Augmenting transcranial direct current stimulation with (D)-cycloserine for depression: a pilot study.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that causes changes in cortical excitability. Recent double-blind placebo-controlled clinical trials suggest that tDCS may be efficacious in the treatment of depression. Pharmacological agents that prolong the effects of tDCS could lead to greater cumulative changes in cortical excitability, producing greater and more prolonged efficacy. One agent shown to prolong the excitability-enhancing effects of tDCS in healthy subjects is D-Cycloserine, a partial agonist at the glycine-binding site of N-methyl-D-aspartate receptors. We investigated whether combining prefrontal tDCS with D-Cycloserine could enhance and/or prolong the antidepressant effect of tDCS. METHODS: Five depressed subjects who had relapsed or failed to achieve remission after receiving a previous course of prefrontal tDCS were recruited. In this open-label pilot study, subjects ingested 100-mg D-Cycloserine 2 hours before tDCS sessions. Subjects received 20 minutes of tDCS at 2 mA on consecutive weekdays for a total of 20 sessions. The anode was placed at pF3 and the cathode at F8 (10/20 system). Clinical response was assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: The change in Montgomery-Åsberg Depression Rating Scale scores was not greater with the combination of D-Cycloserine and tDCS than had previously been produced by tDCS alone. No significant additional adverse effects were reported. CONCLUSIONS: This pilot open-label study found that pretreatment with 100-mg D-Cycloserine 2 hours before tDCS was well tolerated but did not enhance the antidepressant efficacy of anodal prefrontal tDCS.

Can transcranial direct current stimulation enhance outcomes from cognitive training? A randomized controlled trial in healthy participants.

Computer-administered cognitive training (CT) tasks are a common component of cognitive remediation treatments. There is growing evidence that transcranial direct current stimulation (tDCS), when given during cognitive tasks, improves performance. This randomized, controlled trial explored the potential synergistic effects of CT combined with tDCS in healthy participants. Altogether, 60 healthy participants were randomized to receive either active or sham tDCS administered during training on an adaptive CT task (dual n-back task), or tDCS alone, over 10 daily sessions. Cognitive testing (working memory, processing speed, executive function, reaction time) was conducted at baseline, end of the 10 sessions, and at 4-wk follow-up to examine potential transfer effects to non-trained tasks. Altogether, 54 participants completed the study. Over the 10 'online' sessions, participants in the active tDCS+CT condition performed more accurately on the CT task than participants who received sham tDCS+CT. The performance enhancing effect, however, was present only during tDCS and did not result in greater learning (i.e. improvement over sessions) on the CT task. These results confirm prior reports of enhancement of cognitive function during tDCS stimulation. At follow-up, the active tDCS+CT group, but not the sham tDCS+CT group, showed greater gains on a non-trained test of attention and working memory than the tDCS-only group (p < 0.01). Although this gain can mainly be attributable to training, this result suggests that active tDCS may have a role in further enhancing outcomes.

Transcranial direct current stimulation (tDCS) for depression: analysis of response using a three-factor structure of the Montgomery-Åsberg depression rating scale.

BACKGROUND: There is growing evidence that transcranial direct current stimulation (tDCS) may be an effective treatment for depression. However, no study to date has profiled the antidepressant effects of tDCS using items or factors on depression symptom severity rating scales. This could potentially provide information about the mechanisms by which tDCS achieves its antidepressant effects and also identify clinical predictors of response. METHODS: The present study analysed scores on the Montgomery-Åsberg depression rating scale (MADRS) from a randomised, sham-controlled trial of tDCS (Loo et al., 2012. British Journal of Psychiatry. 200, 52-59) using a three-factor model of MADRS items (Suzuki et al., 2005. Depression and Anxiety. 21, 95-97) encompassing dysphoria, retardation and vegetative symptoms. RESULTS: Participants in the active tDCS treatment group showed significant improvement in dysphoria while participants in the sham treatment group did not. While both groups showed improvement in retardation symptoms, improvement was significantly greater in the active tDCS group. Both groups also showed improvement in vegetative symptoms but there were no between-group differences. LIMITATIONS: Further studies with larger sample sizes are warranted to investigate the generalisability of results and whether the MADRS factor structure may change as a result of the specific treatment used. CONCLUSIONS: tDCS appears to be particularly effective in treating dysphoria and retardation, but not vegetative symptoms of depression. This may have implications for selection of types of depression most likely to respond to this treatment.

Anodal transcranial direct current stimulation increases brain intracellular pH and modulates bioenergetics.

