The role of neuromodulation to drive neural plasticity in stroke recovery: a narrative review

Cong Wang

doi:10.4103/2773-2398.339171

REVIEW

Year : 2022 | Volume : 1 | Issue : 1 | Page : 2-8

The role of neuromodulation to drive neural plasticity in stroke recovery: a narrative review

Cong Wang
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland; Australian Research Council Centre of Excellence for Integrative Brain Function, Clayton, Victoria, Australia

Date of Submission	21-Dec-2021
Date of Decision	08-Feb-2022
Date of Acceptance	01-Mar-2022
Date of Web Publication	29-Mar-2022

Correspondence Address:
Cong Wang
Queensland Brain Institute, The University of Queensland, Brisbane, Queensland; Australian Research Council Centre of Excellence for Integrative Brain Function, Clayton, Victoria
Australia

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-2398.339171

Abstract

Stroke is one of the leading causes of death and adult disability globally, representing one of the highest burdens of disease worldwide. Recent advancements of neuromodulation techniques emerge as promising tools for enhancing stroke recovery, such as transcranial electric stimulation and transcranial magnetic stimulation, which can induce short- and long-term changes of synaptic excitability to restore the impaired functions in stroke patients. The review focuses on discussing the neuroplastic mechanisms of those brain stimulation techniques in stroke rehabilitation, also including some new options for neuromodulation which have great potential in stroke rehabilitation, such as optogenetic stimulation and environmental stimulation. In general, these techniques allow the excitation and synchronization of the neural activity after stroke, which could potentially induce long-term potentiation. As a result, the neuroplastic effect can lead to better functional connection in the brain network in assisting stroke recovery. Future directions include the clarification of the pathways of synaptic plasticity in the whole brain network following neuromodulation after stroke, and investigation of the different roles of distinctive cell populations in neural plasticity enhancement. Additional studies are essential for developing standard protocols in neuromodulation based on a better understanding of the molecular and cellular processes for the ultimate optimization of clinical efficacy.

Keywords: brain stimulation; neural plasticity; neuromodulation; stroke rehabilitation; synapse

How to cite this article:
Wang C. The role of neuromodulation to drive neural plasticity in stroke recovery: a narrative review. Brain Netw Modulation 2022;1:2-8

How to cite this URL:
Wang C. The role of neuromodulation to drive neural plasticity in stroke recovery: a narrative review. Brain Netw Modulation [serial online] 2022 [cited 2023 Jun 7];1:2-8. Available from: http://www.bnmjournal.com/text.asp?2022/1/1/2/339171

Funding: This work is supported by grants from the U21 Health Research Group Early Career Researcher Fund (https://u21health.org/early-career-researcher-fund) and the University of Queensland Research Stimulus Fellowship.

Introduction

Stroke is a neurological condition resulting from a blockage of a blood vessel or sudden bleeding in a part of the brain. In general, stroke is classified into two major types of whereby blood flow is interrupted either by a blood clot (ischemic stroke) or a blood vessel that bursts and leaks (hemorrhagic stroke). Stroke frequently causes lifelong disability in survivors, with a resulting economic and financial burden globally measured as years of healthy life that are lost due to premature death or disability (Katan and Luft, 2018). Treatment options are unfortunately extremely limited at present and there has been very little progress in the development of stroke recovery technology since the discovery of tissue plasminogen activator, which itself cannot be used to treat patients with some pre-existing health conditions (Henninger and Fisher, 2016) and is only efficacious when delivered to patients within 4.5-hour window after stroke (Davis and Donnan, 2009). Therefore, effective therapeutic interventions for stroke remain a critical unmet medical need.

Stroke rehabilitation can be achieved via neuroplastic processes such as synapse strengthening, neural circuit rewiring, axonal sprouting, spinogenesis and neurogenesis, which allow the brain to change and adapt to damage following stroke. Researchers and clinicians have harnessed these neuroplasticity properties to promote recovery in stroke survivors with the aid of neuromodulatory pharmaceutical agents and stimulation techniques such as exercises, pharmacological interventions, and brain stimulation (Murphy and Corbett, 2009; Silasi and Murphy, 2014; Boddington and Reynolds, 2017; Caglayan et al., 2019; Szelenberger et al., 2020).

