Kátia Monte-Silva

Shaping the Optimal Repetition Interval for Cathodal Transcranial Direct Current Stimulation (tDCS)

Transcranial DC stimulation (tDCS) is a plasticity-inducing noninvasive brain stimulation tool with various potential therapeutic applications in neurological and psychiatric diseases. Currently, the duration of the aftereffects of stimulation is restricted. For future clinical applications, stimulation protocols are required that produce aftereffects lasting for days or weeks. Options to prolong the effects of tDCS are further prolongation or repetition of tDCS. Nothing is known thus far about optimal protocols in this behalf, although repetitive stimulation is already performed in clinical applications. Thus we explored the effects of different break durations on cathodal tDCS-induced cortical excitability alterations. In 12 subjects, two identical periods of cathodal tDCS (9-min duration; 1 mA) with an interstimulation interval of 0 (no break), 3, or 20 min or 3 or 24 h were performed. The results indicate that doubling stimulation duration without a break prolongs the aftereffects from 60 to 90 min after tDCS. When the second stimulation was performed during the aftereffects of the first, a prolongation and enhancement of tDCS-induced effects for ≤ 120 min after stimulation was observed. In contrast, when the second stimulation followed the first one after 3 or 24 h, the aftereffects were initially attenuated, or abolished, but afterwards re-established for up to 120 min after tDCS in the 24-h condition. These results suggest that, for prolonging the aftereffects of cathodal tDCS, stimulation interval might be important.

Dose-Dependent Inverted U-Shaped Effect of Dopamine (D2-Like) Receptor Activation on Focal and Nonfocal Plasticity in Humans

The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D2-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D2/D3 dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D2-like receptor activation produced an inverted “U”-shaped dose–response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of ropinirole impaired plasticity. However, no dose-dependent response effect of D2-like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D2-like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.

After-effects of transcranial direct current stimulation (tDCS) on cortical spreading depression

Abnormal cortical excitability influences susceptibility to cortical spreading depression (CSD) in migraine. Because transcranial direct current stimulation (tDCS) is capable of inducing lasting changes of cortical excitability, we investigated the after-effects of tDCS on the propagation velocity of CSD in the rat. Twenty-five anesthetised rats received either anodal, cathodal or sham tDCS. The stimulation was applied for 20 min at a current strength of 200 microA after the recording of three baseline CSD measurements. Starting 5 min after tDCS, a further three CSDs were elicited and CSD velocity recorded at intervals of 20 min. tDCS and CSD recording was performed under anaesthesia with chloralose and urethane. As compared to the baseline velocity of 3.14 mm/min, anodal tDCS induced a significant increase of propagation velocity during the first post-tDCS recording (3.49 mm/min). In contrast to anodal tDCS, neither cathodal tDCS nor sham tDCS, which consisted of an initial ramped DC stimulation lasting only 20 s, showed a significant effect on CSD propagation velocity. As anodal tDCS is known to induce a lasting increase of cortical excitability in the clinical setting, our results support the notion that CSD propagation velocity reflects cortical excitability. Since cortical excitability and susceptibility to CSD is elevated in migraine patients, anodal tDCS - by increasing cortical excitability - might increase the probability of migraine attack in these patients, even beyond the end of its application.

