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Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes?
Accepted Manuscript Title: Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes? Authors: Roanne Hurley, Liana Machado PII: DOI: Reference:
S0149-7634(17)30380-9 https://doi.org/10.1016/j.neubiorev.2017.09.029 NBR 2958
To appear in: Received date: Revised date: Accepted date:
22-5-2017 8-9-2017 26-9-2017
Please cite this article as: Hurley, Roanne, Machado, Liana, Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes?.Neuroscience and Biobehavioral Reviews https://doi.org/10.1016/j.neubiorev.2017.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Running head: METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes?
Roanne Hurley and Liana Machado* University of Otago and Brain Research New Zealand
Author Note Roanne Hurley, Department of Psychology and Brain Health Research Centre, University of Otago, Dunedin, New Zealand and Brain Research New Zealand, Auckland, New Zealand; Liana Machado, Department of Psychology and Brain Health Research Centre, University of Otago, Dunedin, New Zealand and Brain Research New Zealand, Auckland, New Zealand. This research was supported by a Fanny Evans Postgraduate Scholarship, the Neurological Foundation of New Zealand (1315-SPG), and the University of Otago. *Correspondence concerning this article should be addressed to Dr. Liana Machado, Department of Psychology, University of Otago, William James Building, 275 Leith Walk, Dunedin 9054, New Zealand. E-mail: [email protected]
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Highlights
tDCS priming protocols show promise over traditional continuous stimulation.
Metaplastic regulatory mechanisms appear to underpin the enhanced effects. More research investigating optimal priming doses and delay periods is needed.
Abstract
Transcranial direct current stimulation (tDCS) has been trialled by many researchers attempting to improve brain function. Outcomes have been quite variable with seemingly similar protocols yielding either inconsistent or insufficiently robust improvements for clinical translation. A potentially fruitful avenue for increasing benefits conferred by tDCS stems from findings from motor and visual cortex studies that indicate tDCS priming prior to a subsequent period of stimulation (tDCS or transcranial magnetic stimulation) can in some cases boost outcomes compared to protocols without priming. The heightened effects from tDCS priming protocols are thought to be underpinned by metaplastic interactions, in which the state induced by the priming influences the effects of the second stimulation period. The purpose of the current review is to evaluate the potential of tDCS priming protocols to boost outcomes. After dissecting the literature, we conclude that although outcomes have varied, tDCS priming protocols have demonstrated sufficient promise to warrant attention from researchers trying to enhance the efficacy of tDCS. Key Words: electrical brain stimulation; transcranial direct current stimulation; transcranial magnetic stimulation; TMS; rTMS; non-invasive brain stimulation; NIBS; motor; MEP; visual; VEP; priming protocols
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Introduction
Despite numerous studies demonstrating that transcranial direct current stimulation (tDCS) applied over cortical regions can enhance brain function, tDCS therapies have yet to translate to the clinic (Yavari et al., 2017a). A key factor prohibiting clinical translation has been the inability to consistently yield robust tDCS effects (Li et al., 2015). Thus, researchers need to look to new strategies to enhance outcomes. One strategy that has shown promise in studies investigating motor and visual cortex excitability entails the application of a prior period of tDCS (i.e., priming) before a subsequent period of non-invasive brain stimulation (NIBS), which has involved either tDCS or repetitive transcranial magnetic stimulation (rTMS). Using this strategy, researchers have shown that tDCS priming can alter the effects of subsequent NIBS in a manner that shows potential with respect to generating more robust outcomes. The altered effects have been attributed to the initial priming stimulation setting in motion regulatory metaplastic mechanisms that protect against subsequent under- or overactivity. In considering the potential of tDCS priming protocols to boost effects through metaplastic interactions, in this review we first provide a brief introduction to metaplasticity (Section 2), and then report on studies investigating effects of tDCS priming protocols on motor cortex excitability (Section 3) and visual cortex excitability (Section 4). To ensure that readers can easily interpret each study’s design and outcomes, Table 1 displays the methodology and results of the reviewed studies in a visual format, with results symbols colour coded to indicate whether the outcomes were consistent with standard expected effects (black/grey) or with effects expected based on principles of metaplasticity (red). In cases where the outcomes could be consistent with metaplasticity but a lack of critical control conditions prevented confirmation of this, the results symbol is coloured with black and red
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stripes. The right column of Table 1 summarises all outcomes that could be consistent with metaplasticity.
2
Brief background on metaplasticity in relation to tDCS priming
Neurons can modify their structure and function in response to activity and, depending on the activity, undergo persistent forms of synaptic plasticity involving longterm-potentiation (an increase in synaptic strength, otherwise known as LTP) or long-termdepression (a decrease in synaptic strength, otherwise known as LTD) (Takeuchi et al., 2014; Thompson, 2000). In the Bienenstock et al. (1982) model of synaptic modification (referred to as BCM), in order to preserve network stability and allow for ongoing LTP or LTD, a bidirectional sliding threshold dynamically adjusts depending on prior synaptic activity. The model was later extended to incorporate homeostatic regulatory mechanisms that work between distinct periods of activity to keep plasticity within a physiologically useful range, resulting in what is often referred to as homeostatic metaplasticity (Cooper and Bear, 2012), which contrasts with non-homeostatic forms of metaplasticity (Karabanov et al., 2015). Metaplasticity is distinguished from conventional plasticity in that the plasticity of the current state of the neuron depends on past states induced by separate prior events (Hulme et al., 2013), which can be excitatory or inhibitory in nature. Importantly, the BCM model of homeostatic metaplasticity dictates that prior excitation will elevate the excitation threshold and thus decrease the predisposition for excitation, whereas prior inhibition will lower the excitation threshold and thus increase the predisposition for excitation. These scenarios could provide tDCS researchers with unique windows to apply stimulation and capitalise on the altered propensity for change. The following sections review studies that investigated this possibility using tDCS priming protocols. However, before considering the findings from these studies, it is
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important to point out that both tDCS and transcranial magnetic stimulation (TMS) are associated with highly variable inter-and intra-individual responsiveness (Brückner and Kammer, 2016; Chew et al., 2015; Datta et al., 2012; López-Alonso et al., 2014; Wiethoff et al., 2014). Although group level effects have been reported in numerous studies, their value has been diminished by inconsistency across studies and by reports of low intra-individual reliability across multiple sessions (Brückner and Kammer, 2016; Dyke et al., 2016). Nevertheless, evidence shows that individuals more sensitive to single-pulse TMS yielded greater tDCS effects (Labruna et al., 2016), and in some of the metaplasticity studies reviewed here individuals showing greater responsiveness to tDCS also showed more robust outcomes following rTMS (Bocci et al., 2014; Lang et al., 2004; Siebner et al., 2004). In sum, although it is encouraging to see evidence of consistency in responsiveness at an intraindividual level, and this bodes well with respect to efforts to develop individualised protocols (Giordano et al., 2017; Yavari et al., 2017b), readers should keep in mind that variability in outcomes is clearly an issue limiting the utility of these NIBS tools.
