Talk Abstract: Few emerging therapies for neuropsychiatric disorders has engaged as much excitement and also debate as transcranial Direct Current Stimulation (tDCS). To identify the potential of tDCS and move beyond the hype, this talk addresses the technology and cellular foundations of tDCS. For decades, it has been established that direct current stimulation can modulate plasticity; new research is unraveling the cellular mechanisms of how direct current stimulation can produce nuanced and targeted changes in brain function. Over the past decade, the technology of tDCS has advanced from basic clinical stimulator using two electrodes to High-Definition tDCS (HD-tDCS) using arrays of electrodes and to Remove-Supervised technology for home use. These new technologies have allowed categorical enhanced in the targeting (HD-tDCS) and deployment (Remote-Supervised) of tDCS. Finally, new approaches to optimize tDCS using imaging and biomarkers, including used EEG reciprocity, have provided new insight on therapeutic mechanisms as well as rational methods to select patients and individualize tDCS. The thesis of this talk is that tDCS is grounded in well-established biophysical principles but that emerging technologies will support robust and efficacious translation to patients.
Non-invasive brain stimulation (NIBS) combined with behavioral training is a promising strategy to augment recovery after stroke. Current research efforts have been mainly focusing on primary motor cortex (M1) stimulation. However, the translation from proof-of-principle to clinical applications is not yet satisfactory. Possible reasons are the heterogeneous properties of stroke, generalization of the stimulation protocols, and hence the lack of patient stratification. One strategy to overcome these limitations could be the evaluation of alternative stimulation targets, like the cerebellum. In this regard, first studies provided evidence that non-invasive cerebellar stimulation can modulate cerebellar processing and linked behavior in healthy subjects. The cerebellum provides unique plasticity mechanisms and has vast connections to interact with neocortical areas. Moreover, the cerebellum could serve as a non-lesioned entry to the motor or cognitive system in supratentorial stroke. In the current article, we review mechanisms of plasticity in the cortico-cerebellar system after stroke, methods for non-invasive cerebellar stimulation, and possible target symptoms in stroke, like fine motor deficits, gait disturbance, or cognitive impairments, and discuss strategies for multi-focal stimulation.
Wessel MJ, Zimerman M, Hummel FC. Non-invasive brain stimulation: an interventional tool for enhancing behavioral training after stroke. Front Hum Neurosci. 2015;9:265. https://doi.org/10.3389/fnhum.2015.00265.
Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving activities of daily living, and physical and cognitive functioning, in people after stroke. Cochrane Database Syst Rev. 2016;3:CD009645. https://doi.org/10.1002/14651858.CD009645.pub3.
Ameli M, Grefkes C, Kemper F, Riegg FP, Rehme AK, Karbe H, et al. Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann Neurol. 2009;66(3):298–309. https://doi.org/10.1002/ana.21725.PubMedCrossRefGoogle Scholar
Demirtas-Tatlidede A, Alonso-Alonso M, Shetty RP, Ronen I, Pascual-Leone A, Fregni F. Long-term effects of contralesional rTMS in severe stroke: safety, cortical excitability, and relationship with transcallosal motor fibers. NeuroRehabilitation. 2015;36(1):51–9. https://doi.org/10.3233/NRE-141191.PubMedGoogle Scholar
Wang CC, Wang CP, Tsai PY, Hsieh CY, Chan RC, Yeh SC. Inhibitory repetitive transcranial magnetic stimulation of the contralesional premotor and primary motor cortices facilitate poststroke motor recovery. Restor Neurol Neurosci. 2014;32(6):825–35. https://doi.org/10.3233/RNN-140410.PubMedGoogle Scholar
Boggio PS, Nunes A, Rigonatti SP, Nitsche MA, Pascual-Leone A, Fregni F. Repeated sessions of noninvasive brain DC stimulation is associated with motor function improvement in stroke patients. Restor Neurol Neurosci. 2007;25(2):123–9.PubMedGoogle Scholar
Takasawa M, Watanabe M, Yamamoto S, Hoshi T, Sasaki T, Hashikawa K, et al. Prognostic value of subacute crossed cerebellar diaschisis: single-photon emission CT study in patients with middle cerebral artery territory infarct. AJNR Am J Neuroradiol. 2002;23(2):189–93.PubMedGoogle Scholar
Schulz R, Frey BM, Koch P, Zimerman M, Bönstrup M, Feldheim J, et al. Cortico-cerebellar structural connectivity is related to residual motor output in chronic stroke. Cereb Cortex. 2017;27:635–45. https://doi.org/10.1093/cercor/bhv251.
