Kerrie-Anne Ho

A computational modelling study of transcranial direct current stimulation montages used in depression.

Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which involves passing a mild electric current to the brain through electrodes placed on the scalp. Several clinical studies suggest that tDCS may have clinically meaningful efficacy in the treatment of depression. The objective of this study was to simulate and compare the effects of several tDCS montages either used in clinical trials or proposed, for the treatment of depression, in different high-resolution anatomically-accurate head models. Detailed segmented finite element head models of two subjects were presented, and a total of eleven tDCS electrode montages were simulated. Sensitivity analysis on the effects of changing the size of the anode, rotating both electrodes and displacing the anode was also conducted on selected montages. The F3-F8 and F3-F4 montages have been used in clinical trials reporting significant antidepressant effects and both result in relatively high electric fields in dorsolateral prefrontal cortices. Other montages using a fronto-extracephalic or fronto-occipital approach result in greater stimulation of central structures (e.g. anterior cingulate cortex) which may be advantageous in treating depression, but their efficacy has yet to be tested in randomised controlled trials. Results from sensitivity analysis suggest that electrode position and size may be adjusted slightly to accommodate other priorities, such as skin discomfort and damage.

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

BACKGROUND Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. OBJECTIVES Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. METHODS Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. RESULTS ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). CONCLUSIONS Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments.

Continuation transcranial direct current stimulation for the prevention of relapse in major depression.

BACKGROUND Transcranial direct current stimulation (tDCS) is gaining attention as an effective new treatment for major depression. Little is known, however, of the duration of antidepressant effects following acute treatment. In this study, we describe the use of continuation tDCS treatment for up to 6 months following clinical response to an acute treatment course. METHODS Twenty-six participants pooled from two different studies involving different tDCS protocols received continuation tDCS treatment on a weekly basis for 3 months and then once per fortnight for the final 3 months. Mood ratings were completed at 3 and 6 months. Analyses examined clinical predictors of relapse during continuation tDCS treatment. RESULTS The cumulative probability of surviving without relapse was 83.7% at 3 months and 51.1% at 6 months. Medication resistance was found to be a predictor of relapse during continuation tDCS. LIMITATIONS This was an open label prospective study with no control group. Two different forms of tDCS were used. CONCLUSION Similar to other antidepressant treatments, continuation tDCS appears to be a useful strategy to prevent relapse following clinical response. These preliminary data suggest that the majority of patients maintained antidepressant benefit with a continuation schedule of at least weekly treatment. Future controlled studies are required to confirm these findings.

A pilot study of alternative transcranial direct current stimulation electrode montages for the treatment of major depression

BACKGROUND Typically, transcranial direct current stimulation (tDCS) treatments for depression have used bifrontal montages with anodal (excitatory) stimulation targeting the left dorsolateral prefrontal cortex (DLPFC). There is limited research examining the effects of alternative electrode montages. OBJECTIVE/HYPOTHESIS This pilot study aimed to examine the feasibility, tolerability and safety of two alternative electrode montages and provide preliminary data on efficacy. The montages, Fronto-Occipital (F-O) and Fronto-Cerebellar (F-C), were designed respectively to target midline brain structures and the cerebellum. METHODS The anode was placed over the left supraorbital region and the cathode over the occipital and cerebellar region for the F-O and F-C montages respectively. Computational modelling was used to determine the electric fields produced in the brain regions of interest compared to a standard bifrontal montage. The two montages were evaluated in an open label study of depressed participants (N=14). Mood and neuropsychological functioning were assessed at baseline and after four weeks of tDCS. RESULTS Computational modelling revealed that the novel montages resulted in greater activation in the anterior cingulate cortices and cerebellum than the bifrontal montage, while activation of the DLPFCs was higher for the bifrontal montage. After four weeks of tDCS, overall mood improvement rates of 43.8% and 15.9% were observed under the F-O and F-C conditions, respectively. No significant neuropsychological changes were found. LIMITATIONS The clinical pilot was open-label, without a control condition and computational modelling was based on one healthy participant. CONCLUSIONS Results found both montages safe and feasible. The F-O montage showed promising antidepressant potential.

Neuromodulation Therapies for Geriatric Depression

Depression is frequent in old age and its prognosis is poorer than in younger populations. The use of pharmacological treatments in geriatric depression is limited by specific pharmacodynamic age-related factors that can diminish tolerability and increase the risk of drug interactions. The possibility of modulating cerebral activity using brain stimulation techniques could result in treating geriatric depression more effectively while reducing systemic side effects and medication interactions. This may subsequently improve treatment adherence and overall prognosis in the older patient. Among clinically available neuromodulatory techniques, electroconvulsive therapy (ECT) remains the gold standard for the treatment of severe depression in the elderly. Studies have proven that ECT is more effective and has a faster onset of action than antidepressants in the treatment of severe, unipolar, geriatric depression and that older age is a predictor of rapid ECT response and remission. The application of novel and more tolerable forms of ECT for geriatric depression is currently being examined. Preliminary results suggest that right unilateral ultrabrief ECT (RUL-UB ECT) is a promising intervention, with similar efficacy to brief-pulse ECT and fewer adverse cognitive effects. Overall findings in repetitive transcranial magnetic stimulation (rTMS) suggest that it is a safe intervention in geriatric depression. Higher rTMS stimulation intensity and more treatments may need to be given in the elderly to achieve optimal results. There is no specific data on vagus nerve stimulation in the elderly. Transcranial direct current stimulation, magnetic seizure therapy and deep brain stimulation are currently experimental, and more data from geriatric samples is needed.