3
Motor cortex studies demonstrate tDCS priming can elicit metaplastic outcomes
This section focuses solely on studies measuring the amplitude of motor evoked potentials (MEPs, as indexed using TMS) that did not involve participants making voluntary movements (in association with behavioural tests), as the threshold for plasticity can be influenced by prior or concurrent voluntary muscular activity (Ridding and Ziemann, 2010), thus making it impossible to attribute any changes in plasticity specifically to the NIBS. The seminal tDCS priming studies, Siebner et al. (2004) and Lang et al. (2004), revealed that when 10 min of 1 mA active tDCS priming was followed 10 min later by a subthreshold rTMS protocol (which alone had no influence on MEP amplitude), the standard polaritydependent aftereffects induced by tDCS on its own reversed: anodal tDCS (AtDCS) priming
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was associated with reduced MEP amplitudes and cathodal tDCS (CtDCS) priming was associated with increased MEP amplitudes. Moreover, individuals showing the largest excitability changes following the tDCS priming had the greatest reversals post rTMS. These outcomes are consistent with homeostatic metaplasticity patterns seen at a neuronal level. Consistent with the seminal tDCS priming studies, which used a subthreshold rTMS protocol, evidence of metaplastic interactions also emerged in more recent studies that applied 10 or more minutes of tDCS priming prior to an excitatory rTMS protocol. Namely, AtDCS priming abolished or reversed MEP increases induced by rTMS when the period of rTMS commenced immediately after the tDCS period (Cambieri et al., 2012; Cosentino et al., 2012) or when they were separated by 30 min (Cosentino et al., 2012), and the metaplastic outcomes persisted when a second period of rTMS was applied immediately following the first (commencing 10 min post AtDCS priming) (Cambieri et al., 2012). Conversely, with prior CtDCS priming, the excitatory rTMS protocols still induced excitatory changes (Cambieri et al., 2012; Cosentino et al., 2012), which could suggest that metaplasticity affected the outcomes given that CtDCS had an attenuating influence on MEP amplitudes in the subthreshold rTMS studies (Lang et al., 2004; Siebner et al., 2004). However, in the absence of sham rTMS (SrTMS) comparison conditions in Cosentino et al. (2012) and Cambieri et al. (2012), a viable alternative interpretation of the results from the CtDCS conditions is that the priming had no effect, which seems plausible in light of recent reports indicating low reliability and high variability for post-stimulation CtDCS effects (Dyke et al., 2016; Strube et al., 2016; Wiethoff et al., 2014). The application of 1 mA tDCS priming prior to a subsequent period of 1 mA tDCS also yielded outcomes indicative of metaplastic interactions (Fricke et al., 2011; Monte-Silva et al., 2013; Monte-Silva et al., 2010). Namely, in contrast to the standard polarity-dependent aftereffects seen following single periods of tDCS and the prolongation of these standard
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polarity-dependent aftereffects when a second dose of tDCS was applied consecutively (i.e., 0-min delay; except, as discussed later in this section, in the case of an unusually long continuous period that spanned 26 min), metaplastic outcomes emerged in several cases when a delay was introduced prior to applying a second period of tDCS. Of note, in Fricke et al. (2011), the standard polarity-dependent aftereffects were abolished or reversed when a brief delay intervened between two 5 or 7 min periods of CtDCS or AtDCS (such that the second dose occurred during the aftereffects of the first dose, as indicated by the duration of singledose effects). Moreover, in some cases, the reversed aftereffects outlasted the aftereffects of a continuous dose of tDCS, which indicates that these priming protocols have the potential to confer enhanced effects. However, it should be noted that metaplastic outcomes did not emerge when a brief delay was inserted between two 9 min periods of CtDCS (Monte-Silva et al., 2010), yet consistent with metaplasticity, inserting a brief delay between two 13 min periods of AtDCS disrupted the expected excitatory effects (Monte-Silva et al., 2013). Thus, although the findings from priming protocols with a brief delay between two periods of tDCS have been somewhat variable, overall it seems that shorter periods of tDCS may be more effective for generating metaplastic outcomes. Metaplastic outcomes also emerged when applying the second period of tDCS outside of the timeframe of the priming-period aftereffects, such that the delay exceeded the duration of single-dose effects. Specifically, standard inhibitory effects associated with a continuous dose of CtDCS were delayed for at least 25 min (Monte-Silva et al., 2010), and standard excitatory effects associated with a single dose of AtDCS were abolished or reversed into inhibitory effects (Fricke et al., 2011; Monte-Silva et al., 2013). However, note that inserting a delay that exceeded the timeframe of the priming period aftereffects did not always yield outcomes consistent with metaplastic interactions. Namely, when two 5 min periods of AtDCS or CtDCS were separated by a 30 min delay, standard polarity-dependent effects
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emerged (Fricke et al., 2011). Given that increasing the priming period to 7 min of AtDCS reversed the outcomes, it seems likely that the triggering of metaplastic interactions depends on combined influences of priming dose and delay interval. Irrespective of the intricacies, outcomes from each of these studies demonstrate that applying the second period of tDCS outside of the window of tDCS priming aftereffects can yield metaplastic outcomes. However, the magnitude of change induced in these conditions did not exceed that of a continuous period of tDCS. Thus, in contrast to some of the tDCS-tDCS priming protocols that involved a brief delay, there is no indication that outcomes can be boosted when the second period of tDCS is applied after the priming effects have subsided. One particularly interesting finding from the studies reviewed in this section is that an extended period of continuous tDCS reversed standard polarity-dependent aftereffects. Specifically, in Monte-Silva et al. (2013), a 26 min period of AtDCS reduced subsequent MEP amplitudes for 120 min. We presume this atypical outcome reflects the unusually long stimulation period. Consistent with this conjecture, reversals in standard rTMS outcomes have also emerged when doubling the duration of inhibitory or excitatory protocols (Gamboa et al., 2010) and when applying two excitatory rTMS protocols back-to-back with no intervening delay (Rothkegel et al., 2010). Interestingly, standard polarity-dependent aftereffects have also been reversed by increasing the intensity of a 20 min period of CtDCS from 1 to 2 mA (Batsikadze et al., 2013). Strictly speaking based on the BCM model, such reversals should not be attributable to metaplasticity as the protocols did not involve two distinct periods of stimulation (Hulme et al., 2013). However, given that a single bout of activity has been shown to simultaneously trigger both conventional synaptic and metaplastic regulatory processes (Abraham, 2008), it may be possible that homeostatic metaplastic processes regulated activity during the single bout of NIBS. More broadly, reversed outcomes following lengthier and higher intensity periods of tDCS indicate that researchers wanting to
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elicit standard polarity-dependent aftereffects might be best to apply a lower dose of stimulation. Taken together, the studies reviewed in this section provide sufficient evidence to indicate that tDCS priming protocols involving a subsequent period of rTMS or tDCS can influence subsequent motor excitability in a metaplastic manner. With respect to boosting outcomes, the most promising protocols from this section involved two periods of tDCS with the second period applied during the aftereffects of the priming. Of note, two 5 min periods of CtDCS separated by a 3 min delay elicited excitatory effects that lasted twice as long as a continuous 10 min dose of AtDCS, and two 5 min periods of AtDCS separated by a 3 min delay elicited inhibitory effects that lasted twice as long as a continuous 10 min dose of CtDCS (Fricke et al., 2011). The more enduring effects afforded by tDCS priming bode well with respect to efforts to develop more effective protocols for improving brain function. Yet, there remains a clear need for studies that systematically manipulate the doses and delay interval to identify the most effective protocols.