D1-Receptor Impact on Neuroplasticity in Humans

Dopamine improves learning and memory formation. The neurophysiological basis for these effects might be a focusing effect of dopamine on neuroplasticity: Accordingly, in humans l-dopa prolongs focal facilitatory plasticity, but turns nonfocal facilitatory plasticity into inhibition. Here we explore the impact of D1 receptors on plasticity. Nonfocal plasticity was induced by transcranial direct current stimulation (tDCS), and focal plasticity by paired associative stimulation (PAS). Subjects received sulpiride, a D2 antagonist, to increase the relative contribution of D1 receptors to dopaminergic activity, combined sulpiride and l-dopa, to increase the relation of D1/D2 activity further, or placebo medication. Under placebo, anodal tDCS and excitatory PAS (ePAS) increased motor cortex excitability. Cathodal tDCS and inhibitory PAS (iPAS) reduced it. Sulpiride abolished iPAS-induced inhibition, but not ePAS-generated facilitation, underlining the importance of D1-receptor activity for focal facilitatory neuroplasticity. Combining sulpiride with l-dopa reestablished iPAS-induced inhibition, but did not affect ePAS-induced plasticity. tDCS-induced plasticity, which was abolished by sulpiride in a former study, also recovered. Thus enhancing D1 activity further relative to D2 activity is relevant for facilitatory and inhibitory plasticity. However, comparison with former results show that an appropriate balance of D1 and D2 activity seems necessary to (1) consolidate the respective excitability modifications and (2) to elicit a focusing effect.

Effects of transcranial direct current stimulation coupled with repetitive electrical stimulation on cortical spreading depression

We have recently shown that two techniques of brain stimulation - repetitive electrical stimulation (ES) (that mimics transcranial magnetic stimulation) and transcranial direct current stimulation (tDCS) - modify the velocity of cortical spreading depression (CSD) significantly. Herein we aimed to study the effects of these two techniques combined on CSD. Thirty-two Wistar rats were divided into four groups according to the treatment: sham tDCS/sham ES, sham tDCS/1 Hz ES, anodal tDCS/1 Hz ES, cathodal tDCS/1 Hz ES. Our findings show that 1 Hz ES reduced CSD velocity, and this effect was modified by either anodal or cathodal tDCS. Anodal tDCS induced larger effects than cathodal tDCS. Hereby CSD velocity was actually increased significantly after anodal tDCS/1 Hz ES. Our results show that combining two techniques of brain stimulation can modify significantly the effects of ES alone on cortical excitability as measured by the neurophysiological parameter of cortical spreading depression and therefore provide important insights into the effects of this new approach of brain stimulation on cortical activity.

Site‐specific effects of mental practice combined with transcranial direct current stimulation on motor learning

Mental practice can induce significant neural plasticity and result in motor performance improvement if associated with motor imagery tasks. Given the effects of transcranial direct current stimulation (tDCS) on neuroplasticity, the current study tested whether tDCS, using different electrode montages, can increase the neuroplastic effects of mental imagery on motor learning. Eighteen healthy right‐handed adults underwent a randomised sham‐controlled crossover experiment to receive mental training combined with either sham or active anodal tDCS of the right primary motor cortex (M1), right supplementary motor area, right premotor area, right cerebellum or left dorsolateral prefrontal cortex (DLPFC). Motor performance was assessed by a blinded rater using: non‐dominant handwriting time and legibility, and mentally trained task at baseline (pre) and immediately after (post) mental practice combined with tDCS. Active tDCS significantly enhances the motor‐imagery‐induced improvement in motor function as compared with sham tDCS. There was a specific effect for the site of stimulation such that effects were only observed after M1 and DLPFC stimulation during mental practice. These findings provide new insights into motor imagery training and point out that two cortical targets (M1 and DLPFC) are significantly associated with the neuroplastic effects of mental imagery on motor learning. Further studies should explore a similar paradigm in patients with brain lesions.

Efficacy of Coupling Repetitive Transcranial Magnetic Stimulation and Physical Therapy to Reduce Upper-Limb Spasticity in Patients With Stroke: A Randomized Controlled Trial

