Transcranial direct current stimulation in the treatment of depression




Paul B. FITZGERALD
MBBS, MPM, PhD, FRANZCP
Monash Alfred Psychiatry Research Centre (MAPrc)
The Alfred and Monash University School of Psychology and Psychiatry
Melbourne, AUSTRALIA

Transcranial direct current stimulation in the treatment of depression

by P. B. Fitzgerald,Australia


Transcranial direct current stimulation (tDCS) is a novel noninvasive method for selectively modulating cortical activation. tDCS involves the application of a low-amplitude current to the scalp via cathodal and anodal electrodes. To date it has been shown to affect a range of motor, somatosensory, visual, affective, and cognitive functions. Techniques similar to modern tDCS were first applied to the treatment of depression in the late 1960s. However, with the expansion of medication treatment of depression, there was a loss of interest in the technique. In the last decade there has been a substantial resurgence of interest in tDCS, led by a series of studies demonstrating its brain effects and apparent safety. As tDCS appears to be able to both increase and decrease brain activity depending on the location of the anode and cathode, it appears suitable for the potential treatment of disorders where abnormalities are seen in cortical activity, such as depression. Several sham-controlled clinical trials of tDCS in patients with clinical depression have now been conducted. Several of these trials have demonstrated antidepressant effects despite the trials being of relatively short duration. However, one trial found no difference between active and sham stimulation, possibly related to the use of a relatively low stimulation dose. In conclusion, tDCS has potential to be developed as a highly novel and innovative treatment for patients with depression. However, substantial clinical trials are required to both demonstrate efficacy and explore the optimal parameters for provision of the treatment.

Medicographia. 2011;33:202-208 (see French abstract on page 208)



Depression is a common, disabling, and difficult to treat psychiatric disorder. A substantial proportion of patients with depression do not respond to standard treatment approaches. A range of new brain stimulation technologies are being investigated for their capacity to have therapeutic effects in the treatment of major depressive disorder (MDD).

Repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) has been evaluated in a series of studies over the last 15 years and has recently been approved for the treatment of depression under certain circumstances by the Food and Drug Administration (FDA) in the United States.1 Another form of noninvasive brain stimulation is transcranial direct current stimulation (tDCS). The aim of this paper is to review the application of tDCS in the treatment of depression and its therapeutic possibilities.

Depression and its treatment

MDD is a disorder of high prevalence, many patients experience frequent and disabling relapses of their illness, and there is a significant rate ofmorbidity andmortality. Depression clearly has a highly significant impact on individual patients, health care systems, and society. Despite developments in medication treatments over the last 20 years, a significant percentage of patients, estimated to be approximately 30%, fail to respond to several trials of standard antidepressant medication.2 A substantial proportion of these patients remain depressed for prolonged periods of time with few therapeutic options. Themain treatment option currently available for these patients with “treatment-resistant depression” (TRD), is electroconvulsive therapy (ECT). This is particularly effective in this population, but is complicated by cognitive side effects, need for anesthesia (and the risks of this), and considerable stigma.3 Many patients refuse to have ECT or refuse to have a second course of ECT despite the success of an initial treatment course, due to the development of cognitive side effects. They may also have general concerns about its effects on the brain or concerns related to the widespread stigma associated with ECT. In addition, ECT is not an ideal treatment for patients with a range of medical comorbidities that complicate the administration of multiple general anesthetics. It may also be problematic in pregnancy or the postpartum period if a woman desires to continue breastfeeding an infant. Clearly there is a need to develop alternative depression treatment strategies for this clinical population.

A number of findings from investigative studies into MDD have influenced the development of brain stimulation therapies. One of the early influential findings was that resting blood flow in patients with MDD appears to be reduced in the left DLPFC. This was identified in early positron emission tomography (PET) studies, such as those conducted by George et al.4 This finding directly influenced the development of rTMS protocols using high-frequency stimulation to increase activity in left DLPFC.5 A range of more recent neuroimaging findings, using tasks that produce brain activation either with a cognitive or affective paradigm, do not consistently report a reduction in left prefrontal activity. More commonly, they report overactivity of right dorsolateral prefrontal regions (for example, Figure 1).6,7 This has supported the development of rTMS paradigms applying low-frequency stimulation that reduces brain activity to the right DLPFC.8 There is also a suggestion that targets outside of the frontal cortex may be useful in the treatment of depression with noninvasive brain stimulation.9

Figure 1
Figure 1. Right dorsolateral prefrontal hyperactivity in patients
with depression.

