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Abstract

Neuroplasticity is critical for learning, memory, and recovery of lost function following neurological damage. Noninvasive brain stimulation (NIBS) techniques can induce neuroplastic changes in the human cortex that are behaviorally relevant, raising the exciting possibility that these techniques might be therapeutically beneficial for neurorehabilitation following brain injury. However, the short duration and instability of induced effects currently limits their usefulness. To date, trials investigating the therapeutic value of neuroplasticity-inducing NIBS have used either single or multiple treatment sessions, typically repeated once-daily for 1 to 2 weeks. Although multiple stimulation sessions are presumed to have cumulative effects on neuroplasticity induction, there is little direct scientific evidence to support this “once-daily” approach. In animal models, the repeated application of stimulation protocols spaced using relatively short intervals (typically of the order of minutes) induces long-lasting and stable changes in synaptic efficacy. Likewise, learning through spaced repetition facilitates the establishment of long-term memory. In both cases, the spacing interval is critical in determining the outcome. Emerging evidence in healthy human populations suggests that the within-session spacing of NIBS protocols may be an effective approach for significantly prolonging the duration of induced neuroplastic changes. Similar to findings in the animal and learning literature, the interval at which spaced NIBS is applied seems to be a critical factor influencing the neuroplastic response. In this Point of View article, we propose that to truly exploit the therapeutic opportunities provided by NIBS, future clinical trials should consider the optimal spacing interval for repeated applications.

Keywords

neuroplasticity NIBS transcranial magnetic stimulation transcranial direct current stimulation long-term potentiation long-term depression learning memory

It is now well established that the human brain has a remarkable capacity to change its connectivity throughout life by interaction with the environment. This “neuroplasticity” is an essential property of the nervous system and is critical for learning, memory, and recovery from neurological damage. Recently developed noninvasive brain stimulation (NIBS) techniques can induce neuroplastic change in the human cortex,¹ sharing features in common with the plasticity observed in vitro and in vivo in animal experimentation^2,3 as well as the plasticity associated with behavioral learning.^4,5 This has provided novel opportunities to study neuroplasticity in conscious human subjects and, intriguingly, has opened up possibilities for neurorehabilitation following brain injury.

Although a number of NIBS studies have offered some promise for therapeutic application, the effects on behavior have mostly been quite small. The reasons for this are not completely clear, but interestingly, there is a disconnect between the approaches most effective for the induction and maintenance of plastic change in the animal and learning literature and those currently used in neurorehabilitation. Data from studies using animal models suggest that the repeated application of stimulation trains in a relatively tightly spaced manner (typically of the order of minutes) is important for the consolidation of plastic change, and likewise, learning a behavioral task through such spaced repetition facilitates the establishment of long-term memory. This contrasts with clinical studies investigating the therapeutic value of NIBS, which have tended to use repeated sessions of stimulation spaced over consecutive days, with little consideration for what might be the optimal interval for such spacing.

In this Point of View article, we highlight recent findings from our research as well as that from others to consider the potential of spaced NIBS for inducing long-lasting, clinically relevant neuroplasticity in the human cortex. We combine insights from animal models and the learning literature to make recommendations for future research.

NIBS and Neuroplasticity in the Human Cortex

Many NIBS studies have focused on the primary motor cortex (M1) because neuroplasticity within this region can be easily investigated by measuring the change in amplitude of peripherally recorded electromyographic potentials (motor-evoked potentials; MEPs) in response to single pulses of transcranial magnetic stimulation (TMS). With appropriate controls, increases in the size of the MEP are considered consistent with an increase in the excitability of neural circuits within M1, and conversely, smaller MEPs are consistent with decreased excitability. These excitability changes can be used as a marker of synaptic strength change in networks activated by the TMS pulse. Although other cortical regions have been targeted,^6-8 characterization of the induced effects is less straightforward.

Although many different types of neuroplasticity-inducing NIBS techniques exist, each with their own array of stimulation characteristics, for the most part, they can be grouped into 2 main modalities: one involving trains of repetitive TMS pulses (rTMS) and the other involving weak electric currents applied through 2 electrodes (1 anode and 1 cathode) attached to the scalp (transcranial direct current stimulation; tDCS). Both induce aftereffects on MEP amplitudes that outlast the period of stimulation, usually for around 30 to 60 minutes. The magnitude and direction of aftereffects depends on numerous factors, including the number, frequency, intensity, and pattern of pulses (for rTMS) and the polarity and strength of applied currents (for tDCS).¹ Additionally, when applied to the human M1, these neuroplasticity-inducing NIBS techniques have been shown to interact with and influence some forms of motor learning,^4,5 providing evidence of behavioral significance.