De Vico FF, Clausi S, Leggio M, Chavez M, Valencia M, Maglione AG, et al. Interhemispheric connectivity characterizes cortical reorganization in motor-related networks after cerebellar lesions. Cerebellum. 2017;16:358–75. https://doi.org/10.1007/s12311-016-0811-z.
Chida K, Ogasawara K, Aso K, Suga Y, Kobayashi M, Yoshida K, et al. Postcarotid endarterectomy improvement in cognition is associated with resolution of crossed cerebellar hypoperfusion and increase in 123I-iomazenil uptake in the cerebral cortex: a SPECT study. Cerebrovasc Dis Basel Switz. 2010;29(4):343–51. https://doi.org/10.1159/000278930.CrossRefGoogle Scholar
Sebastian R, Saxena S, Tsapkini K, Faria AV, Long C, Wright A, et al. Cerebellar tDCS: a novel approach to augment language treatment post-stroke. Front Hum Neurosci. 2017;10:695. https://doi.org/10.3389/fnhum.2016.00695.
van Dun K, Bodranghien FC, Marien P, Manto MU. tDCS of the cerebellum: where do we stand in 2016? Technical issues and critical review of the literature. Front Hum Neurosci. 2016;10:199. https://doi.org/10.3389/fnhum.2016.00199.
Machado AG, Cooperrider J, Furmaga HT, Baker KB, Park HJ, Chen Z, et al. Chronic 30-Hz deep cerebellar stimulation coupled with training enhances post-ischemia motor recovery and peri-infarct synaptophysin expression in rodents. Neurosurgery. 2013;73(2):344–53. https://doi.org/10.1227/01.neu.0000430766.80102.ac.
Chieffo R, Comi G, Leocani L. Noninvasive neuromodulation in poststroke gait disorders: rationale, feasibility, and state of the art. Neurorehabil Neural Repair. 2015;30:71–82. https://doi.org/10.1177/1545968315586464.
Grimaldi G, Oulad Ben Taib N, Manto M, Bodranghien F. Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation: tremor reduction and re-programming of the timing of antagonist commands. Front Syst Neurosci. 2014;8:9. https://doi.org/10.3389/fnsys.2014.00009.
Samaei A, Ehsani F, Zoghi M, Hafez Yosephi M, Jaberzadeh S. Online and offline effects of cerebellar transcranial direct current stimulation on motor learning in healthy older adults: a randomized double-blind sham-controlled study. Eur J Neurosci. 2017;45(9):1177–85. https://doi.org/10.1111/ejn.13559.PubMedCrossRefGoogle Scholar
Miler JA, Meron D, Baldwin DS, Garner M. The effect of prefrontal transcranial direct current stimulation on attention network function in healthy volunteers. Neuromodulation. 2017. https://doi.org/10.1111/ner.12629.
Spielmann K, van der Vliet R, van de Sandt-Koenderman WM, Frens MA, Ribbers GM, Selles RW, et al. Cerebellar cathodal transcranial direct stimulation and performance on a verb generation task: a replication study. Neural Plast. 2017;2017:1254615. https://doi.org/10.1155/2017/1254615.
Verhage MC, Avila EO, Frens MA, Donchin O, van der Geest JN. Cerebellar tDCS does not enhance performance in an implicit categorization learning task. Front Psychol. 2017;8:476. https://doi.org/10.3389/fpsyg.2017.00476.
tDCS act directly—with focused precision—on the areas of the brain that govern the physical and mental functions in need of rehabilitation. Through the use of these devices we’re able to greatly enhance the efficacy of rehabilitation itself.
To evaluate effects of somatosensory stimulation in the form of repetitive peripheral nerve sensory stimulation (RPSS) in combination with transcranial direct current stimulation (tDCS), tDCS alone, RPSS alone, or sham RPSS + tDCS as add-on interventions to training of wrist extension with functional electrical stimulation (FES), in chronic stroke patients with moderate to severe upper limb impairments in a crossover design. We hypothesized that the combination of RPSS and tDCS would enhance the effects of FES on active range of movement (ROM) of the paretic wrist to a greater extent than RPSS alone, tDCS alone or sham RPSS + tDCS.
