Reliability,sensitivity, and predictive value of fMRI during multiple object tracking as a marker of cognitive training gain in combination with tDCS in stroke survivors

Computerized cognitive training (CCT) combined with transcranial direct current stimulation (tDCS) has showed some promise in alleviating cognitive impairments in patients with brain disorders, but the robustness and possible mechanisms are unclear. In this prospective double‐blind randomized clinical trial, we investigated the feasibility and effectiveness of combining CCT and tDCS, and tested the predictive value of and training‐related changes in fMRI‐based brain activation during attentive performance (multiple object tracking) obtained at inclusion, before initiating training, and after the three‐weeks intervention in chronic stroke patients (>6 months since hospital admission). Patients were randomized to one of two groups, receiving CCT and either (a) tDCS targeting left dorsolateral prefrontal cortex (1 mA), or (b) sham tDCS, with 40s active stimulation (1 mA) before fade out of the current. Of note, 77 patients were enrolled in the study, 54 completed the cognitive training, and 48 completed all training and MRI sessions. We found significant improvement in performance across all trained tasks, but no additional gain of tDCS. fMRI‐based brain activation showed high reliability, and higher cognitive performance was associated with increased tracking‐related activation in the dorsal attention network and default mode network as well as anterior cingulate after compared to before the intervention. We found no significant associations between cognitive gain and brain activation measured before training or in the difference in activation after intervention. Combined, these results show significant training effects on trained cognitive tasks in stroke survivors, with no clear evidence of additional gain of concurrent tDCS.     

Polarity and timing-dependent effects of transcranial direct current stimulation in explicit motor learning

Transcranial direct current stimulation (tDCS) is attracting increasing interest as a therapeutic tool for neurorehabilitation, particularly after stroke, because of its potential to modulate local excitability and therefore promote functional plasticity. Previous studies suggest that timing is important in determining the behavioural effects of brain stimulation. Regulatory metaplastic mechanisms exist to modulate the effects of a stimulation intervention in a manner dependent on prior cortical excitability, thereby preventing destabilization of existing cortical networks. The importance of such timing dependence has not yet been fully explored for tDCS. Here, we describe the results of a series of behavioural experiments in healthy controls to determine the importance of the relative timing of tDCS for motor performance. Application of tDCS during an explicit sequence-learning task led to modulation of behaviour in a polarity specific manner: relative to sham stimulation, anodal tDCS was associated with faster learning and cathodal tDCS with slower learning. Application of tDCS prior to performance of the sequence-learning task led to slower learning after both anodal and cathodal tDCS. By contrast, regardless of the polarity of stimulation, tDCS had no significant effect on performance of a simple reaction time task. These results are consistent with the idea that anodal tDCS interacts with subsequent motor learning in a metaplastic manner and suggest that anodal stimulation modulates cortical excitability in a manner similar to motor learning.     

Corticospinal excitability enhancement with simultaneous transcranial near-infrared stimulation and anodal direct current stimulation of motor cortex

ObjectivesNon-invasive brain stimulation (NIBS) is beneficial to many neurological and psychiatric disorders by modulating neuroplasticity and cortical excitability. However, recent studies evidence that single type of NIBS such as transcranial direct current stimulation (tDCS) does not have meaningful clinical therapeutic responses due to their small effect size. Transcranial near-infrared stimulation (tNIRS) is a novel form of NIBS. Both tNIRS and tDCS implement its therapeutic effects by modulating cortical excitability but with different mechanisms. We hypothesized that simultaneous tNIRS and tDCS is superior to single stimulation, leading to a greater cortical excitability.MethodsSixteen healthy subjects participated in a double-blind, sham-controlled, cross-over designed study. Motor evoked potentials (MEPs) were used to measure motor cortex excitability. The changes of MEP were calculated and compared in the sham condition, tDCS stimulation condition, tNIRS condition and the simultaneous tNIRS and anodal tDCS condition.ResultstDCS alone and tNIRS alone both elicited higher MEP after stimulation, while the MEP amplitude in the simultaneous tNIRS and tDCS condition was significantly higher than either tNIRS alone or tDCS alone. The enhancement lasted up to at least 30 minutes after stimulation, indicating simultaneous 820 nm tNIRS with 2 mA anodal tDCS have a synergistic effect on cortical plasticity.ConclusionsSimultaneous application of tNIRS with tDCS produces a stronger cortical excitability effect.SignificanceThe simultaneous tNIRS and tDCS is a promising technology with exciting potential as a means of treatment, neuro-enhancement, or neuro-protection.     