Although it is difficult to provide direct evidence of the mechanisms responsible for the changes in cortical excitability induced by NIBS, changes in the efficacy of cortical synaptic connections in response to stimulation are thought to play a key role. The strengthening and weakening of synaptic connections brought about by long-term potentiation (LTP) and long-term depression (LTD), respectively, has been studied extensively in animal models and represents one of a number of processes that underlie the neuroplastic capacity of the human nervous system.⁹ There are several lines of evidence that suggest that LTP-/LTD-like mechanisms are involved in the neuroplastic response to NIBS.¹⁰ For example, pharmacological studies have shown that antagonists of NMDA (N-methyl-d-aspartate) receptors, which are important for several forms of LTP and LTD,⁹ prevent the neuroplastic effects of several NIBS protocols.^2,3 Additionally, in vitro experiments in animal slice preparations show that reduced inhibitory neurotransmission through GABA_A (γ-aminobutyric acid) receptors facilitates LTP/LTD induction, and likewise, a reduction in GABAergic inhibition in humans as a result of temporary ischemic nerve block enhances rTMS-induced neuroplasticity.^11,12

Based on the evidence that NIBS can induce neuroplastic change in the cortex that appears to be a result of LTP/LTD-like mechanisms, together with the importance of these mechanisms in learning and memory, it is not surprising that there has been significant interest in using these techniques to influence behavior in both healthy individuals and patients with neurological or psychiatric disorders.¹³ However, although current NIBS techniques have provided important insights into human neuroplasticity and offered some promise for therapeutic application, there are still some significant issues associated with their use.

Limitations of Current NIBS Techniques

Early- or Late-Phase Neuroplasticity?

Despite considerable evidence linking the aftereffects of various NIBS protocols with LTP and LTD, the duration of induced effects is not entirely consistent with that seen in animal models. Whereas experimentally induced changes in synaptic efficacy can persist for many hours, days, or even weeks in vivo in awake animals,¹⁴ the changes induced by NIBS typically last no longer than ~1 hour in adults.^15,16

In animal models, at least 2 temporally and mechanistically distinct phases of LTP/LTD have been shown to exist: a transient early phase lasting less than a few hours and an enduring late phase lasting up to 8 to 10 hours in slice preparations and many days or weeks in vivo.¹⁷ Whereas early-phase LTP/LTD occurs through posttranslational modifications of preexisting proteins, late-phase LTP/LTD is also dependent on de novo protein synthesis and gene transcription.^18-22 The time course of effects suggests that the neuroplastic response to NIBS involves mechanisms similar to those responsible for early-phase LTP/LTD induction and not those responsible for the longer-lasting late-phase neuroplastic response often reported in the animal literature.

The dependence on early-phase, but not late-phase, LTP/LTD would explain the short duration and also the instability of the NIBS-induced neuroplastic effects under behaviorally relevant conditions. Experiments in animal models have shown that early-phase LTP/LTD can be readily reversed, either by subsequent physiological activity at the stimulated synapse^23,24 or following application of a weak stimulation protocol, which, by itself, has no lasting effects on synaptic transmission.^25-27 Functionally, this reversal of early-phase LTP and LTD (termed depotentiation and de-depression, respectively) is thought to protect against the stabilization of synaptic modifications generated by random or incidental activity.²⁸ In humans, induced changes in cortical excitability following NIBS are readily reversed by behavioral engagement of the stimulated cortex,^29-32 and similarly, this reversal of NIBS-induced effects has also been shown when a second, weaker NIBS protocol is used to activate the stimulated cortex shortly following neuroplasticity induction.^32,33 It is worth noting that although this reversal of NIBS-induced neuroplasticity has been demonstrated using neurophysiological indices of cortical excitability, it is unclear whether behavioral measures of cortical function might be similarly reversed. Nevertheless, these characteristics of short duration and instability are potentially highly limiting when NIBS is being used to modify behavior in healthy populations or in patient populations in a clinical setting.