Depressed patients compared with controls during two cognitive tasks (a planning Tower of London (TOL) task and a working memory n-back task). Significant
regions of activation (cluster level threshold PO corr<0.001) comparing patient responses to controls for the pooled data (mean TOL and n-back). Axial slices correspond to z=–16, 20, and 48 mm are shown. Reproduced from reference 7: Fitzgerald et al. Hum Brain Mapp. 2008;29(4):
490-501. © 2008, Wiley-Liss, Inc.

Transcranial direct current stimulation (tDCS)

tDCS is a noninvasive method for the stimulation of the brain, involving the application of a low-amplitude direct electrical current to the brain through stimulating electrodes placed on the scalp ().10 The concept of tDCS has a long historical precedent with descriptions of the use of electrical forms of brain stimulation dating back hundreds, if not thousands, of years. A form of stimulation analogous to contemporary tDCS was first envisaged in the 1950s and 1960s. Early research in animals demonstrated that cortical stimulation (within the cortex or under the scalp surface) with an anode would increase neuronal activity, while cathodal stimulation produced opposite effects (see review in 11). These early studies however, suggested that tDCS effects were not homogenous, and that they may be related to the current’s direction in relationship to the orientation of particular nerve cells.12-14 Since the relative rediscovery of this technique in the last 10 years, there has been a considerable explosion in tDCS research across cognitive neuroscience, neurophysiology, and more recently psychiatry domains. This research has substantially enhanced our understanding of the technique, its neurophysiological effects, and its potential application in neuropsychiatric disorders.

_ Mechanism of action
Contemporary tDCS protocols typically involve the application of a 1 mA or 2 mA direct current (DC) for up to 20 minutes between two surface electrodes. These may vary in size, but are commonly _35cm2 (5×7 cm). The electrodes are placed on the scalp, one serving as the anode and the other as the cathode. Current flows from the anode to the cathode, some being diverted through the scalp and some moving through the brain.15

Figure 2
Figure 2. Eldith transcranial direct current stimulation (tDCS)
stimulator with electrodes. Photo by the author.

Figure 3
Figure 3. Demonstration of frontal transcranial direct current
stimulation (tDCS) in a subject. Photo by the author.

Anodal tDCS typically has an excitatory effect on the local cerebral cortex, probably by depolarizing neurons. The converse applies under the cathode, likely through a process of hyperpolarization (Figure 4).16 The effects of tDCS are often described as subthreshold because stimulation does not result in the specific stimulation of action potentials, but changes the background level of activity and the likelihood that neurons will fire when physiologically stimulated.

Themechanismof action of tDCS has been explored in a number of ways including using the application of various pharmacological agents. For example, sodium and calcium channel blockers eliminate the effects of anodal stimulation, while blocking N-methyl-D-aspartate (NMDA) receptors prevents the long-term effects of tDCS regardless of direction.16 The involvement of ion channels has also been supported by studies of the effects of tDCS on cortical activity. Ardolino et al17 studied the effects of cathodal tDCS on spontaneous neural activity and on motor responses evoked by stimulation of the central and peripheral nervous system.The authors concluded that the aftereffects of tDCS have a nonsynaptic mechanism of action based on changes in neural membrane function. An alternative approach to understanding the effects of tDCS has used a combination of tDCS and transcranial magnetic stimulation (TMS). In these experiments, tDCS stimulation is applied to the motor cortex, and TMS is used to measure motor cortical excitability and cortical inhibition. For example, Nitsche et al14 found that during stimulation, cathodal tDCS reduced intracortical facilitation. Post-stimulation, anodal tDCS increased facilitation and reduced inhibition. The inverse applied for cathodal tDCS. This suggests that tDCS has effects both on inhibitory and excitatory neurons in the cortex, and perhaps the sum effect of stimulation depends on the overall balance of tDCS effects on these individual cell populations. Interestingly, anodal stimulation has been shown to have effects on a TMS paradigm referred to as I-wave facilitation. This paradigm is modulated by gamma-aminobutyric acid (GABA)ergic drugs and ketamine, an NMDA antagonist, but not by ion channel blockers.18,19 This suggests that synaptic pathways, as well as ion channel processes, may be involved in the action of tDCS.