Transcranial direct current stimulation is an emerging treatment for brain disorders but its mode of action is not well understood. We applied 10 min 1 mA anodal transcranial direct current stimulation (tDCS) inside the bore of a 3 T MRI scanner to the left dorsolateral prefrontal cortex of 13 healthy volunteers (aged 19-28 yr) in a blinded, sham-controlled, cross-over design. Brain bioenergetics were measured from the left temporo-frontal region using 31P magnetic resonance spectroscopy before, during and for 20 min following tDCS. Brain pH rose during tDCS and remained elevated afterwards. Phosphomonoesters were significantly decreased while inorganic phosphate (Pi) also fell. Partial-least squares discriminant analysis of the data revealed two significantly different subject groups: one where phosphocreatine (PCr), ATP and Pi fell along with a larger increase in pH and one where PCr and ATP increased along with a smaller increase in pH and a slower and more sustained decrease in Pi. Group membership was predicted by baseline pH and ATP. We interpreted the effects of tDCS as driving two biochemical processes: cellular consumption of ATP causing hydrolysis of PCr via the creatine kinase reaction driving the increase in pH; synthesis of ATP and PCr by mitochondria with concomitant drop in Pi and phosphomonoester levels.

Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial.

BACKGROUND: Preliminary evidence suggests transcranial direct current stimulation (tDCS) has antidepressant efficacy. AIMS: To further investigate the efficacy of tDCS in a double-blind, sham-controlled trial (registered at www.clinicaltrials.gov: NCT00763230). METHOD: Sixty-four participants with current depression received active or sham anodal tDCS to the left prefrontal cortex (2 mA, 15 sessions over 3 weeks), followed by a 3-week open-label active treatment phase. Mood and neuropsychological effects were assessed. RESULTS: There was significantly greater improvement in mood after active than after sham treatment (P<0.05), although no difference in responder rates (13% in both groups). Attention and working memory improved after a single session of active but not sham tDCS (P<0.05). There was no decline in neuropsychological functioning after 3-6 weeks of active stimulation. One participant with bipolar disorder became hypomanic after active tDCS. CONCLUSIONS: Findings confirm earlier reports of the antidepressant efficacy and safety of tDCS. Vigilance for mood switching is advised when administering tDCS to individuals with bipolar disorder.

Fronto-extracephalic transcranial direct current stimulation as a treatment for major depression: an open-label pilot study.

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 < 0.001). Participants showed greater initial treatment response with F-EX tDCS than with BF tDCS (p < 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.

Hypomania induction in a patient with bipolar II disorder by transcranial direct current stimulation (tDCS).

OBJECTIVES: To report a case of hypomania induced by transcranial direct current stimulation (tDCS) given with an extracephalic reference electrode. Transcranial direct current stimulation is a noninvasive brain stimulation technique in which a weak current is applied through the scalp to produce changes in neuronal excitability in the underlying cerebral tissue. Recent clinical trials have shown promising results with left anodal prefrontal tDCS in treating depression. When the reference cathodal electrode in tDCS is moved from the cranium to an extracephalic position, larger areas of both cerebral hemispheres are stimulated, with potential implications for both efficacy and safety. METHODS: We report the case of a 33-year-old female with bipolar II disorder, on mood stabilizer medication, who had previously participated in a clinical trial of tDCS given with a bifrontal electrode montage for the treatment of major depression without incident, but became hypomanic when she received a later course of tDCS given with a frontoextracephalic configuration. Factors contributing to the development of hypomania in the second course of tDCS are examined. RESULTS: No substantial differences were found in the patient's clinical presentation between the 2 tDCS courses to explain the emergence of hypomania only after the second course. The different montage used in the second course appeared to be the main contributory factor in the induction of hypomania. CONCLUSIONS: The reported case suggests that frontoextracephalic tDCS has antidepressant properties and the potential to induce hypomanic symptoms. In particular, it raises the question of whether frontoextracephalic tDCS requires additional precautions when administered to bipolar patients compared to bifrontal tDCS.

A double-blind, sham-controlled trial of transcranial direct current stimulation for the treatment of depression.

Two recent sham-controlled studies found that transcranial direct current stimulation (tDCS) was an effective treatment for depression. As tDCS is painless, relatively safe and inexpensive, its efficacy in treating depression warrants further investigation. This double-blind, randomized study tested tDCS at the same stimulation parameters as a previous positive study (1 mA current strength, five treatment sessions, active or sham, given on alternate days) in 40 depressed participants. Anodal stimulation was centred over the left dorsolateral prefrontal cortex, with the cathode placed on the lateral aspect of the contralateral orbit. tDCS was continued up to a total of ten active sessions per participant. Mood outcomes were measured by psychiatrist raters blind to treatment condition using the Montgomery-Asberg and other depression rating scales. Psychomotor speed was assessed immediately before and after a single tDCS session and attention, frontal executive function, working memory and verbal learning were assessed after each group of five sessions. Overall depression scores improved significantly over ten tDCS treatments, but there was no between-group difference in the five-session, sham-controlled phase. tDCS was found to be safe, with no adverse effects on neuropsychological function, and only minor side-effects. It is recommended that the efficacy of tDCS in depression be further evaluated over a longer treatment period, using enhanced stimulation parameters.