NIBS and Neurorehabilitation

Whereas the therapeutic potential of NIBS has been explored for a range of neurological and psychiatric disorders, perhaps one of the strongest rationales that can be made is for its clinical use in the rehabilitation of upper-limb function following motor stroke. Neuroplastic reorganization of cortical circuits is important for much of the functional recovery seen following stroke,³⁴ and it is proposed that NIBS applied in conjunction with standard physical therapy might facilitate recovery by interacting with and enhancing this natural, functionally beneficial neuroplasticity.¹³ In principle, this should be a highly effective treatment strategy. Whereas a general lack of individualized treatment parameters tailored to suit patients’ specific needs may be an important factor preventing the implementation of NIBS in clinical practice (eg, see Di Pino et al³⁵), the limitations of current NIBS protocols may also have had an impact on the clinical effectiveness of this approach in stroke rehabilitation in 2 ways. First, the short lifetime of induced effects limits the therapeutic window during which functional gains through physical therapy can be achieved. Second, and critically, the possibility that any induced effects might be susceptible to activity-dependent reversal means that the movement task designed to benefit from the neuroplastic effects of NIBS may, in itself, disrupt these NIBS-induced changes.

In an attempt to overcome these limitations, many studies investigating the possible therapeutic benefits of NIBS in stroke have adopted the approach of applying multiple treatment sessions, usually once a day, for numerous days or weeks. In fact, this has become common practice in clinical trials for many other disorders as well.³⁶ The hypothesis seems to be that repeated daily applications of NIBS will have cumulative effects on the induction/maintenance of neuroplastic changes, and indeed, there is some limited evidence for this in healthy populations.³⁷ A number of reports in the stroke literature have shown promising results using this approach, with improvements in motor function lasting weeks,^38,39 even months^40-42 following 1 to 2 weeks of daily treatment sessions. However, others have shown less-convincing results,^43,44 with 2 recent Cochrane reviews of 19 randomized controlled trials using rTMS⁴⁵ and 15 randomized controlled trials using tDCS⁴⁶ highlighting the lack of evidence for either treatment strategy being effective in stroke rehabilitation.

Is There Any Merit in Using Repeated NIBS?

Despite the considerable number of clinical trials that have used repeated sessions of NIBS over multiple consecutive days, we are no closer to determining the real therapeutic value of this approach. There is little direct scientific support for the once-daily treatment schedule chosen in most studies; rather, it is more likely that this spacing interval has been used on practical or convenience grounds. To date, there is insufficient evidence to suggest that the current strategies used in clinical studies are optimal for inducing long-term, behaviorally relevant neuroplastic change. This is not to say, however, that the repeated application of NIBS protocols should be dismissed as an approach without further consideration. To exploit the true potential of NIBS techniques to investigate human neuroplasticity and induce functionally beneficial change, it is likely that approaches capable of inducing late-phase LTP/LTD-like effects are needed. There are significant clues in the animal and learning literature that may help point us in the right direction for such development.

Toward Establishing Long-Lasting Neuroplasticity in the Human Cortex

Strategies for Late-Phase LTP/LTD Induction in Animal Studies

Experiments in animal models suggest that whereas a single train of repetitive, high-frequency electrical stimulation is usually sufficient to induce the short-lasting early-phase LTP, repeated stimulation trains applied in a spaced manner are typically required to convert this into consolidated late-phase plasticity. This was first shown in the hippocampus of chronically prepared, unanesthetized rabbits, with repeated stimulation trains (spacing intervals of ~20-30 minutes) inducing LTP that persisted for 16 weeks.⁴⁷ Similar increases in the persistence of hippocampal LTP following repeated trains of high-frequency stimulation have been observed in the dentate gyrus of awake rats.^48-51 Most notably, Abraham et al⁴⁸ reported stable LTP lasting many months, and up to 1 year in 1 animal, following 4 sets of high-frequency stimulation trains spaced at 10-minute intervals. The repeated and spaced application of high-frequency stimulation trains is also required to induce long-lasting LTP in the neocortex.⁵² Moreover, long-lasting LTD has also been demonstrated in slice preparations following spaced induction protocols.⁵³

Using mouse hippocampal slice preparations, Woo and Nguyen⁵⁴ showed that LTP induced using 4 trains of high-frequency stimulation was resistant to depotentiation by a weak, low-frequency stimulation train applied shortly after LTP induction, and this resistance to depotentiation was blocked by inhibitors of protein synthesis. A similar stabilization of LTP was observed in the developing Xenopus visual system, with repeated stimulation trains spaced at 5-minute intervals inducing LTP at retinotectal synapses that was resistant to depotentiation by spontaneous activation of the postsynaptic tectal neuron.²⁴ The stabilization of LTP was only present when trains were applied with a spaced pattern, with the same number of stimuli applied en masse inducing LTP that was easily disrupted by spontaneous activity. Furthermore, stabilization was highly dependent on the interval separating stimulation trains, revealing a nonmonotonic inverse-U function with small deviations either side of the optimal 5-minute interval resulting in less LTP stabilization.