Figure 4
Figure 4. Anodal and cathodal stimulation of motor cortex.
Changes in cortical excitability (measured as the motor evoked potential (MEP)
response to single transcranial magnetic stimulation pulses). Time course of
polarity-specific motor cortex excitability changes outlasting stimulation duration,
shown after 5 min direct current stimulation at 1 mA. MEP amplitudes returned
to baseline within 5 min. Asterisks indicate significant differences between MEP
amplitudes after stimulation and at baseline (two-tailed t test, paired samples,
P<0.05).

Modified from reference 16: Nitsche et al. J Physiol. 2003;533(pt 1):293-301.
© 2003, The Physiological Society.

Interestingly, it has been observed that the effects of tDCS have a number of features in common with other forms of plastic neuronal change. In particular, tDCS effects are depend- ent on stimulation intensity and duration, appear to be intracortical in origin, and to be dependent on NMDA receptor activity.20 In summary, although the immediate effects of tDCS appear to be on changing membrane polarization, this seems to have secondary effects on synaptic activity, altering aspects of neuronal plasticity for some period of time after the stimulation ends.

From a different perspective, the mechanism of action of tDCS has been explored using functional neuroimaging (fMRI) techniques. Functionalmagnetic resonance imaging and PET studies have been conducted looking at the effects of both anodal and cathodal tDCS. However, the results of these studies are predominately focused on motor cortical stimulation, rather than stimulation of brain areas relevant to the treatment of depression, and there has been some inconsistency within the findings. For example, Lang et al21 using PET found that both anodal and cathodal stimulation increased underlying regional blood flow, whereas an earlier fMRI study reported a decrease in activity with cathodal tDCS and no change with anodal stimulation.22

It is notable that we now are aware of a variety of factors that influence the effects of tDCS that need to be taken into account in the design of clinical trials. Clearly, tDCS effects are dependent on whether anodal or cathodal stimulation is applied to the site of interest. It also appears to be the case that the orientation of electrodes in regard to each other may also be important: orientation would affect the direction of the current induced during tDCS. The direction of this current in relationship to the orientation of neuronal components is likely to affect the overall degree of change in cortical excitability produced by the technique. Optimal electrode arrangements have been established for stimulation of motor cortex, but no research has explored the optimal parameters for stimulation of prefrontal regions that are most relevant to depression. There is also very little knowledge about optimal stimulation parameters for producing relevant brain effects, in terms of stimulation intensity and duration. Stimulation in clinical applications is usually provided at either 1 or 2 mA, but there are no substantial comparative studies in clinical groups. The duration of stimulation also varies dramatically from 10 or 20 minutes per day to up to 8 hours per day, with no studies having compared variations in stimulation periods.

_ Safety
There are a number of potential safety issues for consideration in the use of tDCS, and our overall knowledge of the safety of the technique is somewhat limited. The effects of DC stimulation in the brain are determined by the current strength, duration of stimulation, and the size of the stimulated area.23 The total charge applied to the brain is determined by these three factors. Nitsche et al have described safe limits for the total charge of stimulation although these parameters should be still considered somewhat preliminary.23 The majority of currently used protocols, which tend to involve a current between 1 and 2 mA applied for 20 minutes or less to an area between 25 and 35 cm2, typically fall well within these safety guidelines.

A series of studies have attempted to establish the safety of tDCS. For example, tDCS has been shown not to elevate serum neuron specific enolase levels,13 a sensitive marker of neuronal damage, or to induce brain edema or alterations of the blood brain barrier and cerebral tissue detectable by magnetic resonance imaging (MRI).24 These studies have typically involved two electrodes placed on the head, with some concerns raised about the possibility of effects if one electrode it is placed in a noncephalic position.