4
Visual cortex studies demonstrate tDCS priming can elicit metaplastic outcomes
Occipital cortex research provides evidence that tDCS priming can change visual excitability in a manner similar to the metaplastic patterns seen in motor cortex studies. In the seminal study, Lang et al. (2007) found that while 10 min of 1 mA AtDCS reduced the subsequent phosphene threshold (i.e., the level of single-pulse TMS output required to cause the participant to perceive an illusory flash of light) for about 20 min, consistent with standard polarity-dependent effects, application of a subsequent period of subthreshold rTMS (which alone had no influence on phosphene threshold) negated the excitatory effects and thus provided tentative evidence for metaplastic interactions. In contrast, although CtDCS increased subsequent phosphene thresholds, these standard polarity-dependent effects were
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more short-lived and CtDCS priming prior to subthreshold rTMS had no influence on subsequent phosphene thresholds, indicating that the CtDCS priming protocol was ineffective, which contrasts with motor cortex findings (Lang et al., 2004; Siebner et al., 2004). More convincing evidence of metaplastic interactions emerged when Bocci et al. (2014) applied a higher priming dose (20 min of 1.5 mA tDCS) and used suprathreshold rTMS protocols. Specifically, when a slightly inhibitory 1 Hz rTMS protocol was preceded by AtDCS priming, the excitatory effects of AtDCS on its own (see AtDCS-SrTMS protocol in Table 1) were reversed such that visual evoked potential (VEP) amplitudes were significantly reduced for 60 min. These inhibitory effects outstripped those induced by the equivalent sham tDCS protocol and the CtDCS-SrTMS protocol, which demonstrates that tDCS priming protocols can boost outcomes. Metaplastic outcomes also emerged when CtDCS priming preceded the 1 Hz rTMS protocol (i.e., the inhibitory effects of CtDCS on its own reversed into VEP increases), but in this case the effects did not outstrip the excitatory effects induced by the AtDCS-SrTMS protocol (i.e., the priming protocol did not yield added benefits). When active priming preceded a slightly excitatory 5 Hz rTMS protocol, polaritydependent reversals also occurred, but in the case of the CtDCS priming protocol the reversed effects were shorter lived. Overall, the tDCS priming protocols that involved the slightly inhibitory 1 Hz rTMS provided the most promising outcomes. Importantly, the level of change in VEP amplitudes after tDCS correlated with the largest reversals post rTMS, which parallels the NIBS motor sensitivity findings (Lang et al., 2004; Siebner et al., 2004). In sum, tDCS priming protocols over visual cortex induced changes in the direction, magnitude, and duration of effects that are indicative of metaplastic interactions and are in line with changes seen in the motor cortex studies. The protocols that induced the most robust metaplastic outcomes included a delay after the tDCS priming, and used higher priming
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current strength (1.5 mA) followed by a slightly inhibitory suprathreshold rTMS protocol. However, as most of these variables were not systematically manipulated, it is not possible from these studies to single out the variables key to boosting outcomes. Moreover, as no visual cortex studies have reported on tDCS-tDCS priming protocols, which yielded the most promising motor outcomes, it remains unclear how the tDCS-rTMS priming protocols might stack up in the context of visual cortex.
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Metaplasticity summary
The present review indicates that metaplastic like phenomena occur in response to tDCS priming protocols applied over motor and visual cortex. The effects elicited by these protocols fit with the growing body of evidence demonstrating that the state of the brain at one point in time can influence outcomes at a later point. Of particular relevance with respect to boosting outcomes, in some instances tDCS priming protocols elicited more robust effects than equivalent protocols without priming. However, as priming protocols elicited a range of metaplastic outcomes that varied between studies in a way that could not be clearly accounted for by parameter differences (e.g., dose and delay interval), excitement about the prospect of heightened gains must be tempered appropriately. Moreover, no insight could to gleaned as to whether the instances of boosted outcomes have clinical potential as all of the studies reviewed here involved healthy populations, in which effects may differ from clinical populations (Bikson et al., 2012). In sum, while the studies to date indicate potential for tDCS priming to boost post-stimulation outcomes, considerable future research involving systematic manipulation of the relevant variables and suitable comparison control conditions is needed to determine optimal protocols for exploiting these natural mechanisms.
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References
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Running head: METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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Table 1. Summary of motor and visual studies using tDCS priming protocols Study
Sample Stimulation
tDCS Priming Protocol and Outcomes
Metaplastic Results
First author (year)
N ppts
Duration and details of the two stimulation periods: tDCS polarity (A = anodal, C = cathodal, S = sham) and strength (mA), delay interval duration, rTMS active or sham (SrTMS). Outcomes: increase (up arrow), decrease (down arrow), or no change (x).
This column details only outcomes consistent with tDCS priming yielding subsequent metaplastic changes.
tDCS electrode positions and rTMS protocol
Motor studies applying tDCS priming prior to rTMS First author (year) Siebner
N ppts
(2004)
8 ppts
active/reference rTMS dose
Baseline MEPs
tDCS priming
LM1/RSO
Delay
10 min
15 min S
1 Hz rTMS@85% RMT (subthreshold)
5 ppts* Lang (2004)
10 ppts
A
10-min MS
1
C
1
A
1
C
MS 10-min MS 10-min MS
S
10-min MS 10-min
1 10 min
5 Hz rTMS@100% AMT (subthreshold)
TMS 10-min TMS 10-min
A
1
C 1
10-min TMS
A
1
5 ppts*
10-min rTMS 10-min rTMS
C
1 Cosentino (2012)
LM1/RSO 12 ppts
5 Hz rTMS@120% RMT (suprathreshold)
12 min
rT
MS
15 min 1.5 (2 xAbaseline C 1.5 sessions) S 1.5
Significant differences compared to (cf) baseline, unless stated in bold. Mean MEPs post rTMS
rT rT SrT
Decrease post rTMS.