The Spacing Effect in Learning and Memory

Perhaps not surprisingly given the critical role of LTP/LTD in learning, there are striking parallels between the animal data regarding the consolidation of synaptic plasticity from a transient early phase to a more persistent late phase and what is known about the time course of learning. Similar to the early and late phases of LTP/LTD, memories are initially transient and easily disrupted before being consolidated into a longer-lasting and more stable form after extended training.⁵⁵ As well as having different time courses, these components of memory are also mechanistically distinct, with de novo protein synthesis and gene transcription required for long-term memory but not short-term memory.^56-58

It is well known that distributed learning through spaced trials results in longer-lasting memory than learning through massed practice. This phenomenon, described as the spacing effect,⁵⁹ has been shown in humans in a variety of tasks, including verbal memory tasks^60,61 and motor skill learning,^62,63 and is mediated by cellular mechanisms similar to those involved in late-phase LTP.⁶⁴

Within-Session Spacing of NIBS: Preliminary Evidence

Based on this evidence in the animal and learning literature, it seems likely that applying NIBS protocols in a spaced, within-session manner may be a useful strategy to induce lasting, resilient, and behaviorally significant neuroplasticity. Indeed, there is emerging evidence from healthy human populations to suggest that this might be the case.

Nyffeler et al⁸ were the first to study the within-session spacing of NIBS with the aim of inducing longer-lasting plasticity. Using an LTD-like plasticity-inducing rTMS paradigm known as continuous theta burst stimulation (cTBS),^3,16 they demonstrated that whereas a single train applied to the frontal eye field cortical region in healthy humans induced delays in saccadic eye movements lasting around 30 minutes, 2 cTBS trains spaced using a 15-minute interval extended the duration of these behavioral aftereffects to more than 2 hours.⁸ Similar findings have been shown in the human M1 using neurophysiological measures, with 2 cTBS trains separated by 20 minutes inducing a stronger LTD-like MEP depression than a single train.⁶⁵ Likewise, we have reported that cTBS trains spaced using a 10-minute interval induced stronger and more persistent aftereffects in the human M1 than a single train,^32,66,67 with MEP depression lasting at least 2 hours following the second stimulation train.⁶⁶

The within-session spacing of NIBS has also been investigated in the human M1 using anodal and cathodal tDCS, which induce LTP-like and LTD-like neuroplastic changes in cortical excitability, respectively.² Whereas a single cathodal tDCS protocol induced MEP depression lasting 1 hour, 2 protocols separated by short intervals of 3 or 20 minutes prolonged the aftereffects to around 2 hours poststimulation.⁶⁸ The duration of LTP-like aftereffects induced by anodal tDCS were similarly prolonged when 2 protocols were applied using 3- or 20-minute spacing intervals, with MEP facilitation still present the day after stimulation.⁶⁹

Mechanisms of Spaced NIBS-Induced Long-Lasting Neuroplasticity

Although the mechanisms by which spaced NIBS trains induce stronger and longer-lasting aftereffects are not yet clear, there is some evidence suggesting involvement of mechanisms similar to those involved in the protein synthesis–dependent late-phase synaptic plasticity observed in animal models. First, similar to findings in the developing Xenopus visual system that showed late-phase LTP when stimulation trains were applied in a spaced manner, but not when applied en masse,²⁴ simply doubling the length of NIBS protocols does not induce the same long-lasting aftereffects as spaced NIBS trains.^68-70 Also, the interval at which spaced NIBS are applied seems to be a critical factor influencing the neuroplastic response. For spaced cathodal tDCS, both the 3- and 20-minute spacing intervals resulted in long-lasting MEP depression; however, the magnitude of this response was significantly greater for the 20-minute interval.⁶⁸ Conversely, even longer spacing intervals of 3 or 24 hours occluded the long-lasting LTP and LTD-like effects induced by spaced anodal and cathodal tDCS protocols, respectively.^68,69 This nonmonotonic relationship between spacing interval and the magnitude and duration of induced aftereffects is similar to that reported in animal models investigating late-phase LTP²⁴ and is also consistent with behavioral findings in studies investigating spaced learning and long-term memory.^60,71,72

