Journal of Affective Disorders 134 (2011) 459–463
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Journal of Affective Disorders j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j a d
Brief report
Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: An open-label pilot study Donel M. Martin a, Angelo Alonzo a, Philip B. Mitchell a, Perminder Sachdev b, c, Verònica Gálvez d, e, f, Colleen K. Loo a, g,⁎ a
Black Dog Institute, School of Psychiatry, University of New South Wales, Sydney, Australia School of Psychiatry, University of New South Wales, Sydney, Australia c Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, Australia d Visiting Academic, School of Psychiatry, University of New South Wales, Sydney, Australia, Black Dog Institute, Sydney, Australia e Mood Disorders Clinical and Research Unit, Psychiatry Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain f Neuroscience Group, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain g St George Hospital, South Eastern Sydney Health, Sydney, Australia b
a r t i c l e
i n f o
Article history: Received 23 December 2010 Received in revised form 5 May 2011 Accepted 5 May 2011 Keywords: Transcranial direct current stimulation Depression Montage Effectiveness Safety
a b s t r a c t Background: Several recent trials have reported transcranial direct current stimulation (tDCS) to be effective in treating depression, though the relative benefits of different electrode montages remain unexplored. Whereas all recent studies have used a bifrontal (BF) electrode montage, studies published in the 1960s and 1970s placed one electrode in an extracephalic position, with some positive reports of efficacy. This study investigated the efficacy and safety of tDCS given with a fronto-extracephalic (F-EX) montage. Methods: 2 mA tDCS was administered for 20 min every weekday over four weeks in 11 participants with a Major Depressive Episode who had previously shown inadequate response to, or relapsed following, a course of BF tDCS. For F-EX tDCS the anode was placed on the left dorsolateral prefrontal cortex and the cathode on the right upper arm. Depression severity and neuropsychological function were assessed before and after the treatment course. Antidepressant response was compared across an equivalent treatment period for both montages. Results: F-EX tDCS was shown to be safe and well tolerated. Depression ratings improved after acute treatment on the Montgomery Åsberg Depression Rating Scale (p b 0.001). Participants showed greater initial treatment response with F-EX tDCS than with BF tDCS (p b 0.001). Limitations: This was an open label pilot study. The two comparison treatments were applied consecutively. Conclusion: F-EX tDCS appears to be safe and to have antidepressant effects, and may lead to more rapid improvement than tDCS given with a BF montage. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Transcranial direct current stimulation (tDCS) is attracting widespread attention as a promising new treatment for Major
⁎ Corresponding author at: Black Dog Institute, Prince of Wales Hospital, Barker St, Randwick, 2031, Australia. Tel.: + 61 2 9382 3721; fax: + 61 2 9382 8208. E-mail address:
[email protected] (C.K. Loo). 0165-0327/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2011.05.018
Depressive Disorder (MDD) on the basis of its low cost, good safety profile and promising reports of efficacy (ArulAnandam and Loo, 2009; Boggio et al. 2008; Fregni et al. 2006; Nitsche et al., 2008; Priori et al., 2009). tDCS is a non-invasive technique which involves the passing of a very weak direct electrical current through the cerebral cortex using electrodes placed upon the scalp. Several minutes of stimulation can induce changes in cortical excitability which persists for over an hour (Nitsche et al.,
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2003; Nitsche and Paulus, 2001). The direction of these excitability changes differs with the polarity of the stimulating electrode, with activation reported after anodal stimulation and inhibition after cathodal stimulation (Nitsche and Paulus, 2000). Cortical activation is further dependent on factors such as electrode size, shape, and position (Bikson et al., 2008). These stimulus parameters are therefore important when using tDCS as a therapeutic treatment. Early studies which investigated tDCS as a treatment for depression tended to use electrode montages consisting of two anodes positioned over the frontal cortex and a cathode placed extracephalically for stimulation across the brainstem (for review see Arul-Anandam and Loo, 2009). However, recent studies have used an alternative approach using a bifrontal (BF) montage for more focal frontal stimulation, with an anode placed over the left dorsolateral prefrontal cortex (LDLPFC) and a cathode located over the contralateral supraorbital region (Boggio et al., 2008; Fregni et al., 2006; Loo et al., 2010). The premise for this montage is based upon empirical pathophysiological findings in MDD (Mayberg, 2003), and findings from transcranial magnetic stimulation showing