SrT
Increase post rTMS.
r 20 sec r
0-8 min
10-18 min
Mean MEPs post rTMS Expected increases post rTMS counteracted at 08 and reversed at 10-18 min cf AtDCS-SrTMS.
r
1
Expected decreases post rTMS counteracted at 0-8 and reversed at 10-18 min cf CtDCS-SrTMS.
S S MEPs during rTMS (6 rTMS trains of 10 pulses every 2 min)
rT
MS 0-min
Expected increases during rTMS reversed. rT
Increases during rTMS not counteracted by CtDCS priming.
rT
MS 0-min rT
7 ppts* LM1/R Shoulder
MS 10 min rT
11 ppts
10-20 min
rT MS 0-min MS
A 1.5
(2012)
0-10 min
12 min
7 ppts* Cambieri
MEPs (direction of change )
rT
1
1 LM1/RSO
rTMS
5 Hz rTMS@120% RMT (suprathreshold)
MS
A 1 10 min C 1
30-min MS 0-min 0-min MS
rT
rT
0-10 min MS rT MS
Expected increases during rTMS counteracted.
10-20 min rT
MEPs during rTMS (5 rTMS trains of 10 pulses every 2 min) Expected increases during rTMS counteracted at 0-10 and 10-20 min.
0-min
Increases during rTMS not counteracted by CtDCS priming at 0-10 or 10-20 min.
Motor studies applying tDCS priming prior to tDCS First author (year) MonteSilva (2010)
N ppts
active/reference
Baseline MEPs
tDCS priming
Delay
tDCS
Post tDCS MEPs change direction
LM1/RSO 9 min 1
C
1
C
1
9 min C
C
C
1
1 1
C
1 C
1
C
C 1
change duration
Significant differences cf baseline, unless stated in bold. Mean MEPs post tDCS at 0, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min, same evening and next day (ND)
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
2
12 ppts
Fricke (2011)
0-60
12 ppts
0-min
0-90
12 ppts
3-min
0-120
Decrease prolonged for extra 30 min.
12 ppts
20-min
0-120 20-30
12 ppts
3-hr
60
12 ppts
24-hr
25, 60-120
Decrease prolonged for extra 30 min. Greater decrease at 20-30 min cf 0-min delay protocol. Decrease disrupted (significant only at 60 min post). Decrease disrupted (significant only at 25 and 60120 min). Mean MEPs post tDCS at 0, 1, 2, 3, 4, 10, 15, 20, 25, 30, 60 and 90 min
LM1/RSO 9 ppts
5 min
5 min 0-5 0-min
0-30
3-min
15-30 0-60
30-min 8 ppts
5 min
Increase at 15-30 min. Increase at 0-60 min cf 0-min delay CtDCS protocol.
0-5 5 min 0-5
8 ppts
0-min
0-30
3-min
1-3 10-30
30-min
0-5
5 min
Decrease at 10-30 min cf 0-min delay AtDCS protocol.
5 min 0-2 1-min
No expected increase.
10-min
0-25
20-min 12 ppts
7 min
Decrease for 25 min. No expected increase.
5 min 0-20 1-min
No expected increase. 10-12 0-60
3-min A 1 1 1 MonteSilva (2013)
15 ppts
A A
10-min 1 20-min 1 30-min 1
A
0-20
A A
1 No expected increase.
LM1/RSO 13 min
A1
Decrease at 10-12 min. Decrease at 0-60 min cf single dose 7 min AtDCS protocol. No expected increase. Decrease at 0-20 min cf single dose 7 min AtDCS protocol.
Mean MEPs post tDCS at 0, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min, same evening and next day (ND)
13 min A1
0-60
0-min
A1
0-120
Unexpected decrease at 0-120 min.
A1 A1
3-min
A1 A1
0, ND
A1
20-min
A1
ND
Increase at 0 min and ND (i.e., largely delayed excitatory effects). Increase ND only (i.e., delayed excitatory effects).
20
Decrease at 20 min.
A1 A1
3-hr
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
3 24-hr
5
Decrease at 5 min.
Visual studies applying tDCS priming prior to rTMS First author (year) Lang
N ppts
active/reference rTMS dose
9 ppts
Oz/Cz
Baseline PT/VEP
tDCS priming
Delay
10 min
15 min
S (2007)
1 x 20 sec 5 Hz rTMS@90% phosphene threshold (subthreshold)
1
A
1
C
1
A
1
C
1 Bocci
10 ppts
Oz/R Shoulder
A 1.5 20 min C 1.5 1.5
(2014)
S A
1 Hz rTMS@85% RMT (suprathreshold)
rTMS
1.5 C 1.5
none MS none MS MS none MS none MS none MS
Post rTMS PT/VEPs direction of change 0 min 5 min 15 min
rT rT SrT SrT
0 min 30 min 60 min
MS 15-20 rT min MS 1 Hz 15-20 rT min MS 1 Hz 15-20 min
1.5
A
1.5
C
1.5
15-20 rT min5 Hz MS
rT
MS 5 Hz rT 15-20 MS 5 Hz min
60 sec
5 Hz rTMS@85% RMT (suprathreshold)
Mean VEPs post rTMS (increase indicates excitatory change)
rT
MS 1 Hz S
Mean PT post rTMS (decrease indicates excitatory change) Expected decrease post rTMS counteracted cf AtDCS-SrTMS.
rT
SrT 20 SrTmin
Significant difference as a percentage of baseline
15-20 min 15-20 min 15-20 min
*
Decrease at 0-60 min post rTMS (i.e., prolonged inhibitory effects). *Greater decrease cf CtDCSSrTMS and StDCS-1Hz rTMS. Increase at 0-60 min post rTMS (inhibitory protocol).
Decrease at 0-60 min post rTMS (excitatory protocol). Increase post rTMS. Greater increase cf StDCS5Hz rTMS.
ppts* = participants from main pool retested. tDCS electrode positions: Cz = central midpoint, L = left, M1 = primary motor cortex, Oz = central occipital cortex, R = right, SO = supraorbital area. rTMS protocol: AMT = active motor threshold, Hz = Hertz (times per second), RMT = resting motor threshold. Outcome measures: MEP = motor evoked potential, PT = phosphene threshold, VEP = visual evoked potential. Protocol symbols and colours:
= single-pulse TMS, orange = rTMS, green = tDCS.
Result symbols and colours: upward arrow = increase, downward arrow = decrease, grey arrow = trend level change consistent with standard expected effect, x = no change, black = result consistent with standard expected effect, red = result consistent with metaplasticity, black/red striped = result could be consistent with metaplasticity (additional research needed to confirm).
