 weeks from start. Changes in depression scores were not correlated with changes in BDNF levels over time, regardless of treatment response or group.
These studies show that neuroplasticity significantly improves from tDCS MDD treatment. BDNF levels were different at every outcome of the experiments. Although expected, some BDNF levels did not change at all . There was found no relationship between BDNF levels and changes in measured neuroplasticity after tDCS treatment. The plasticity is therefore not an direct result of the BDNF levels, and BDNF levels are not representative for treatment response.
Discussion
tDCS shows powerful anti-depressant effects, by significantly improving mood in MDD patients. Treatment seems most effective when it is combined with antidepressants, but more antidepressants should be tested to support these findings. The antidepressant effects of tDCS seem less strong in treatment-resistant patients, but larger trials are needed to confirm this. tDCS significantly improves LTP-like neuroplasticity in the MDD patient. Against expectation, this plasticity is not an direct result of BDNF levels. Also, BDNF levels are no good indicator for treatment response.
Transcranial direct current stimulation of the DLPFC is very promising in the treatment of major depressive disorder. It improves neuroplasticity, but fully underlying biological mechanisms are yet to be determined.
The contrary unexpected findings of no differences in BDNF levels after tDCS treatment are supposed tocould be due to the results of several possible explanations. Fritsch et al. (2010) stated that tDCS without simultaneous training of the area may not induce same effects as were found in their mice. Also, it should not be neglected that there are significant species differences between mice an humans, and that there are difficulties in translating mice slice experiments to human conditions. Player et al. (2014) hypothesized that BDNF levels were already raised prior to the brain stimulation and had limited potential for further increases. Thirteen out of eighteen patients were on antidepressants prior and during the treatment in their study. Although Palm et al. (2013) were already limited by a sample size of only 19 patients, they could not rule out that the duration of sample storage had an effect on BDNF levels in their study. Since their tDCS treatment did not induced significant mood improvement either, no further conclusions could be made. The findings of Brunoni et al. (2015), which were no changed BDNF levels after tDCS, are in line with previous tDCS reports examining BDNF levels. After analysing these studies taken together, they stated that BDNF does not appear to be a surrogate biomarker of tDCS antidepressant response, and might not even be involved in the pathophysiological mechanisms of tDCS.
Recent findings that have shed new light on the mechanisms of tDCS, are the role of caspase-3 positive cells and neural stem cells. Pelletier et al. (2015) showed significantly less capase-3 cells after cathodal tDCS In rats. Caspase cells play a key role in cell apoptosis. Also, there was an extensive increase in proliferating cells and neural stem cells in the stimulated region.
The results of the studies in this review are in line with the concept that tDCS could contribute in MDD treatment. The technique is indeed convenient for targeting neuroplasticity defects. However, the results were not in line with previous thoughts on the effects of tDCS on BDNF levels.
tDCS is way more effective than current treatment for MDD such as antidepressants, that often contain weighty side effects . The findings in this review give more reason to bring tDCS treatment in practice. This technique combines the non-pharmalogical advantages of rTMS , convenience of use, portability of the devices and low-costs of treatment. Overall, MDD treatment will get more effective and accessible, without the weighty side effects of antidepressants. This improvement will help more people suffering from MDD.
Understanding the cellular and molecular mechanism of tDCS could contribute to development of more specific treatments. This is why it would be very useful to study more molecular cascades associated with neuroplasticity, before and after tDCS treatment in depressed patients. The cascades of my particular interest are caspase-3 positive cells and neural stem cells, since Pelletier et al. (2015) have shown significant improvement in rat brains after tDCS in vivo.
Also, larger trials of tDCS treatment are needed to study the efficacy in treatment-resistant patients. More antidepressants should be tested in combination with tDCS to confirm superior efficacy when these treatments are combined.
Depression disorders have been prevailing too long, disabling nearly 300 million people worldwide. Optimizing treatment by putting tDCS treatment in practice, will make a thorough change in world health and lead to more remission.