antidepressant efficacy with LDLPFC stimulation (Schutter, 2009). Structural and functional imaging studies, however, have implicated additional frontal (i.e., ventrolateral, ventromedial, orbitofrontal, and anterior cingulate), subcortical (i.e., amygdala, hippocampus, and basal ganglia) and other brain regions (e.g., cerebellum) in the pathophysiology of depression (Davidson et al., 2002; Fitzgerald et al., 2008; Phillips et al., 2003). Studies of antidepressant medications have further shown that treatment response is associated with reciprocal limbic–paralimbic and striatal decreases and dorsal cortical increases in glucose metabolism (Kennedy et al., 2001; Kennedy et al., 2007). These empirical findings therefore suggest that tDCS modulation of broader cerebral regions may be more effective in ameliorating depressive symptomatology. Computer modelling studies have shown that placing one electrode on the frontal cortex and the other extracephalically results in much more widespread activation of brain regions than placing both electrodes frontally (Bikson et al., 2008; Miranda et al., 2006; Wagner et al., 2007). Increasing the inter-electrode distance also reduces current shunting across the scalp, thus increasing the proportion of current entering the brain (Miranda et al., 2006). Based on these findings we hypothesised that using an extracephalic cathode would result in increased modulation of frontal and subcortical networks, leading to greater antidepressant efficacy. In an open label pilot study, antidepressant effects and safety of tDCS given with a fronto-extracephalic (F-EX) electrode montage were examined. Treatment outcomes were then compared with BF tDCS, given over a comparable treatment period at the same electrical stimulus parameters in an earlier trial involving the same participants.
In the BF tDCS trial, participants had received active or sham tDCS, given every weekday for three weeks, and continued with open-label tDCS for a further three weeks. Mood was assessed using the Montgomery Åsberg Depression Rating Scale (MADRS; Montgomery and Åsberg, 1979), rated by a psychiatrist or psychologist who was blinded to treatment condition, at baseline and after 8 and 15 treatments. In this BF trial, eight participants had failed to show a significant clinical response after three weeks of treatment (defined as a 50% reduction in MADRS scores from baseline), and three had relapsed after responding to BF tDCS. Eight participants had received active BF tDCS treatment during the placebo-controlled phase and three during open-label treatment. The mean interval between receiving BF tDCS and entering the F-EX tDCS trial was 6.9 ± 5.0 (range 0.5–16) months. Identical selection and exclusion criteria were implemented in both studies. All participants (9 unipolar and 2 bipolar) met the DSM-IV criteria for a Major Depressive Episode (MDE) as assessed by the Mini International Neuropsychiatric Interview (Sheehan et al., 1998) and confirmed by study psychiatrists (C.K.L. and V.G.), and had a score of ≥20 on the MADRS. Treatment resistance was gauged using the Maudsley Staging Method (MSM; Fekadu et al., 2009). Exclusion criteria included drug or alcohol abuse or dependence, other Axis-1 disorders, neurological disorders, or failure to respond to electroconvulsive therapy in the current MDE. Participants were either medication free or remained on stable doses of antidepressant medications to which they had failed to respond after an adequate trial of at least four weeks at effective doses. In the BF tDCS study, five participants were on antidepressant medications. The same participants and one additional participant were on antidepressant medications in the F-EX tDCS study. Both studies were approved by the Human Research Ethics Committee of the University of New South Wales. Written informed consent was obtained from all participants prior to commencement of each study. 2.2. tDCS
2. Methods
Participants received open label active F-EX tDCS treatment over 20 consecutive weekdays. Sessions were given every weekday rather than second daily, in line with a recent study suggesting this may optimise stimulation outcomes (Alonzo et al., in press). tDCS was given continuously for 20 min at 2 mA using an Eldith DC-stimulator (NeuroConn GmbH, Germany). A 7 × 5 cm anodal electrode was placed over the LDLPFC, identified as the pF3 site on the 10/20 EEG system. For the F-EX montage, a 10 × 10 cm cathodal electrode was placed over the right upper arm, and for the BF montage a 7 × 5 cm cathode was placed over the contralateral orbit (F8 on the 10/20 system). Electrodes were made of conductive rubber and were covered by sponges soaked in saline and held in place by rubber bands. Current was gradually ramped up and down over 30 s. The safety procedure utilised during stimulation was as previously described (Loo et al., 2011).
2.1. Participants
2.3. Depression ratings
This pilot study involved 11 participants who had previously participated in a double-blind, placebo-controlled clinical trial investigating BF tDCS as a treatment for major depression.