S0149-7634(17)30380-9 https://doi.org/10.1016/j.neubiorev.2017.09.029 NBR 2958
To appear in: Received date: Revised date: Accepted date:
22-5-2017 8-9-2017 26-9-2017
Please cite this article as: Hurley, Roanne, Machado, Liana, Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes?.Neuroscience and Biobehavioral Reviews https://doi.org/10.1016/j.neubiorev.2017.09.029 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Running head: METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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Using tDCS priming to improve brain function: Can metaplasticity provide the key to boosting outcomes?
Roanne Hurley and Liana Machado* University of Otago and Brain Research New Zealand
Author Note Roanne Hurley, Department of Psychology and Brain Health Research Centre, University of Otago, Dunedin, New Zealand and Brain Research New Zealand, Auckland, New Zealand; Liana Machado, Department of Psychology and Brain Health Research Centre, University of Otago, Dunedin, New Zealand and Brain Research New Zealand, Auckland, New Zealand. This research was supported by a Fanny Evans Postgraduate Scholarship, the Neurological Foundation of New Zealand (1315-SPG), and the University of Otago. *Correspondence concerning this article should be addressed to Dr. Liana Machado, Department of Psychology, University of Otago, William James Building, 275 Leith Walk, Dunedin 9054, New Zealand. E-mail: [email protected]
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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Highlights
tDCS priming protocols show promise over traditional continuous stimulation.
Metaplastic regulatory mechanisms appear to underpin the enhanced effects. More research investigating optimal priming doses and delay periods is needed.
Abstract
Transcranial direct current stimulation (tDCS) has been trialled by many researchers attempting to improve brain function. Outcomes have been quite variable with seemingly similar protocols yielding either inconsistent or insufficiently robust improvements for clinical translation. A potentially fruitful avenue for increasing benefits conferred by tDCS stems from findings from motor and visual cortex studies that indicate tDCS priming prior to a subsequent period of stimulation (tDCS or transcranial magnetic stimulation) can in some cases boost outcomes compared to protocols without priming. The heightened effects from tDCS priming protocols are thought to be underpinned by metaplastic interactions, in which the state induced by the priming influences the effects of the second stimulation period. The purpose of the current review is to evaluate the potential of tDCS priming protocols to boost outcomes. After dissecting the literature, we conclude that although outcomes have varied, tDCS priming protocols have demonstrated sufficient promise to warrant attention from researchers trying to enhance the efficacy of tDCS. Key Words: electrical brain stimulation; transcranial direct current stimulation; transcranial magnetic stimulation; TMS; rTMS; non-invasive brain stimulation; NIBS; motor; MEP; visual; VEP; priming protocols
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Introduction
Despite numerous studies demonstrating that transcranial direct current stimulation (tDCS) applied over cortical regions can enhance brain function, tDCS therapies have yet to translate to the clinic (Yavari et al., 2017a). A key factor prohibiting clinical translation has been the inability to consistently yield robust tDCS effects (Li et al., 2015). Thus, researchers need to look to new strategies to enhance outcomes. One strategy that has shown promise in studies investigating motor and visual cortex excitability entails the application of a prior period of tDCS (i.e., priming) before a subsequent period of non-invasive brain stimulation (NIBS), which has involved either tDCS or repetitive transcranial magnetic stimulation (rTMS). Using this strategy, researchers have shown that tDCS priming can alter the effects of subsequent NIBS in a manner that shows potential with respect to generating more robust outcomes. The altered effects have been attributed to the initial priming stimulation setting in motion regulatory metaplastic mechanisms that protect against subsequent under- or overactivity. In considering the potential of tDCS priming protocols to boost effects through metaplastic interactions, in this review we first provide a brief introduction to metaplasticity (Section 2), and then report on studies investigating effects of tDCS priming protocols on motor cortex excitability (Section 3) and visual cortex excitability (Section 4). To ensure that readers can easily interpret each study’s design and outcomes, Table 1 displays the methodology and results of the reviewed studies in a visual format, with results symbols colour coded to indicate whether the outcomes were consistent with standard expected effects (black/grey) or with effects expected based on principles of metaplasticity (red). In cases where the outcomes could be consistent with metaplasticity but a lack of critical control conditions prevented confirmation of this, the results symbol is coloured with black and red
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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stripes. The right column of Table 1 summarises all outcomes that could be consistent with metaplasticity.
2
Brief background on metaplasticity in relation to tDCS priming
Neurons can modify their structure and function in response to activity and, depending on the activity, undergo persistent forms of synaptic plasticity involving longterm-potentiation (an increase in synaptic strength, otherwise known as LTP) or long-termdepression (a decrease in synaptic strength, otherwise known as LTD) (Takeuchi et al., 2014; Thompson, 2000). In the Bienenstock et al. (1982) model of synaptic modification (referred to as BCM), in order to preserve network stability and allow for ongoing LTP or LTD, a bidirectional sliding threshold dynamically adjusts depending on prior synaptic activity. The model was later extended to incorporate homeostatic regulatory mechanisms that work between distinct periods of activity to keep plasticity within a physiologically useful range, resulting in what is often referred to as homeostatic metaplasticity (Cooper and Bear, 2012), which contrasts with non-homeostatic forms of metaplasticity (Karabanov et al., 2015). Metaplasticity is distinguished from conventional plasticity in that the plasticity of the current state of the neuron depends on past states induced by separate prior events (Hulme et al., 2013), which can be excitatory or inhibitory in nature. Importantly, the BCM model of homeostatic metaplasticity dictates that prior excitation will elevate the excitation threshold and thus decrease the predisposition for excitation, whereas prior inhibition will lower the excitation threshold and thus increase the predisposition for excitation. These scenarios could provide tDCS researchers with unique windows to apply stimulation and capitalise on the altered propensity for change. The following sections review studies that investigated this possibility using tDCS priming protocols. However, before considering the findings from these studies, it is
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important to point out that both tDCS and transcranial magnetic stimulation (TMS) are associated with highly variable inter-and intra-individual responsiveness (Brückner and Kammer, 2016; Chew et al., 2015; Datta et al., 2012; López-Alonso et al., 2014; Wiethoff et al., 2014). Although group level effects have been reported in numerous studies, their value has been diminished by inconsistency across studies and by reports of low intra-individual reliability across multiple sessions (Brückner and Kammer, 2016; Dyke et al., 2016). Nevertheless, evidence shows that individuals more sensitive to single-pulse TMS yielded greater tDCS effects (Labruna et al., 2016), and in some of the metaplasticity studies reviewed here individuals showing greater responsiveness to tDCS also showed more robust outcomes following rTMS (Bocci et al., 2014; Lang et al., 2004; Siebner et al., 2004). In sum, although it is encouraging to see evidence of consistency in responsiveness at an intraindividual level, and this bodes well with respect to efforts to develop individualised protocols (Giordano et al., 2017; Yavari et al., 2017b), readers should keep in mind that variability in outcomes is clearly an issue limiting the utility of these NIBS tools.