OBJECTIVE To assess the efficacy of inhibitory repetitive transcranial magnetic stimulation (rTMS) for decreasing upper-limb muscle tone after chronic stroke. DESIGN A randomized sham-controlled trial with a 4-week follow-up. SETTING Research hospital. PARTICIPANTS Patients with stroke (N=20) with poststroke upper limb spasticity. INTERVENTIONS The experimental group received rTMS to the primary motor cortex of the unaffected side (1500 pulses; 1Hz; 90% of resting motor threshold for the first dorsal interosseous muscle) in 10 sessions, 3d/wk, and physical therapy (PT). The control group received sham stimulation and PT. MAIN OUTCOME MEASURES Modified Ashworth scale (MAS), upper-extremity Fugl-Meyer assessment, FIM, range of motion, and stroke-specific quality-of-life scale. All outcomes were measured at baseline, after treatment (postintervention), and at a 4-week follow-up. A clinically important difference was defined as a reduction of ≥1 in the MAS score. RESULTS Friedman test revealed that PT is efficient for significantly reducing the upper limb spasticity of patients only when it is associated with rTMS. In the experimental group, 90% of the patients at postintervention and 55.5% at follow-up showed a decrease of ≥1 in the MAS score, representing clinically important differences. In the control group, 30% of the patients at postintervention and 22.2% at follow-up experienced clinically meaningful changes. There were no differences between the groups at any time for any of the other outcome measures, indicating that both groups demonstrated similar behaviors over time for all variables. CONCLUSIONS rTMS associated with PT can be beneficial in reducing poststroke spasticity. However, more studies are needed to clarify the clinical changes underlying the reduction in spasticity induced by noninvasive brain stimulations.

D2 Receptor Block Abolishes Theta Burst Stimulation-Induced Neuroplasticity in the Human Motor Cortex

Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced.

The impact of transcranial direct current stimulation (tDCS) combined with modified constraint-induced movement therapy (mCIMT) on upper limb function in chronic stroke: a double-blind randomized controlled trial

Abstract Purpose: This pilot double-blind sham-controlled randomized trial aimed to determine if the addition of anodal tDCS on the affected hemisphere or cathodal tDCS on unaffected hemisphere to modified constraint-induced movement therapy (mCIMT) would be superior to constraints therapy alone in improving upper limb function in chronic stroke patients. Methods: Twenty-one patients with chronic stroke were randomly assigned to receive 12 sessions of either (i) anodal, (ii) cathodal or (iii) sham tDCS combined with mCIMT. Fugl–Meyer assessment (FMA), motor activity log scale (MAL), and handgrip strength were analyzed before, immediately, and 1 month (follow-up) after the treatment. Minimal clinically important difference (mCID) was defined as an increase of ≥5.25 in the upper limb FMA. Results: An increase in the FMA scores between the baseline and post-intervention and follow-up for active tDCS group was observed, whereas no difference was observed in the sham group. At post-intervention and follow-up, when compared with the sham group, only the anodal tDCS group achieved an improvement in the FMA scores. ANOVA showed that all groups demonstrated similar improvement over time for MAL and handgrip strength. In the active tDCS groups, 7/7 (anodal tDCS) 5/7 (cathodal tDCS) of patients experienced mCID against 3/7 in the sham group. Conclusion: The results support the merit of association of mCIMT with brain stimulation to augment clinical gains in rehabilitation after stroke. However, the anodal tDCS seems to have greater impact than the cathodal tDCS in increasing the mCIMT effects on motor function of chronic stroke patients. Implications for Rehabilitation The association of mCIMT with brain stimulation improves clinical gains in rehabilitation after stroke. The improvement in motor recovery (assessed by Fugl–Meyer scale) was only observed after anodal tDCS. The modulation of damaged hemisphere demonstrated greater improvements than the modulation of unaffected hemispheres.

Dopaminergic impact on cortical excitability in humans.

Dopamine is a major neuromodulatory agent of the central nervous system. The neurotransmitter has a non-linear dose-dependent effect on cortical excitability and activity, which depends on spontaneous activity, dopamine concentration, and dopaminergic sub-receptors, amongst others. By its impact on cortical and subcortical network activity and excitability, dopamine modulates such cognitive performance as attention, as well as learning and memory formation. Although animal studies have enhanced our knowledge about the physiology of dopamine considerably, the transferability of the results to conscious humans is limited due to altered spontaneous neuronal activity in anesthetized animals or slice experiments. Recently emerged noninvasive brain stimulation techniques enable the exploration of cortical excitability in humans. Here we review the respective experimental results and derive conclusions about how dopamine might affect the cortical excitability of the human brain.