Exploring and optimizing the neuroplastic effects of anodal transcranial direct current stimulation over the primary motor cortex of older humans

BackgroundtDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults.Methods32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation.ResultsAll active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min).ConclusionsOur study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas.     

Review of Transcranial Direct Current Stimulation in Poststroke Recovery

Abstract

Motor impairment, dysphagia, aphasia, and visual impairment are common disabling residual deficits experienced by stroke survivors. Recently, many novel rehabilitative modalities have been investigated for their potential to ameliorate such deficits and to improve functional outcomes. Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), have emerged as a promising tool to facilitate stroke recovery. tDCS can alter cortical excitability to induce brain plasticity by modulating the lesioned, contralesional, or bilateral hemispheres with various stimulation modalities. Along with peripheral therapies, tDCS can lead to subsequent sustained behavioral and clinical gains in patients with stroke. In this review, we summarize characteristics of tDCS (method of stimulation, safety profile, and mechanism) and its application in the treatment of various stroke-related deficits, and we highlight future directions for tDCS in this capacity.     

Transcranial Direct Current Stimulation Effects on the Excitability of Corticospinal Axons of the Human Cerebral Cortex

BackgroundTranscranial direct current stimulation (tDCS) of the human cerebral cortex modulates cortical excitability non-invasively in a polarity-specific manner: anodal tDCS leads to lasting facilitation of motor cortex excitability.ObjectiveTo further elucidate the underlying physiological mechanisms of tDCS.MethodsWe recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation of the primary motor cortex before and after a 20 min period of anodal tDCS in a conscious patient who had electrode implanted in the cervical epidural space for the control of pain. We performed magnetic stimulation of the motor cortex using a direction of the induced current in the brain capable of activating both corticospinal axons, evoking D-wave activity, and cortico-cortical axons projecting upon corticospinal cells, evoking I-wave activity.ResultsAnodal tDCS increased the excitability of cortical circuits generating both D and I-wave activity, with a more prolonged effect on D-wave activity. The changes in motor evoked potential recorded from hand muscles produced by tDCS were in agreement with the effects produced on intracortical circuitry.ConclusionsEpidural recordings of corticospinal activity in our patient indicate that anodal tDCS develops its facilitatory effects by an increase in the excitability of corticospinal axons and by an increase of activity in cortico-cortical projections onto pyramidal tract neurones, modulating motor cortex excitability with both synaptic (I waves) and non-synaptic (D waves) mechanisms.     

Premotor transcranial direct current stimulation (tDCS) affects primary motor excitability in humans

Recent studies have shown that repetitive transcranial magnetic stimulation (rTMS) over the premotor cortex (PM) modifies the excitability of the ipsilateral primary motor cortex (M1). Transcranial direct current stimulation (tDCS) is a new method to induce neuroplasticity in humans non-invasively. tDCS generates neuroplasticity directly in the cortical area under the electrode, but might also induce effects in distant brain areas, caused by activity modulation of interconnected areas. However, this has not yet been tested electrophysiologically. We aimed to study whether premotor tDCS can modify the excitability of the ipsilateral M1 via cortico-cortical connectivity. Sixteen subjects received cathodal and anodal tDCS of the PM and eight subjects of the dorsolateral prefrontal cortex. Premotor anodal, but not premotor cathodal or prefrontal tDCS, modified selectively short intracortical inhibition/intracortical facilitation (SICI/ICF), while motor thresholds, single test-pulse motor-evoked potential and input–output curves were stable throughout the experiments. Specifically, anodal tDCS decreased intracortical inhibition and increased paired-pulse excitability. The selective influence of premotor tDCS on intracortical excitability of the ipsilateral M1 suggests a connectivity-driven effect of tDCS on remote cortical areas. Moreover, this finding indirectly substantiates the efficacy of tDCS to modulate premotor excitability, which might be of interest for applications in diseases accompanied by pathological premotor activity.     