The primary depression outcome measure was the MADRS. Secondary outcome measures included the Inventory of Depressive Symptomatology (IDS; Rush et al. 1986, 1996),
D.M. Martin et al. / Journal of Affective Disorders 134 (2011) 459–463
Clinician Global Impression-Severity of Illness Scale (CGI-S; Guy, 1976), and the self-rated versions of the Quick Inventory of Depressive Symptoms (QIDS-SR; Rush et al. 2003), and MADRS (MADRS-SR; Svanborg and Åsberg, 1994). Participants were rated by the same psychiatrist or psychologist at baseline and after treatments 8, 15, and 20. Seven participants had the same rater in both studies. Raters were aware that treatment was given on an open label basis in the F-EX study. 2.4. Neuropsychological assessment Neuropsychological functioning was assessed at baseline and after 20 treatment sessions using the following tests chosen to examine specific effects on memory and frontal lobe functions: Rey Auditory Verbal Learning Test (RAVLT; Rey, 1964), Digit Span (Wechsler, 1981), Letter Number Sequencing (Wechsler, 1997), Stroop Test (Regard, 1981), and Controlled Oral Word Association Test (COWAT; Benton and Hamsher, 1989). Acute effects of tDCS were assessed pre and post treatments 1 and 20 by administration of the Symbol Digit Modalities Test (SDMT; Smith, 1991) and simple and choice reaction-time (RT) tests. Alternative forms were used for the RAVLT, COWAT, and SDMT to help reduce practise effects. 2.5. Data analysis 2.5.1. F-EX study All mood ratings and neuropsychological test scores were analysed for change over the four weeks of treatment with repeated measures analyses of variance (ANOVAs) testing for main effect of time. For the neuropsychological outcomes, percentage change in MADRS ratings from baseline was entered as a covariate to control for mood effects. Acute cognitive changes at treatments 1 and 20 were also examined using repeated measures ANOVAs testing for main effects of time. Pearson's correlations examined potential associations between the time interval between studies and change in mood at each post baseline rating. 2.5.2. Comparison with BF tDCS study Potential differences in mood response due to different electrode montages, as assessed by MADRS scores, were examined using a fully repeated measures ANOVA testing for an interaction effect between time and electrode montage over the first three weeks of treatment in both studies. 3. Results 3.1. F-EX study Participants had a mean age of 46.7 (SD ± 13.1) years and 73% were female. The average duration of current MDE prior to receiving F-EX tDCS was 23.2 ± 26.6 months. Mean MSM scores were 7.6 ± 2.5 (i.e., moderate treatment resistance), mean total failed antidepressants in the current episode was 2.64 ± 2.54, and mean number of previous episodes was 7.95 ± 10.9. One participant with bipolar depression was withdrawn from the F-EX study after 14 treatment sessions due to the onset of hypomania (see Galvez et al., 2011).
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The results for depressive and neuropsychological outcomes are presented in Table 1. For all depression outcomes, results showed a significant main effect of time (p b 0.01). The average change in scores on the MADRS rating scale was 43.8% after four weeks of acute treatment. For the neuropsychological outcomes there was no significant main effect of time across the treatment period on any measure. For tests of acute effects, there was a significant main effect of time on the simple RT test following treatment 1, indicating slower RTs post treatment (F(1,9) = 7.55, p = 0.023). For the other tests of acute effects at treatment 1 and 20 the main effect of time was nonsignificant. 3.2. Comparison with BF tDCS study Participants' responses to the different electrode montages in the studies described above are shown in Fig. 1. Individual responses to F-EX tDCS are shown in Fig. 2. The repeated measures ANOVA revealed a significant interaction effect between time and electrode montage, with a quadratic trend (F(1,9) = 32.1, p b 0.001). For both studies after three weeks of treatment no participants met the criteria for remission (i.e., MADRS ≤ 10); two of the eight participants who had failed to respond (i.e., N50% reduction in MADRS scores from baseline) to BF tDCS, however, subsequently responded to F-EX tDCS. Results of the correlation analyses showed no significant associations between time interval between studies and change in mood (p's N 0.05). 4. Discussion This open-label pilot study found that F-EX tDCS administered across 20 daily treatment sessions was an effective and safe antidepressant treatment. On average, MADRS scores
Table 1 Depression and neuropsychological test scores. Baseline
Post 20
Variables
M (SD)
M (SD)
F
df
P