3
Motor cortex studies demonstrate tDCS priming can elicit metaplastic outcomes
This section focuses solely on studies measuring the amplitude of motor evoked potentials (MEPs, as indexed using TMS) that did not involve participants making voluntary movements (in association with behavioural tests), as the threshold for plasticity can be influenced by prior or concurrent voluntary muscular activity (Ridding and Ziemann, 2010), thus making it impossible to attribute any changes in plasticity specifically to the NIBS. The seminal tDCS priming studies, Siebner et al. (2004) and Lang et al. (2004), revealed that when 10 min of 1 mA active tDCS priming was followed 10 min later by a subthreshold rTMS protocol (which alone had no influence on MEP amplitude), the standard polaritydependent aftereffects induced by tDCS on its own reversed: anodal tDCS (AtDCS) priming
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was associated with reduced MEP amplitudes and cathodal tDCS (CtDCS) priming was associated with increased MEP amplitudes. Moreover, individuals showing the largest excitability changes following the tDCS priming had the greatest reversals post rTMS. These outcomes are consistent with homeostatic metaplasticity patterns seen at a neuronal level. Consistent with the seminal tDCS priming studies, which used a subthreshold rTMS protocol, evidence of metaplastic interactions also emerged in more recent studies that applied 10 or more minutes of tDCS priming prior to an excitatory rTMS protocol. Namely, AtDCS priming abolished or reversed MEP increases induced by rTMS when the period of rTMS commenced immediately after the tDCS period (Cambieri et al., 2012; Cosentino et al., 2012) or when they were separated by 30 min (Cosentino et al., 2012), and the metaplastic outcomes persisted when a second period of rTMS was applied immediately following the first (commencing 10 min post AtDCS priming) (Cambieri et al., 2012). Conversely, with prior CtDCS priming, the excitatory rTMS protocols still induced excitatory changes (Cambieri et al., 2012; Cosentino et al., 2012), which could suggest that metaplasticity affected the outcomes given that CtDCS had an attenuating influence on MEP amplitudes in the subthreshold rTMS studies (Lang et al., 2004; Siebner et al., 2004). However, in the absence of sham rTMS (SrTMS) comparison conditions in Cosentino et al. (2012) and Cambieri et al. (2012), a viable alternative interpretation of the results from the CtDCS conditions is that the priming had no effect, which seems plausible in light of recent reports indicating low reliability and high variability for post-stimulation CtDCS effects (Dyke et al., 2016; Strube et al., 2016; Wiethoff et al., 2014). The application of 1 mA tDCS priming prior to a subsequent period of 1 mA tDCS also yielded outcomes indicative of metaplastic interactions (Fricke et al., 2011; Monte-Silva et al., 2013; Monte-Silva et al., 2010). Namely, in contrast to the standard polarity-dependent aftereffects seen following single periods of tDCS and the prolongation of these standard
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polarity-dependent aftereffects when a second dose of tDCS was applied consecutively (i.e., 0-min delay; except, as discussed later in this section, in the case of an unusually long continuous period that spanned 26 min), metaplastic outcomes emerged in several cases when a delay was introduced prior to applying a second period of tDCS. Of note, in Fricke et al. (2011), the standard polarity-dependent aftereffects were abolished or reversed when a brief delay intervened between two 5 or 7 min periods of CtDCS or AtDCS (such that the second dose occurred during the aftereffects of the first dose, as indicated by the duration of singledose effects). Moreover, in some cases, the reversed aftereffects outlasted the aftereffects of a continuous dose of tDCS, which indicates that these priming protocols have the potential to confer enhanced effects. However, it should be noted that metaplastic outcomes did not emerge when a brief delay was inserted between two 9 min periods of CtDCS (Monte-Silva et al., 2010), yet consistent with metaplasticity, inserting a brief delay between two 13 min periods of AtDCS disrupted the expected excitatory effects (Monte-Silva et al., 2013). Thus, although the findings from priming protocols with a brief delay between two periods of tDCS have been somewhat variable, overall it seems that shorter periods of tDCS may be more effective for generating metaplastic outcomes. Metaplastic outcomes also emerged when applying the second period of tDCS outside of the timeframe of the priming-period aftereffects, such that the delay exceeded the duration of single-dose effects. Specifically, standard inhibitory effects associated with a continuous dose of CtDCS were delayed for at least 25 min (Monte-Silva et al., 2010), and standard excitatory effects associated with a single dose of AtDCS were abolished or reversed into inhibitory effects (Fricke et al., 2011; Monte-Silva et al., 2013). However, note that inserting a delay that exceeded the timeframe of the priming period aftereffects did not always yield outcomes consistent with metaplastic interactions. Namely, when two 5 min periods of AtDCS or CtDCS were separated by a 30 min delay, standard polarity-dependent effects
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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emerged (Fricke et al., 2011). Given that increasing the priming period to 7 min of AtDCS reversed the outcomes, it seems likely that the triggering of metaplastic interactions depends on combined influences of priming dose and delay interval. Irrespective of the intricacies, outcomes from each of these studies demonstrate that applying the second period of tDCS outside of the window of tDCS priming aftereffects can yield metaplastic outcomes. However, the magnitude of change induced in these conditions did not exceed that of a continuous period of tDCS. Thus, in contrast to some of the tDCS-tDCS priming protocols that involved a brief delay, there is no indication that outcomes can be boosted when the second period of tDCS is applied after the priming effects have subsided. One particularly interesting finding from the studies reviewed in this section is that an extended period of continuous tDCS reversed standard polarity-dependent aftereffects. Specifically, in Monte-Silva et al. (2013), a 26 min period of AtDCS reduced subsequent MEP amplitudes for 120 min. We presume this atypical outcome reflects the unusually long stimulation period. Consistent with this conjecture, reversals in standard rTMS outcomes have also emerged when doubling the duration of inhibitory or excitatory protocols (Gamboa et al., 2010) and when applying two excitatory rTMS protocols back-to-back with no intervening delay (Rothkegel et al., 2010). Interestingly, standard polarity-dependent aftereffects have also been reversed by increasing the intensity of a 20 min period of CtDCS from 1 to 2 mA (Batsikadze et al., 2013). Strictly speaking based on the BCM model, such reversals should not be attributable to metaplasticity as the protocols did not involve two distinct periods of stimulation (Hulme et al., 2013). However, given that a single bout of activity has been shown to simultaneously trigger both conventional synaptic and metaplastic regulatory processes (Abraham, 2008), it may be possible that homeostatic metaplastic processes regulated activity during the single bout of NIBS. More broadly, reversed outcomes following lengthier and higher intensity periods of tDCS indicate that researchers wanting to
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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elicit standard polarity-dependent aftereffects might be best to apply a lower dose of stimulation. Taken together, the studies reviewed in this section provide sufficient evidence to indicate that tDCS priming protocols involving a subsequent period of rTMS or tDCS can influence subsequent motor excitability in a metaplastic manner. With respect to boosting outcomes, the most promising protocols from this section involved two periods of tDCS with the second period applied during the aftereffects of the priming. Of note, two 5 min periods of CtDCS separated by a 3 min delay elicited excitatory effects that lasted twice as long as a continuous 10 min dose of AtDCS, and two 5 min periods of AtDCS separated by a 3 min delay elicited inhibitory effects that lasted twice as long as a continuous 10 min dose of CtDCS (Fricke et al., 2011). The more enduring effects afforded by tDCS priming bode well with respect to efforts to develop more effective protocols for improving brain function. Yet, there remains a clear need for studies that systematically manipulate the doses and delay interval to identify the most effective protocols.