Materials and Methods
The primary outcome was the active ROM of extension of the paretic wrist. Secondary outcomes were ROM of wrist flexion, grasp, and pinch strength of the paretic and nonparetic upper limbs, and ROM of wrist extension of the nonparetic wrist. Outcomes were blindly evaluated before and after each intervention. Analysis of variance with repeated measures with factors “session” and “time” was performed.
After screening 2499 subjects, 22 were included. Data from 20 subjects were analyzed. There were significant effects of “time” for grasp force of the paretic limb and for ROM of wrist extension of the nonparetic limb, but no effects of “session” or interaction “session x time.” There were no significant effects of “session,” “time,” or interaction “session x time” regarding other outcomes.
Single sessions of PSS + tDCS, tDCS alone, or RPSS alone did not improve training effects in chronic stroke patients with moderate to severe impairment.
Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.
Transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) are the most commonly used methods of non-invasive transcranial brain stimulation that has been abbreviated by previous authors as either as NIBS or NTBS. Here we use NIBS since it seems to be the most common term at the present time. When it was first introduced in 1985, TMS was employed primarily as a tool to investigate the integrity and function of the human corticospinal system (Barker et al., 1985). Single pulse stimulation was used to elicit motor evoked potentials (MEPs) that were easily evoked and measured in contralateral muscles (Rothwell et al., 1999). The robustness and repeatability of measures of conduction time, stimulation threshold and “hot spot” location allowed TMS to be developed into a standard tool in clinical neurophysiology.
As we review below, a number of NIBS protocols can lead to effects on brain excitability that outlast the period of stimulation. These may reflect basic synaptic mechanisms involving long-term potentiation (LTP)- or long-term depression (LTD)-like plasticity, and because of this there has been great interest in using the methods as therapeutic interventions in neurological and psychiatric diseases. Furthermore, recently they are more frequently applied to modify memory processes and to enhance cognitive function in healthy individuals. However, apart from success in treating some patients with depression (Lefaucheur et al., 2014; Padberg et al., 2002, 1999), there is little consensus that they have improved outcomes in a clinically meaningful fashion in any other conditions. The reason for this is probably linked to the reason why many other protocols failed to reach routine clinical neurophysiology: they are too variable both within and between individuals to make them practically useful in a health service setting (Goldsworthy et al., 2014; Hamada et al., 2013; Lopez-Alonso et al., 2014, 2015).
Below we review the evidence for the mechanisms underlying the “neuroplastic” effects of NIBS, and then consider the problems in reproducibility and offer some potential ways forward in research. […]
Fig. 1. There are three major lines of evidence supporting NIBS produces effects through mechanisms of synaptic plasticity: (1) Drugs that modulate the function of critical receptors/channels for plasticity, e.g. Ca2+ channels and NMDA receptors, alter the effect of NIBS; (2) NIBS mainly changes I-waves rather than the D-wave in the epidural recording of descending volleys evoked by TMS, suggesting the effect of NIBS occurs trans-synaptically; and (3) NIBS interacts between protocols and with motor practice and cognitive learning processes, suggesting the effect of NIBS is involves in plasticity-related motor and psychological processes.
[Purpose] Homonymous hemianopia is one of the most common symptoms following neurologic damage leading to impairments of functional abilities and activities of daily living. There are two main types of restorative
rehabilitation in hemianopia: “border training” which involves exercising vision at the edge of the damaged visual field, and “blindsight training,” which is based on exercising the unconscious perceptual functions deep
inside the blind hemifield. Only border effects have been shown to be facilitated by transcranial direct current stimulation (tDCS). This pilot study represents the first attempt to associate the modulatory effects of tDCS over
the parieto-occipital cortex to blindsight treatment in the rehabilitation of the homonymous hemianopia.
[Subjects and Methods] Patients TA and MR both had chronic hemianopia. TA underwent blindsight treatment which was combined with tDCS followed by blindsight training alone. MR underwent the two training rounds in reverse order.