MADRS IDS-C CGI-S QIDS-SR MADRS-SR RAVLT total a RAVLT delay a Digit Span forwards a Digit Span backwards a Letter Number Sequencing a STROOP interference (sec) a COWAT total words a
31.0 33.6 4.50 19.0 13.9 59.9 12.2 11.3 8.50 12.1
17.0 20.0 3.10 10.1 6.70 61.1 12.5 11.6 8.80 11.6
(6.07) (7.19) (0.74) (5.12) (3.13) (12.8) (2.99) (3.37) (2.86) (4.09)
34.2 12.7 40.1 14.3 26.1 0.53 1.79 2.26 0.34 0.96
9 8 9 9 9 8 8 8 8 8
b 0.001 0.007 b 0.001 0.004 0.001 0.488 0.218 0.171 0.576 0.355
22.7 (14.3)
20.4 (12.2)
0.83
7
0.392
43.9 (22.3)
46.7 (17.0)
1.55
8
0.248
(6.55) (9.66) (0.71) (6.08) (4.15) (11.0) (2.70) (3.20) (3.75) (4.23)
MADRS — Montgomery Åsberg Depression Rating Scale; IDS-C — Inventory of Depressive Symptoms-Clinician rated; CGI-S — Clinical Global ImpressionSeverity of Illness Scale; QIDS-SR — Quick Inventory of Depressive Symptoms-Self Rated; MADRS-SR — Montgomery Åsberg Depression Rating Scale-Self Rated; RAVLT — Rey Auditory Verbal Learning Task; COWAT — Controlled Oral Word Association Test. a Indicates analysis covaried for percentage change in MADRS score from baseline at post 20.
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Fig. 1. Comparison of depression outcomes between different electrode placements.MADRS — Montgomery Åsberg Depression Rating Scale. Bifrontal tDCS indicates 2 mA transcranial direct current stimulation using a standard bifrontal electrode montage. Fronto-extracephalic tDCS indicates 2 mA transcranial direct current stimulation using a fronto-extracephalic electrode montage.
were reduced by 43.8% over the treatment course. These results are consistent with previous clinical and open-label trials which also used an extracephalic cathode (Baker, 1970; Costain et al., 1964; Lippold and Redfearn, 1964; Redfearn et al., 1964). Despite using substantially higher stimulus parameters than hitherto reported in studies using an extracephalic cathode, and theoretical concerns about cardiorespiratory risks associated with stimulating across the brainstem or heart nerve (Nitsche et al., 2008), no adverse effects were noted apart from the induction of hypomania in one participant. As this participant had not previously become hypomanic with BF tDCS, we have speculated elsewhere that the F-EX montage may be more likely to induce mania due to stimulation of deeper, limbic brain regions (Galvez et al., 2011). Comparison of depression outcomes between F-EX tDCS and BF tDCS within the same participants revealed that F-EX tDCS produced a more rapid response over a three week
treatment period. Two participants who had not responded to treatment with BF tDCS subsequently responded to F-EX tDCS. No associations were found between time interval between studies and antidepressant efficacy in the F-EX study, indicating that it was unlikely that the first course of BF tDCS had a priming effect on the subsequent F-EX tDCS course. Together these findings suggest that tDCS using a F-EX electrode montage may potentially be more effective than BF tDCS in treating major depression. It is plausible that a F-EX montage could induce greater antidepressant effects by more widespread, direct activation of limbic areas associated with the pathophysiology of depression, including the anterior cingulate, superior temporal gyrus, insula, and basal ganglia (Bikson et al., 2008). There are a number of limitations to this study. Treatment and ratings were done on an open label basis in the F-EX tDCS study, but under placebo-controlled, double-blind conditions for eight of the 11 participants in the BF tDCS study. The participants who received BF tDCS during the double-blind phase may therefore have had lesser expectations of improvement. BF and F-EX tDCS were not given in randomised order, and the time period between treatment courses was not standardised. In conclusion, this study found that tDCS given with a F-EX montage was safe and effective in treating depression, and possibly more potent than tDCS given with a BF montage. This treatment approach needs to be formally compared with BF tDCS in future randomised studies. Future studies are required to further examine the potential efficacy of other alternative electrode montages, treatment frequencies, and tDCS stimulus parameters. Role of funding source This study was supported by an Australian National Health and Medical Research Council (NHMRC) Project Grant, no. 510142. The NHMRC had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest All authors report no conflict of interest. Acknowledgements We would like to acknowledge Michael Player, Jessica Cheung, Vincent Chan, and Joshua Garfield for their assistance with this research.
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Fig. 2. Individual depression outcomes across the F-EX tDCS treatment course. MADRS — Montgomery Åsberg Depression Rating Scale.
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