4
Visual cortex studies demonstrate tDCS priming can elicit metaplastic outcomes
Occipital cortex research provides evidence that tDCS priming can change visual excitability in a manner similar to the metaplastic patterns seen in motor cortex studies. In the seminal study, Lang et al. (2007) found that while 10 min of 1 mA AtDCS reduced the subsequent phosphene threshold (i.e., the level of single-pulse TMS output required to cause the participant to perceive an illusory flash of light) for about 20 min, consistent with standard polarity-dependent effects, application of a subsequent period of subthreshold rTMS (which alone had no influence on phosphene threshold) negated the excitatory effects and thus provided tentative evidence for metaplastic interactions. In contrast, although CtDCS increased subsequent phosphene thresholds, these standard polarity-dependent effects were
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more short-lived and CtDCS priming prior to subthreshold rTMS had no influence on subsequent phosphene thresholds, indicating that the CtDCS priming protocol was ineffective, which contrasts with motor cortex findings (Lang et al., 2004; Siebner et al., 2004). More convincing evidence of metaplastic interactions emerged when Bocci et al. (2014) applied a higher priming dose (20 min of 1.5 mA tDCS) and used suprathreshold rTMS protocols. Specifically, when a slightly inhibitory 1 Hz rTMS protocol was preceded by AtDCS priming, the excitatory effects of AtDCS on its own (see AtDCS-SrTMS protocol in Table 1) were reversed such that visual evoked potential (VEP) amplitudes were significantly reduced for 60 min. These inhibitory effects outstripped those induced by the equivalent sham tDCS protocol and the CtDCS-SrTMS protocol, which demonstrates that tDCS priming protocols can boost outcomes. Metaplastic outcomes also emerged when CtDCS priming preceded the 1 Hz rTMS protocol (i.e., the inhibitory effects of CtDCS on its own reversed into VEP increases), but in this case the effects did not outstrip the excitatory effects induced by the AtDCS-SrTMS protocol (i.e., the priming protocol did not yield added benefits). When active priming preceded a slightly excitatory 5 Hz rTMS protocol, polaritydependent reversals also occurred, but in the case of the CtDCS priming protocol the reversed effects were shorter lived. Overall, the tDCS priming protocols that involved the slightly inhibitory 1 Hz rTMS provided the most promising outcomes. Importantly, the level of change in VEP amplitudes after tDCS correlated with the largest reversals post rTMS, which parallels the NIBS motor sensitivity findings (Lang et al., 2004; Siebner et al., 2004). In sum, tDCS priming protocols over visual cortex induced changes in the direction, magnitude, and duration of effects that are indicative of metaplastic interactions and are in line with changes seen in the motor cortex studies. The protocols that induced the most robust metaplastic outcomes included a delay after the tDCS priming, and used higher priming
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current strength (1.5 mA) followed by a slightly inhibitory suprathreshold rTMS protocol. However, as most of these variables were not systematically manipulated, it is not possible from these studies to single out the variables key to boosting outcomes. Moreover, as no visual cortex studies have reported on tDCS-tDCS priming protocols, which yielded the most promising motor outcomes, it remains unclear how the tDCS-rTMS priming protocols might stack up in the context of visual cortex.
5
Metaplasticity summary
The present review indicates that metaplastic like phenomena occur in response to tDCS priming protocols applied over motor and visual cortex. The effects elicited by these protocols fit with the growing body of evidence demonstrating that the state of the brain at one point in time can influence outcomes at a later point. Of particular relevance with respect to boosting outcomes, in some instances tDCS priming protocols elicited more robust effects than equivalent protocols without priming. However, as priming protocols elicited a range of metaplastic outcomes that varied between studies in a way that could not be clearly accounted for by parameter differences (e.g., dose and delay interval), excitement about the prospect of heightened gains must be tempered appropriately. Moreover, no insight could to gleaned as to whether the instances of boosted outcomes have clinical potential as all of the studies reviewed here involved healthy populations, in which effects may differ from clinical populations (Bikson et al., 2012). In sum, while the studies to date indicate potential for tDCS priming to boost post-stimulation outcomes, considerable future research involving systematic manipulation of the relevant variables and suitable comparison control conditions is needed to determine optimal protocols for exploiting these natural mechanisms.
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Running head: METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
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Table 1. Summary of motor and visual studies using tDCS priming protocols Study
Sample Stimulation
tDCS Priming Protocol and Outcomes
Metaplastic Results
First author (year)
N ppts
Duration and details of the two stimulation periods: tDCS polarity (A = anodal, C = cathodal, S = sham) and strength (mA), delay interval duration, rTMS active or sham (SrTMS). Outcomes: increase (up arrow), decrease (down arrow), or no change (x).
This column details only outcomes consistent with tDCS priming yielding subsequent metaplastic changes.
tDCS electrode positions and rTMS protocol
Motor studies applying tDCS priming prior to rTMS First author (year) Siebner
N ppts
(2004)
8 ppts
active/reference rTMS dose
Baseline MEPs
tDCS priming
LM1/RSO
Delay
10 min
15 min S
1 Hz rTMS@85% RMT (subthreshold)
5 ppts* Lang (2004)
10 ppts
A
10-min MS
1
C
1
A
1
C
MS 10-min MS 10-min MS
S
10-min MS 10-min
1 10 min
5 Hz rTMS@100% AMT (subthreshold)
TMS 10-min TMS 10-min
A
1
C 1
10-min TMS
A
1
5 ppts*
10-min rTMS 10-min rTMS
C
1 Cosentino (2012)
LM1/RSO 12 ppts
5 Hz rTMS@120% RMT (suprathreshold)
12 min
rT
MS
15 min 1.5 (2 xAbaseline C 1.5 sessions) S 1.5
Significant differences compared to (cf) baseline, unless stated in bold. Mean MEPs post rTMS
rT rT SrT
Decrease post rTMS.