[Results] The patients showed better scores in clinical-instrumental, functional, and ecological assessments after tDCS combined with blindsight rehabilitation rather than rehabilitation alone. [Conclusion] In this two-case report parietal-occipital tDCS modulate the effects induced by blindsight treatment on hemianopia.
[Conclusion] In this two-case report parietal-occipital tDCS modulate the effects induced by blindsight treatment on hemianopia.
Transcranial Direct Current Stimulation (tDCS) is an emerging approach for improving capacity in activities of daily living (ADL) and upper limb function after stroke. However, it remains unclear what type of tDCS stimulation is most effective. Our aim was to give an overview of the evidence network regarding the efficacy and safety of tDCS and to estimate the effectiveness of the different stimulation types.
We performed a systematic review of randomised trials using network meta-analysis (NMA), searching the following databases until 5 July 2016: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, and four other databases. We included studies with adult people with stroke. We compared any kind of active tDCS (anodal, cathodal, or dual, that is applying anodal and cathodal tDCS concurrently) regarding improvement of our primary outcome of ADL capacity, versus control, after stroke. PROSPERO ID: CRD42016042055.
We included 26 studies with 754 participants. Our NMA showed evidence of an effect of cathodal tDCS in improving our primary outcome, that of ADL capacity (standardized mean difference, SMD = 0.42; 95% CI 0.14 to 0.70). tDCS did not improve our secondary outcome, that of arm function, measured by the Fugl-Meyer upper extremity assessment (FM-UE). There was no difference in safety between tDCS and its control interventions, measured by the number of dropouts and adverse events.
Comparing different forms of tDCS shows that cathodal tDCS is the most promising treatment option to improve ADL capacity in people with stroke.
An emerging approach for enhancing neural plasticity and hence rehabilitation outcomes after stroke is non-invasive brain stimulation (NIBS). Several stimulation procedures are available, such as repetitive transcranial magnetic stimulation (rTMS) , transcranial direct current stimulation (tDCS) [2, 3, 4], transcranial alternating current stimulation (tACS) , and transcranial pulsed ultrasound (TPU) . In recent years a considerable evidence base for NIBS has emerged, especially for rTMS and tDCS.
tDCS is relatively inexpensive, easy to administer and portable, hence constituting an ideal adjuvant therapy during stroke rehabilitation. It works by applying a weak and constant direct current to the brain and has the ability to either enhance or suppress cortical excitability, with effect lasting up to several hours after the stimulation [7, 8, 9]. Hypothetically, this technique makes tDCS a potentially useful tool to modulate neuronal inhibitory and excitatory networks of the affected and the non-affected hemisphere post stroke to enhance, for example, upper limb motor recovery [10, 11]. Three different stimulation types can be distinguished.
In anodal stimulation, the anodal electrode (+) usually is placed over the lesioned brain area and the reference electrode over the contralateral orbit . This leads to subthreshold depolarization, hence promoting neural excitation .
In cathodal stimulation, the cathode (−) usually is placed over the non-lesioned brain area and the reference electrode over the contralateral orbit , leading to subthreshold polarization and hence inhibiting neural activity .
Dual tDCS means the simultaneous application of anodal and cathodal stimulation .
However, the literature does not provide clear guidelines, not only regarding the tDCS type, but also regarding the electrode configuration , the amount of current applied and the duration of tDCS, or the question if tDCS should be applied as a standalone therapy or in combination with other treatments, like robot-assisted therapy .
There is so far conflicting evidence from systematic reviews of randomised controlled trials on the effectiveness of different tDCS approaches after stroke. For example, over the past two decades more than 30 randomised clinical trials have investigated the effects of different tDCS stimulation techniques for stroke, and there are 55 ongoing trials . However, the resulting network of evidence from randomised controlled trials (RCTs) investigating different types of tDCS (i.e., anodal, cathodal or dual) as well as their comparators like sham tDCS, physical rehabilitation or pharmacological agents has not yet been analyzed in a systematic review so far.