Clinical Pilot Study and Computational Modeling of Bitemporal Transcranial Direct Current Stimulation, and Safety of Repeated Courses of Treatment, in Major Depression.

Objectives This study aimed to examine a bitemporal (BT) transcranial direct current stimulation (tDCS) electrode montage for the treatment of depression through a clinical pilot study and computational modeling. The safety of repeated courses of stimulation was also examined. Methods Four participants with depression who had previously received multiple courses of tDCS received a 4-week course of BT tDCS. Mood and neuropsychological function were assessed. The results were compared with previous courses of tDCS given to the same participants using different electrode montages. Computational modeling examined the electric field maps produced by the different montages. Results Three participants showed clinical improvement with BT tDCS (mean [SD] improvement, 49.6% [33.7%]). There were no adverse neuropsychological effects. Computational modeling showed that the BT montage activates the anterior cingulate cortices and brainstem, which are deep brain regions that are important for depression. However, a fronto-extracephalic montage stimulated these areas more effectively. No adverse effects were found in participants receiving up to 6 courses of tDCS. Conclusions Bitemporal tDCS was safe and led to clinically meaningful efficacy in 3 of 4 participants. However, computational modeling suggests that the BT montage may not activate key brain regions in depression more effectively than another novel montage—fronto-extracephalic tDCS. There is also preliminary evidence to support the safety of up to 6 repeated courses of tDCS.

Comparison of the effects of transcranial random noise stimulation and transcranial direct current stimulation on motor cortical excitability.

Objective The objective of this study was to examine the effect of transcranial random noise stimulation (tRNS) with and without a direct current (DC) offset on motor cortical excitability and compare results to transcranial DC stimulation (tDCS). Methods Fifteen healthy participants were tested in a within-subjects design. Motor-evoked potentials were measured before and up to 90 minutes after stimulation using transcranial magnetic stimulation. Five stimulation conditions were examined: sham, 1-mA tDCS, 2-mA tDCS, 2-mA tRNS (with no DC offset), and 2-mA tRNS + 1-mA DC offset. Results There were no significant differences between the stimulation conditions. An analysis of individual stimulation conditions found that there was a significant increase in motor-evoked potential amplitudes after 1-mA tDCS, 2-mA tDCS, and 2-mA tRNS + DC offset when compared with baseline. Sham and 2-mA tRNS did not result in changes in cortical excitability. Conclusions Although differences between the stimulation conditions did not reach a statistical significance, the findings suggest that stimulation involving a DC (tDCS and tRNS + DC offset) but not solely tRNS is more likely to lead to increases in cortical excitability.

P 209. Transcranial random noise stimulation: A new approach to stimulating the brain

Introduction Transcranial random noise stimulation (tRNS) is a neuromodulatory technique that involves the delivery of a bi-directional, randomly oscillating current. Introduction of a positive DC offset to the stimulation can produce a polarity-specific randomly oscillating current that produces effects similar to that of transcranial direct current stimulation (tDCS). It is thought that tRNS modulates cortical excitability by interfering with the ongoing neural oscillations in the cortex. In contrast to using a direct current, tRNS may avoid the homeostatic neural mechanisms associated with repeated stimulation sessions. This may be an advantage in clinical treatment protocols which seek to induce cumulative neuroplastic changes over multiple sessions. To date, there has only been one reported use of tRNS with a positive DC offset for the treatment of depression. Findings were promising, suggesting therapeutic potential for this form of stimulation (Chan et al. (2012)). Objectives The present study aimed to elucidate the clinical potential of tRNS with a positive offset by examining its effects on motor cortical excitability in healthy participants. We aimed to examine the effect of 2mA tRNS+1 milliamp (mA) offset for 10min on cortical excitability by using single pulse transcranial magnetic stimulation (TMS). This was compared to four other transcranial electrical stimulation (tES) conditions as follows: 2mA tRNS without an offset, 1mA tDCS, 2mA tDCS and sham stimulation. Materials and methods Fifteen healthy participants will be tested across five sessions in a within-subjects design. One form of tES was tested at each session, the order of which was randomised for each participant. tES was applied to the left motor cortex. Sets of 20 motor evoked potentials (MEPs) were elicited in the right first dorsal interosseus (FDI) muscle using single-pulse TMS before and up to 90min after tES. Peak-to-peak amplitude of each MEP was measured. The mean amplitude of all responses after tES was calculated and normalised to the baseline amplitude for each subject. Results Results from the first 10 participants show mean ( sd ) post-tES normalised MEPs as follows: 2mA tRNS+1mA offset, 1.44 (0.38); 2mA tRNS, 1.01 (0.11); 1mA tDCS, 1.24 (0.15); 2mA tDCS, 1.30 (0.18) and sham, 1.06 (0.13). Results from all 15 participants will be subsequently presented. Conclusion This is the first empirical study examining the effect of tRNS with an offset on cortical excitability. Preliminary results suggest that tRNS with an offset leads to an increase in cortical excitability similar to that produced by tDCS. Further, tRNS with an offset appears to be more effective than tRNS without an offset in producing changes in cortical excitability. Funding sources KAH is supported by an Australian Post-Graduate Award and University of New South Wales Brain Sciences Top-Up Scholarship.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial

BACKGROUND Animal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. METHODS This pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h-48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h-48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. RESULTS The subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. LIMITATIONS Pilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. CONCLUSIONS These results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.