SrT
Increase post rTMS.
r 20 sec r
0-8 min
10-18 min
Mean MEPs post rTMS Expected increases post rTMS counteracted at 08 and reversed at 10-18 min cf AtDCS-SrTMS.
r
1
Expected decreases post rTMS counteracted at 0-8 and reversed at 10-18 min cf CtDCS-SrTMS.
S S MEPs during rTMS (6 rTMS trains of 10 pulses every 2 min)
rT
MS 0-min
Expected increases during rTMS reversed. rT
Increases during rTMS not counteracted by CtDCS priming.
rT
MS 0-min rT
7 ppts* LM1/R Shoulder
MS 10 min rT
11 ppts
10-20 min
rT MS 0-min MS
A 1.5
(2012)
0-10 min
12 min
7 ppts* Cambieri
MEPs (direction of change )
rT
1
1 LM1/RSO
rTMS
5 Hz rTMS@120% RMT (suprathreshold)
MS
A 1 10 min C 1
30-min MS 0-min 0-min MS
rT
rT
0-10 min MS rT MS
Expected increases during rTMS counteracted.
10-20 min rT
MEPs during rTMS (5 rTMS trains of 10 pulses every 2 min) Expected increases during rTMS counteracted at 0-10 and 10-20 min.
0-min
Increases during rTMS not counteracted by CtDCS priming at 0-10 or 10-20 min.
Motor studies applying tDCS priming prior to tDCS First author (year) MonteSilva (2010)
N ppts
active/reference
Baseline MEPs
tDCS priming
Delay
tDCS
Post tDCS MEPs change direction
LM1/RSO 9 min 1
C
1
C
1
9 min C
C
C
1
1 1
C
1 C
1
C
C 1
change duration
Significant differences cf baseline, unless stated in bold. Mean MEPs post tDCS at 0, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min, same evening and next day (ND)
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
2
12 ppts
Fricke (2011)
0-60
12 ppts
0-min
0-90
12 ppts
3-min
0-120
Decrease prolonged for extra 30 min.
12 ppts
20-min
0-120 20-30
12 ppts
3-hr
60
12 ppts
24-hr
25, 60-120
Decrease prolonged for extra 30 min. Greater decrease at 20-30 min cf 0-min delay protocol. Decrease disrupted (significant only at 60 min post). Decrease disrupted (significant only at 25 and 60120 min). Mean MEPs post tDCS at 0, 1, 2, 3, 4, 10, 15, 20, 25, 30, 60 and 90 min
LM1/RSO 9 ppts
5 min
5 min 0-5 0-min
0-30
3-min
15-30 0-60
30-min 8 ppts
5 min
Increase at 15-30 min. Increase at 0-60 min cf 0-min delay CtDCS protocol.
0-5 5 min 0-5
8 ppts
0-min
0-30
3-min
1-3 10-30
30-min
0-5
5 min
Decrease at 10-30 min cf 0-min delay AtDCS protocol.
5 min 0-2 1-min
No expected increase.
10-min
0-25
20-min 12 ppts
7 min
Decrease for 25 min. No expected increase.
5 min 0-20 1-min
No expected increase. 10-12 0-60
3-min A 1 1 1 MonteSilva (2013)
15 ppts
A A
10-min 1 20-min 1 30-min 1
A
0-20
A A
1 No expected increase.
LM1/RSO 13 min
A1
Decrease at 10-12 min. Decrease at 0-60 min cf single dose 7 min AtDCS protocol. No expected increase. Decrease at 0-20 min cf single dose 7 min AtDCS protocol.
Mean MEPs post tDCS at 0, 5, 10, 15, 20, 25, 30, 60, 90 and 120 min, same evening and next day (ND)
13 min A1
0-60
0-min
A1
0-120
Unexpected decrease at 0-120 min.
A1 A1
3-min
A1 A1
0, ND
A1
20-min
A1
ND
Increase at 0 min and ND (i.e., largely delayed excitatory effects). Increase ND only (i.e., delayed excitatory effects).
20
Decrease at 20 min.
A1 A1
3-hr
METAPLASTIC EFFECTS IN TDCS PRIMING PROTOCOLS
3 24-hr
5
Decrease at 5 min.
Visual studies applying tDCS priming prior to rTMS First author (year) Lang
N ppts
active/reference rTMS dose
9 ppts
Oz/Cz
Baseline PT/VEP
tDCS priming
Delay
10 min
15 min
S (2007)
1 x 20 sec 5 Hz rTMS@90% phosphene threshold (subthreshold)
1
A
1
C
1
A
1
C
1 Bocci
10 ppts
Oz/R Shoulder
A 1.5 20 min C 1.5 1.5
(2014)
S A
1 Hz rTMS@85% RMT (suprathreshold)
rTMS
1.5 C 1.5
none MS none MS MS none MS none MS none MS
Post rTMS PT/VEPs direction of change 0 min 5 min 15 min
rT rT SrT SrT
0 min 30 min 60 min
MS 15-20 rT min MS 1 Hz 15-20 rT min MS 1 Hz 15-20 min
1.5
A
1.5
C
1.5
15-20 rT min5 Hz MS
rT
MS 5 Hz rT 15-20 MS 5 Hz min
60 sec
5 Hz rTMS@85% RMT (suprathreshold)
Mean VEPs post rTMS (increase indicates excitatory change)
rT
MS 1 Hz S
Mean PT post rTMS (decrease indicates excitatory change) Expected decrease post rTMS counteracted cf AtDCS-SrTMS.
rT
SrT 20 SrTmin
Significant difference as a percentage of baseline
15-20 min 15-20 min 15-20 min
*
Decrease at 0-60 min post rTMS (i.e., prolonged inhibitory effects). *Greater decrease cf CtDCSSrTMS and StDCS-1Hz rTMS. Increase at 0-60 min post rTMS (inhibitory protocol).
Decrease at 0-60 min post rTMS (excitatory protocol). Increase post rTMS. Greater increase cf StDCS5Hz rTMS.
ppts* = participants from main pool retested. tDCS electrode positions: Cz = central midpoint, L = left, M1 = primary motor cortex, Oz = central occipital cortex, R = right, SO = supraorbital area. rTMS protocol: AMT = active motor threshold, Hz = Hertz (times per second), RMT = resting motor threshold. Outcome measures: MEP = motor evoked potential, PT = phosphene threshold, VEP = visual evoked potential. Protocol symbols and colours:
= single-pulse TMS, orange = rTMS, green = tDCS.
Result symbols and colours: upward arrow = increase, downward arrow = decrease, grey arrow = trend level change consistent with standard expected effect, x = no change, black = result consistent with standard expected effect, red = result consistent with metaplasticity, black/red striped = result could be consistent with metaplasticity (additional research needed to confirm).