A network meta-analysis (NMA), also known as multiple treatment comparison meta-analysis or mixed treatment comparison analysis, allows for a quantitative synthesis of the evidence network. This is made possible by combining direct evidence from head-to-head comparisons of three or more interventions within randomised trials with indirect evidence across randomised trials on the basis of a common comparator [17, 18, 19, 20]. Network meta-analysis has many advantages over traditional pairwise meta-analysis, such as visualizing and facilitating the interpretation of the wider picture of the evidence and improving understanding of the relative merits of these different types of neuromodulation when compared to sham tDCS and/or another comparator such as exercise therapy and/or pharmacological agents [21, 22]. By borrowing strength from indirect evidence to gain certainty about all treatment comparisons, network meta-analysis allows comparative effects that have not been investigated directly in randomised clinical trials to be estimated and ranked [22, 23].
The aim of our systematic review with NMA was to give an overview of the evidence network of randomised controlled trials of tDCS (anodal, cathodal, or dual) for improving capacity in activities of daily living (ADL) and upper limb function after stroke, as well as its safety, and to estimate and rank the relative effectiveness of the different stimulation types, while taking into account potentially important treatment effect modifiers.
Recovery of handgrip is critical after stroke since it is positively related to upper limb function. To boost motor recovery, transcranial direct current stimulation (tDCS) is a promising, non-invasive brain stimulation technique for the rehabilitation of persons with stroke. When applied over the primary motor cortex (M1), tDCS has been shown to modulate neural processes involved in motor learning. However, no studies have looked at the impact of tDCS on the learning of a grip task in both stroke and healthy individuals.
To assess the use of tDCS over multiple days to promote motor learning of a grip task using a learning paradigm involving a speed-accuracy tradeoff in healthy individuals.
In a double-blinded experiment, 30 right-handed subjects (mean age: 22.1 ± 3.3 years) participated in the study and were randomly assigned to an anodal (n = 15) or sham (n = 15) stimulation group. First, subjects performed the grip task with their dominant hand while following the pace of a metronome. Afterwards, subjects trained on the task, at their own pace, over 5 consecutive days while receiving sham or anodal tDCS over M1. After training, subjects performed de novo the metronome-assisted task. The change in performance between the pre and post metronome-assisted task was used to assess the impact of the grip task and tDCS on learning.
Anodal tDCS over M1 had a significant effect on the speed-accuracy tradeoff function. The anodal tDCS group showed significantly greater improvement in performance (39.28 ± 15.92%) than the sham tDCS group (24.06 ± 16.35%) on the metronome-assisted task, t(28) = 2.583, P = 0.015 (effect size d = 0.94).
Anodal tDCS is effective in promoting grip motor learning in healthy individuals. Further studies are warranted to test its potential use for the rehabilitation of fine motor skills in stroke patients.
Transcranial direct current stimulation (tDCS) can polarize the cortex of the human brain.
/Hypothesis: We sought to verify the hypothesis that posterior-anterior (PA) but not anterior-posterior (AP) tDCS of primary motor cortex (M1) produces cooperative effects with corticospinal plasticity induced by paired associative stimulation of the supplementary motor area (SMA) to M1 projection (PASSMA→M1) in a highly controlled experimental design.
Three experimental conditions were tested in a double-blinded, randomized crossover design in 15 healthy adults: Navigated PASSMA→M1 during PA-tDCS (35 cm2 electrodes, anode 3 cm posterior to M1 hand area, cathode over contralateral frontopolar cortex, 1 mA, 2 × 5 min) or AP-tDCS (reversed polarity), or sham-tDCS. Effects were analyzed over 120 min post-intervention by changes of motor evoked potential (MEP) amplitude in a hand muscle.
There was no significant effect of tDCS on PASSMA→M1 induced plasticity in the repeated-measures ANOVA. However, post-hoc within-subject contrasts revealed a significant tDCS with PASSMA→M1 interaction. This was explained by PA-tDCS and AP-tDCS modifying the PASSMA→M1 effect into the same direction in 13/15 subjects (87%, p = 0.004 for deviation from equality). Sizes of the PA-tDCS and AP-tDCS effects were correlated (rs = 0.53, p = 0.044). A control experiment demonstrated that PA-tDCS and AP-tDCS alone (without PASSMA→M1) had no effect on MEP amplitude.
Data point to unidirectional tDCS effects on PASSMA→M1 induced plasticity irrespective of tDCS polarity, in contrast to our hypothesis. We propose that radial symmetry of cortical columns, gyral geometry of motor cortex, and cooperativity of plasticity induction can explain the findings.