In regard to side effects of treatment, the most commonly reported issue is an irritation or itching under the electrodes site.25 Skin lesions have been described that are consistent with superficial burning, but it is also possible that these lesions are produced by the shift of electrolytes through the skin during the tDCS procedure (shifts in “dermal equilibrium by DC-iontophoresis under the supraorbital cathode.”26 Headache, fatigue, and nausea have also been reported.25 It has been suggested that electrodes should not be placed above areas where the skull does not have continuous integrity, as this could result in substantial increases in intracranial currents. It is also worth noting that although studies have not yet found substantial safety issues with tDCS, as the methods of administration can vary widely (for example the type of electrode, conducting medium, etc) these will require systematic assessment over time. In addition, long-term safety studies have not been conducted to date.

tDCS in depression: early studies

The first studies that used tDCS in the potential treatment of depression were published between 1964 and the mid-1970s. Application of the technique in depression and other psychiatric disorders stopped for several decades, but was revisited with the conduct of a series of trials in the last 5 years. There are substantial differences in the technologies and experimental protocols applied between the two phases of tDCS research. Perhaps the greatest difference was that the majority of these early studies used bilateral anodal stimulation applied to the frontal area of the brain. A reference electrode was often positioned away from the brain, for example on the knee. The authors often proposed that the effects were through stimulation of the brain stem, and there was no consideration of frontal laterality differences as has driven much of the recent research. A number of the early publications were open-label pilot studies, but several randomized double- blind sham controlled trials were conducted. For example, Costain et al randomized patients to receive 12 days of once-daily stimulation or a sham condition.27 A current of 0.25 mA was used and stimulation was provided for the protracted period of 8 hours per day. Benefits of stimulation were reported by medical observers, but not by patients them selves. A later double-blind trial using similar stimulation parameters did not report any active effects of treatment.28 However, as later pointed out by Carney et al,29 there were significant differences between the characteristics of patients in the two trials. Carney et al argued, supported by their clinical experience in the treatment of 119 patients with the technique (which they called “positive polarization”), that tDCS was most suitable for patients with chronic neurotic or atypical depression not responsive to ECT. Carney et al also described the treatment of a group of patients with persistent hypomania using “negative polarization.”30

Figure 5
Figure 5. Depression symptom response with active DLPFC, and
active occipital or sham tDCS.
Plots showing mood score changes (as indexed by the Hamilton Depression
Rating Scale [HDRS] over time). t0, baseline; t1, immediately after treatment;
t2, 15 days after end of treatment; t3, 30 days after the end of treatment. Each
data-point represents HDRS mean score; error bars indicate standard error of
the mean (SEM).

tDCS in depression: recent research

Interest in the use of tDCS in psychiatry and neurosciences in general was reinvigorated around the year 2000. A series of important studies conducted predominately at Göttingen in Germany demonstrated that tDCS had substantial capacity to change brain activity.12,13 These researchers also conducted a series of studies outlining the effects of a variety of stimulation parameters and explored the safety of the technique. These initial studies have led to a dramatic increase in the use of tDCS in a variety of different applications and cognitive neuroscience, neurology, and psychiatry.11

The first study that truly explored the potential use of tDCS in depression was published by Fregni et al in 2006.31 The authors specifically targeted left DLPFC and applied 5 days of anodal stimulation in 10 patients with major depression (randomized to active or sham). A current of 1 mA was applied for 20 minutes per day on 5 alternating days. Four patients in the active group, but no patients in the sham group, met response criteria and there was a significant difference in the reductions in Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores compared with sham stimulation. The same group then conducted a larger shamcontrolled trial, this time including 40 medication–free patients with major depression.32 They were randomized to either anodal stimulation applied to the DLPFC, anodal stimulation applied to the occipital cortex, or sham tDCS. Ten treatment sessions were applied over 2 weeks, this time at 2 mA for 20 minutes per day. The patients in this study, unlike a number of the rTMS studies being conducted, were not treatmentresistant. A significant improvement in depression was seen in the group that received active stimulation of the DLPFC, but not in the occipital tDCS or sham tDCS groups (Figure 5).