In this review, recent advances in brain stimulation techniques related to stroke recovery are discussed. To carry out the literature search, we used the PubMed research database and entered the keywords “stroke rehabilitation,” “neural plasticity,” “neuromodulation,” “transcranial magnetic stimulation”/”transcranial direct current stimulation”/”paired associated stimulation”/”optogenetical stimulation” or “environmental stimulation.” Articles were selected based on their abstracts, focusing on the last 5 years and selection was completed by a manual search. The collective information is utilized to provide an overview on how stimulation of the adult brain drives neural plasticity to facilitate recovery of function after stroke and outline a roadmap for future directions of research on next-generation strategies and stimulation techniques for stroke treatment.

Neural Plasticity in Brain

“Neural plasticity” refers to the capacity of modification of the nervous system in response to intrinsic or extrinsic stimuli via reorganization of connections, functions, or structure (Cramer et al., 2011). Research over the past century has shown that neural plasticity is a fundamental property of the nervous system in a range of species, from insects to humans. The term “plastic” originates from the Latin word “plasticus” and Greek word “plassein,” meaning “molded or formed” (Malabou, 2008). In colloquial terms, plasticity is referred to as the property of a material of being physically malleable; being “plastic” alludes to the attribute of being able to be shaped without breaking (Bernhardi et al., 2017). Neuroscientists use the term “plasticity” to describe the inherent malleability and resilience of the brain during neural development in responding to the changing environment, aging or pathological insult.

Synaptic plasticity

A synapse is the junction between neurons facilitating their communication, which consists of presynaptic terminal, synaptic cleft, and post-synaptic terminal. The synaptic transmission process includes release of neurotransmitter from the presynaptic terminal, neurotransmitter binding to the postsynaptic terminal, and opening of ion channels on the postsynaptic terminal. In 1949, the Canadian psychologist Donald Hebb (Hebb, 1949) proposed a theory about learning in the brain network in his book “The Organization of Behavior: A Neurophysiological Theory.” The proposal describes changes in the synapses dependent on how active or inactive they are (Hebb, 1949). The proposal describes changes in the synapses depending on their level of activity, summarized as the slogan “neurons fire together, wire together; neurons fire apart, wire apart.” This “Hebb’s postulate” (now known as “synaptic plasticity”) has since had an enormous influence on the studies concerning neurophysiology and has been justified by accumulating morphological, biochemical, molecular and electrophysiological evidence over the years. In 1973, researchers reported long-term synaptic plasticity in the rabbit hippocampus, designated long-term potentiation (LTP) and long-term depression (LTD), whereby activating synapses effectively or ineffectively result in a long-lasting increase/decrease in synaptic strength (Bliss and Lomo, 1973). Bi and Poo (1998) reported a critical window for synaptic plasticity with the peak time for changes in synaptic strength being 20 ms before and after an action potential, a process known as “spiking-time dependent plasticity.” More specifically, firing of the presynaptic neuron before the postsynaptic neuron within the preceding 20 ms results in LTP while firing of the presynaptic neuron after the postsynaptic neuron within the subsequent 20 ms results in LTD. Synaptic plasticity can change either the amount of neurotransmitters released or the number of postsynaptic receptors available.

Structural plasticity

With the rapid technological developments in fluorescence microscopy and staining approaches, induction of synaptic plasticity has been shown to cause structural changes in protrusions along the dendrites of the excitatory synapses, known as spines (Lee et al., 2012). Expression of LTP is associated with spine enlargement while LTD is related to spine shrinkage. The molecular mechanism of this structural plasticity is similar to that of synaptic plasticity. For instance, LTP induction stimuli involving strong synaptic input and large postsynaptic increase in calcium facilitate actin branching and polymerization, providing a protrusive force to mediate spine enlargement. Conversely, LTD-inducing stimuli trigger actin depolymerization, spine shrinkage, and retraction (Chidambaram et al., 2019). Another structural plasticity phenomenon is axonal sprouting, which refers to the growth and extension of new axons and their connections. In the adult brain, axonal sprouting only occurs after injury (Hatakeyama et al., 2020; Joy and Carmichael, 2021).

Role of Neural Plasticity in Stroke Rehabilitation

Stroke results in neuronal death and loss of synaptic connections, generating a core area with irreversible damage and a peri-infarct area, the penumbra, which despite damage, can recover if blood flow is promptly restored (Murphy and Corbett, 2009). The peri-infarct area is the major region of neural plasticity attributable to robust changes in the expression of growth-promoting or growth-inhibiting proteins involved in neuronal rewiring (Carmichael, 2006; Clarkson et al., 2013; Silasi and Murphy, 2014). These plasticity processes include turnover of local synaptic contacts adjacent to the lesion (including spinogenesis and angiogenesis), altered excitability of neuronal circuits adjacent to and connected with the area of damage, and formation of new functional neuronal connections, as evident from remapping of motor, sensory and language functions. Through its neural plasticity property, the human brain has the capability of reorganization by using redundant connections or forming new connections among residual neurons, which may partially compensate for the lost function.