Second, in addition to the longer duration of induced aftereffects being more compatible with the duration of LTP/LTD observed in animal experiments, these spaced protocol-induced aftereffects are more stable, with neither behavioral engagement of M1 (by voluntary contraction) nor application of an experimental de-depressing rTMS protocol capable of reversing the MEP depression induced by spaced cTBS trains.³² The stability of aftereffects induced by spaced stimulation trains in the presence of both normal physiological and externally generated network activity bears striking similarities to findings in the developing Xenopus visual system²⁴ and mouse hippocampal slice preparations,⁵⁴ respectively, and may point to a consolidation of LTD-like effects.

Finally, increasing the number of spaced NIBS trains disproportionately extends the duration of induced neuroplastic changes. Whereas 2 cTBS trains applied to the human frontal eye field induced behavioral aftereffects that lasted ~2 hours, the duration of aftereffects induced by 4 spaced cTBS trains was ~10 hours.⁸ Similar results have been shown with stimulation of the posterior parietal cortex of stroke patients suffering from spatial neglect, with 4 cTBS trains applied to the contralesional hemisphere in a single session improving performance in a visual perception task for up to 32 hours following intervention.⁷³ Strikingly, improvements in spatial neglect symptoms lasted for at least 3 weeks following 8 cTBS trains applied over 2 consecutive days.⁷⁴

Implications for the Clinical Application of NIBS

Recommendations for Future Research

Based on the available evidence in healthy human populations and by drawing parallels with experimental data in the animal and learning literature, we suggest that future clinical trials aimed at testing the therapeutic potential of NIBS strongly consider the spacing interval between stimulation trains. Although the once-daily treatment schedule may be more convenient for the clinician and more easily sustainable for the patient, it is likely that spacing of NIBS needs to be fine-tuned to maximize the likelihood of inducing long-lasting, late-phase LTP/LTD-like neuroplasticity.

To this end, future research will need to focus on the following areas. Because the response to spaced NIBS is highly dependent on the interval between stimulation trains,^68,69 it is important to identify those intervals that are optimal for inducing long-lasting and stable neuroplastic change. Although this has been done to some extent for tDCS, it is very unlikely that the same spacing interval will be optimal for all NIBS variants. Indeed, findings from the learning literature suggest that the optimal interval separating training sessions is influenced by several key factors, including the nature of the task being learned,⁷² and the same principles might apply for the different forms of NIBS.

Similarly, the optimal interval for a particular NIBS protocol in M1 may not necessarily be the same for other cortical targets. Although an objective measure of neuroplasticity is much less straightforward in nonmotor areas compared with M1, combining NIBS with functional neuroimaging techniques may offer new insights.⁷⁵ This will be important for determining appropriate spacing intervals for treating neurological and psychiatric disorders that do not involve M1 as the primary site targeted by NIBS, such as depression and Alzheimer’s disease.

Summary

There is overwhelming evidence to suggest that the use and development of NIBS using spaced application protocols offers significant opportunities for the induction of long-lasting, robust, and behaviorally significant neuroplastic change. We suggest that investigating the optimal spacing interval for such approaches will provide greater insights into the mechanisms and influences on human neuroplasticity and will enable us to more fully exploit the therapeutic opportunities provided by NIBS.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: MRG is supported by an Alzheimer’s Australia Dementia Research Foundation (AADRF) Postdoctoral Fellowship (ID: DGP13F00034).

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Spaced Noninvasive Brain Stimulation

Abstract

Keywords

NIBS and Neuroplasticity in the Human Cortex

Limitations of Current NIBS Techniques

Early- or Late-Phase Neuroplasticity?

NIBS and Neurorehabilitation

Is There Any Merit in Using Repeated NIBS?

Toward Establishing Long-Lasting Neuroplasticity in the Human Cortex

Strategies for Late-Phase LTP/LTD Induction in Animal Studies

The Spacing Effect in Learning and Memory

Within-Session Spacing of NIBS: Preliminary Evidence

Mechanisms of Spaced NIBS-Induced Long-Lasting Neuroplasticity

Implications for the Clinical Application of NIBS

Recommendations for Future Research

Summary

Footnotes

Declaration of Conflicting Interests

Funding

References