Eight out of 21 patients in the active DLPFC group were considered responders to treatment, compared with 2 patients in the shamand no patients in the occipital tDCS group.The benefit of treatment continued during a 30-day follow-up period.

Rigonatti et al have subsequently compared the response to tDCS in this trial with the response to a 6-week course of fluoxetine at 20 mg per day in a nonrandomized comparison.33 Response tomedication treatment was somewhat slower, but of the same magnitude over time. In both of the initial studies of tDCS depression treatment it was well tolerated, with only mild headaches, itching, and transient skin redness reported as potential side effects.

Several studies have now been published exploring the use of tDCS in depression outside of this original group. Ferrucci et al treated 14 inpatients with severe major depression who had been referred for ECT, with left DLPFC tDCS applied at 2 mA, for 20 minutes twice a day for a total of 5 days.34 Treatment produced a 30% reduction in depression rating scale scores, which persisted up to 4 weeks post-treatment. Attention and verbal working memory were assessed and these did not change across the treatment period. Treatment was well tolerated, without adverse events.

Another group evaluated tDCS with a double-blind randomized study including 40 outpatients with depression. Treatment was provided for five treatment sessions, 3 days per week.35 Anodal stimulation was provided to the left DLPFC at 1 mA for 20 minutes. Depression scores improved, but there was no difference between active and sham stimulation. There was no evidence of any impairment in cognitive performance produced by tDCS assessed across a range of cognitive functions. One patient committed suicide during the trial, but there was no suggestion that this was related to the experimental treatment. Side effects included skin redness, itching, or tingling at the electrode sites, headache, lightheadedness, and visual changes. Transient hypomania was seen in 1 patient.

It is worth commenting on the method used for the provision of sham treatment in these studies. Most of the clinical trials of tDCS have utilized a sham design where stimulation is turned on as with active treatment, increased to full stimulation intensity, and then turned off after a short period, usually 30 seconds. This is proposed to mimic the initial onset of skin tingling produced with active tDCS, which dissipates rapidly in a substantial proportion of patients, though not all. Integrity of blinding was assessed in the study by Loo et al and appeared to be robust.35

Conclusions

tDCS is a technique for noninvasive brain stimulation that is currently undergoing a period of intensive research and development. There is clear evidence from the neuroscientific studies conducted on tDCS to date that it has substantial capacity to modulate brain activity, most likely through a mixture of nonsynaptic and synaptic mechanisms. This capacity appears to be accompanied by an ability of the technique to modulate a range of brain functions. For example, tDCS has been shown to modulate working memory and other forms of perception and cognition.11

It is less clear what the use of tDCS will prove to be in the treatment of depression. Depression involves a complex network of brain regions where there is aberrant activity. Some of these regions, such as the DLPFC, are potentially amenable to modulation with noninvasive brain stimulation. However, it is difficult to draw firm conclusions from the research applying tDCS in the treatment of depression to date. This applies most strongly to the early studies, as methodological differences in application of the technique have evolved over time. In regard to the recent series of clinical trials, there is certainly promise in the published data to date. However, antidepressant effects of tDCS have not robustly been demonstrated outside of the group that originally published this application. Considering experience with the development of other noninvasive brain stimulation techniques such as rTMS, it is also likely that these initial trials were using doses and treatment durations likely to prove suboptimal. Initial rTMS trials provided 1 week of treatment, but longer periods of stimulation have clearly been shown to have greater and more beneficial effects.1 This may well prove to be the case with tDCS. In addition, it will be critical for future research to define the optimal patient group for this technique. Patients included in several of the trials to date have not been treatment resistant, unlike many of the trials of rTMS. However, if tDCS can be shown to have antidepressant effects in the general population of patients with depression, given its low cost and simple implementation, it may well prove to be a useful treatment in broad patient populations in areas of the world that do not have access to modern pharmaceutical treatments, or other forms of brain stimulation.

PBF is supported by a NHMRC Practitioner Fellowship. He has received equipment for research in the last two years from Brainsway Ltd and MagVenture A/S.

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Keywords: depression; transcranial direct current stimulation; prefrontal cortex; rTMS