No effect of anodal tDCS on motor cortical excitability and no evidence for responders in a large double-blind placebo-controlled trial

BackgroundTranscranial direct current stimulation (tDCS) has emerged as a non-invasive brain stimulation technique. Most studies show that anodal tDCS increases cortical excitability. However, this effect has been found to be highly variable.ObjectiveTo test the effect of anodal tDCS on cortical excitability and the interaction effect of two participant-specific factors that may explain individual differences in sensitivity to anodal tDCS: the Brain Derived Neurotrophic Factor Val66Met polymorphism (BDNF genotype) and the latency difference between anterior-posterior and lateromedial TMS pulses (APLM latency).MethodsIn 62 healthy participants, cortical excitability over the left motor cortex was measured before and after anodal tDCS at 2 mA for 20 min in a pre-registered, double-blind, randomized, placebo-controlled trial with repeated measures.ResultsWe did not find a main effect of anodal tDCS, nor an interaction effect of the participant-specific predictors. Moreover, further analyses did not provide evidence for the existence of responders and non-responders.ConclusionThis study indicates that anodal tDCS at 2 mA for 20 min may not reliably affect cortical excitability.     

Induction of Late LTP-Like Plasticity in the Human Motor Cortex by Repeated Non-Invasive Brain Stimulation

BackgroundNon-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h.ObjectiveWe aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory.MethodsThe impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval).ResultsThe during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity.ConclusionRepeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.     

Age-dependent non-linear neuroplastic effects of cathodal tDCS in the elderly population: a titration study

BackgroundNeuromodulatory effects of transcranial direct current stimulation (tDCS) in older humans have shown heterogeneous results, possibly due to sub-optimal stimulation protocols associated with limited knowledge about optimized stimulation parameters in this age group. We systematically explored the association between the stimulation dosage of cathodal tDCS and induced after-effects on motor cortex excitability in the elderly.MethodThirty-nine healthy volunteers in two age groups, namely Pre-Elderly (50–65 years) and Elderly (66–80 years), participated in the study. Ten sessions of cathodal tDCS, with a combination of four intensities (1, 2, 3 mA and sham) and three durations (15, 20, 30 min) were conducted over the M1 in each participant. Cortical excitability changes were monitored with TMS-induced motor evoked potentials (MEPs) for up to 2 h after stimulation.ResultsMotor cortex excitability was reduced by cathodal stimulation intensities of 1 and 3 mA in both age groups, in accordance with results observed in the younger age groups of previous studies. For the 2 mA stimulation condition, an age-dependent conversion of plasticity into a stimulation duration-dependent excitability enhancement was observed in the Pre-Elderly group, whereas in the Elderly group, LTD-like plasticity was preserved, or abolished, depending on stimulation duration.ConclusionThe LTD-like plasticity effects induced by cathodal tDCS originally described in young adults are also observable in older humans, but non-linearities of the resulting plasticity were partially preserved only in the Pre-Elderly, but not the Elderly group. These results aid in understanding age-dependent plasticity dynamics in humans, and to define more efficient tDCS protocols in the aging brain.     

Interaction Between Simultaneously Applied Neuromodulatory Interventions in Humans

BackgroundTranscranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to enhance the efficacy of traditional therapies such as neuromuscular electrical stimulation (NMES). Yet, concurrent application of tDCS/NMES may also activate homeostatic mechanisms that block or reverse effects on corticomotor excitability. It is unknown how tDCS and NMES interact in the human primary motor cortex (M1) and whether effects are summative (increase corticomotor excitability beyond that of tDCS or NMES applied alone) or competitive (block or reduce corticomotor excitability effects of tDCS or NMES applied alone).ObjectiveTo investigate corticomotor excitability in response to NMES after concurrent application of tDCS protocols that enhance (anodal tDCS) or suppress (cathodal tDCS) excitability of M1.MethodsWe used transcranial magnetic stimulation (TMS) to examine corticomotor excitability before and after the concurrent application of: i) NMES with anodal tDCS; and ii) NMES with cathodal tDCS. Effects were contrasted to four control conditions: i) NMES alone, ii) anodal tDCS alone, iii) cathodal tDCS alone, and iv) sham stimulation.ResultsConcurrent application of two protocols that enhance excitability when applied alone (NMES and anodal tDCS) failed to induce summative effects on corticomotor excitability, as predicted by homeostatic plasticity mechanisms. Combined cathodal tDCS and NMES suppressed the enhanced excitation induced by NMES, an effect that might be explained by calcium dependent anti-gating models.ConclusionsThese novel findings highlight the complex mechanisms involved when two neuromodulatory techniques are combined and suggest that careful testing of combined interventions is necessary before application in clinical contexts.     

Memory training alters hippocampal neurochemistry in healthy elderly

Accumulating epidemiological evidence supports the notion of brain reserve, but there has been no investigation of neurobiological change associated with brief mental activation training in humans. Healthy older individuals were therefore investigated with magnetic resonance spectroscopy (MRS) in different brain regions before and after 5 weeks of focused memory training. Recall of a test-word list of > 23 items was achieved accompanied by elevation of creatine and choline signals in the hippocampus. Those at risk for neural dysfunction, as indicated by lower neurometabolites at baseline, demonstrated the largest MRS increases after training. Biochemical changes related to cellular energy and cell-membrane turnover were found to increase after structured memory exercises and were limited to the medial temporal lobe.     

Age-related differences of motor cortex plasticity in adults: A transcranial direct current stimulation study

BackgroundCognitive, and motor performance are reduced in aging, especially with respect to acquisition of new knowledge, which is associated with a neural plasticity decline. Animal models show a reduction of long-term potentiation, but not long-term depression, in higher age. Findings in humans are more heterogeneous, with some studies showing respective deficits, but others not, or mixed results, for plasticity induced by non-invasive brain stimulation. One reason for these heterogeneous results might be the inclusion of different age ranges in these studies. In addition, a systematic detailed comparison of the age-dependency of neural plasticity in humans is lacking so far.ObjectiveWe aimed to explore age-dependent plasticity alterations in adults systematically by discerning between younger and older participants in our study.MethodsWe recruited three different age groups (Young: 18–30, Pre-Elderly: 50–65, and Elderly: 66–80 years). Anodal, cathodal, or sham transcranial direct current stimulation (tDCS) was applied over the primary motor cortex with 1 mA for 15 min to induce neuroplasticity. Cortical excitability was monitored by single-pulse transcranial magnetic stimulation as an index of plasticity.ResultsFor anodal tDCS, the results show a significant excitability enhancement, as compared to sham stimulation, for both, Young and the Pre-Elderly groups, while no LTP-like plasticity was obtained in the Elderly group by the applied stimulation protocol. Cathodal tDCS induced significant excitability-diminishing plasticity in all age groups.ConclusionOur study provides further insight in age-related differences of plasticity in healthy humans, which are similar to those obtained in animal models. The decline of LTP-like plasticity in higher age could contribute to cognitive deficits observed in aging.     

Transcranial direct current stimulation and the visual cortex

Neuroplastic changes are defined as enduring changes in the organization of the central nervous system, such as the strength of connections, representational patterns, or neuronal properties, either morphological or functional. In recent years, new tools have emerged to induce and manipulate ongoing neuroplastic changes by external stimulation, either by modification of synchronized neuronal activity or modulation of the spontaneous firing rate. The first is performed by transcranial magnetic stimulation (TMS), the latter by direct current stimulation (tDCS). tDCS as a tool aims to induce prolonged neuronal excitability and activity alterations in the human brain via alterations of the neuronal membrane potential and results in prolonged synaptic efficacy changes. Apart from its impressive persistent excitability effects, it is a non-invasive method and can be applied painlessly. Most likely that up- or downregulation of different cortical areas by tDCS will open a new branch in the area of visual psychophysics.     

Effects of cerebellar neuromodulation in movement disorders: A systematic review

Background

The cerebellum is involved in the pathophysiology of many movement disorders and its importance in the field of neuromodulation is growing.

Random noise stimulation improves neuroplasticity in perceptual learning

Perceptual learning is considered a manifestation of neural plasticity in the human brain. We investigated brain plasticity mechanisms in a learning task using noninvasive transcranial electrical stimulation (tES). We hypothesized that different types of tES would have varying actions on the nervous system, which would result in different efficacies of neural plasticity modulation. Thus, the principal goal of the present study was to verify the possibility of inducing differential plasticity effects using two tES approaches [i.e., direct current stimulation (tDCS) and random noise stimulation (tRNS)] during the execution of a visual perceptual learning task.     

Transcranial direct current stimulation disrupts tactile perception

The excitability of the cerebral cortex can be modulated by various transcranial stimulation techniques. Transcranial direct current stimulation (tDCS) offers the advantage of portable equipment and could, therefore, be used for ambulatory modulation of brain excitability. However, modulation of cortical excitability by tDCS has so far mostly been shown by indirect measures. Therefore, we examined whether tDCS has a direct behavioral/perceptional effect. We compared tactile discrimination of vibratory stimuli to the left ring finger prior to, during and after tDCS applied for 7 min at 1-mA current intensity in 13 subjects. Stimulation was pseudorandomized into cathodal, anodal and sham conditions in a within-subject design. The active electrode was placed over the corresponding somatosensory cortex at C4 according to the 10-20 EEG system and the reference electrode at the forehead above the contralateral orbita. Cathodal stimulation compared with sham induced a prolonged decrease of tactile discrimination, while anodal and sham stimulation did not. Thus, cortical processing can be modulated in a behaviorally/perceptually meaningful way by weak transcranial current stimulation applied through portable technology. This finding offers a new perspective for the treatment of conditions characterized by alterations of cortical excitability.     

Bilateral transcranial direct current stimulation modulates activation-induced regional blood flow changes during voluntary movement

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that induces changes in cortical excitability: anodal stimulation increases while cathodal stimulation reduces excitability. Imaging studies performed after unilateral stimulation have shown conflicting results regarding the effects of tDCS on surrogate markers of neuronal activity. The aim of this study was to directly measure these effects on activation-induced changes in regional cerebral blood flow (ΔrCBF) using positron emission tomography (PET) during bilateral tDCS. Nine healthy subjects underwent repeated rCBF measurements with ¹⁵O-water and PET during a simple motor task while receiving tDCS or sham stimulation over the primary motor cortex (M1). Motor evoked potentials (MEPs) were also assessed before and after real and sham stimulation. During tDCS with active movement, ΔrCBF in M1 was significantly lower on the cathodal than the anodal side when compared with sham stimulation. This decrease in ΔrCBF was accompanied by a decrease in MEP amplitude on the cathodal side. No effect was observed on resting or activated rCBF relative to sham stimulation. We thus conclude that it is the interaction of cathodal tDCS with activation-induced ΔrCBF rather than the effect on resting or activated rCBF itself which constitutes the physiological imaging correlate of tDCS.     

Anodal transcranial direct current stimulation of the motor cortex increases cortical voluntary activation and neural plasticity

Introduction: We examined the cumulative effect of 4 consecutive bouts of noninvasive brain stimulation on corticospinal plasticity and motor performance, and whether these responses were influenced by the brain‐derived neurotrophic factor (BDNF) polymorphism. Methods: In a randomized double‐blinded cross‐over design, changes in strength and indices of corticospinal plasticity were analyzed in 14 adults who were exposed to 4 consecutive sessions of anodal and sham transcranial direct current stimulation (tDCS). Participants also undertook a blood sample for BDNF genotyping (N = 13). Results: We observed a significant increase in isometric wrist flexor strength with transcranial magnetic stimulation revealing increased corticospinal excitability, decreased silent period duration, and increased cortical voluntary activation compared with sham tDCS. Conclusions: The results show that 4 consecutive sessions of anodal tDCS increased cortical voluntary activation manifested as an improvement in strength. Induction of corticospinal plasticity appears to be influenced by the BDNF polymorphism. Muscle Nerve 54 : 903–913, 2016