On account of the recent advances in neuromodulation techniques, researchers and clinicians can modulate the time window between the firing of two neurons in the targeted area (mainly the penumbra). As a result, spiking time-dependent plasticity is induced, reducing the adverse consequences of stroke lesions and improving functional recovery following stroke [Figure 1].

Figure 1: The mechanism of neuromodulation to enhance neural plasticity following stroke.

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Rcurrent Brain Stimulation Techniques For Modulating Plasticity Following Stroke

Different neuromodulation techniques were introduced as followed [Figure 2].

Figure 2: The timeline of all the original studies documented in this review about different neuromodulation techniques.

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Deep brain stimulation

Deep brain stimulation (DBS) is a neurosurgical procedure involving implantation of stimulating electrodes, which are connected to an implantable pulse generator and deliver electric pulses via the device into targeted brain regions (Kringelbach et al., 2007). DBS is a well-established treatment for movement disorders such as Parkinson’s disease, dystonia, and essential tremors. Recently, DBS has been confirmed as a promising strategy for the management of neuropsychiatric conditions, such as obsessive-compulsive disorder, depression, Tourette’s syndrome, and Alzheimer’s disease (Johnson et al., 2013). However, the mechanisms underlying DBS remain poorly understood. Indeed, DBS treatment does not simply involve excitation and inhibition of neural activity but is rather a complex process incorporating a plethora of local and remote factors (Ashkan et al., 2017). Recent findings indicate that DBS acts through multifactorial mechanisms, including immediate neuromodulatory effects, synaptic plasticity, and long-term neuronal reorganization (Ashkan et al., 2017). DBS has also been used for the treatment of several post-stroke disorders, such as neuropathic pain (Lempka et al., 2017), tremor, dystonia and dyskinesia (Elias et al., 2018) and is particularly beneficial for stroke patients with impaired lower limb movement, as the stimulation can reach deep brain areas (Franzini et al., 2008). However, the disadvantages are significant, since the treatment method is invasive with possible postoperative complications including infection, lead fracture, device dislocation, and poorly targeted leads. When considering this approach for stroke recovery, there is also a high chance of increased intracranial pressure that may lead to edema, a risk factor for poor clinical outcomes after stroke (Lefaucheur et al., 2013).

Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) uses two electrodes on the scalp to deliver a low-intensity current. During tDCS, the current flows across the brain from the negatively polarized cathode to the positively polarized anode (Johnson et al., 2013). Neural activity is presumed to be enhanced in the brain region under the anode and decreased in the region under the cathode via modification of transmembrane neuronal potential and cortical excitability. In pyramidal cells, anodic stimulation generally has a facilitative effect through tonic depolarization of neuronal resting membrane potentials. Cathodic stimulation leads to tonic hyperpolarization and overall inhibition of the underlying neuronal population (Jefferys et al., 2003). Following stroke, an imbalance in interhemispheric inhibition is induced. Despite ongoing debates about its utility, tDCS has been shown to be effective in restoring interhemispheric balance and improving stroke recovery via anodic stimulation of the ipsilesional region or cathodal stimulation of the contralesional region (Nitsche et al., 2008). Similar to DBS, the neurobiological mechanisms of tDCS are not well understood at present. Recent rodent studies have demonstrated that anodal tDCS boosts synaptic plasticity via epigenetic regulation of BDNF expression (Podda et al., 2016; Cocco et al., 2020). Tonic modulation of excitability by tDCS could also induce changes in synaptic plasticity that persist for hours or even days following stimulation through modification of NMDA receptor efficiency (Nitsche et al., 2008). Another rodent study also backs up the therapeutic effects of tDCS in inducing neural plasticity after stroke, such as enhanced expression profiling of growth factors (Ahn et al., 2020). Some recent human studies use electroencephalographic measures in response to tDCS to investigate the neuroplasticity after stimulation. For example, one suggesting stronger functional connectivity of the targeted network was associated with the tDCS, which can be a biomarker to assist clinical translation of the therapy (Hordacre et al., 2018), another suggesting the tDCS enhanced beta band oscillation coherence (Nicolo et al., 2018). A recent theoretical study used a biophysical model to predict the efficacy of the tDCS, which depends on ongoing neural activity and plasticity and is relevant with enhancing inhibitory processes (Malerba et al., 2017).

Transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) uses a magnetic field to induce electric fields in cortical tissue. Electric current flows through a coil generating a magnetic field that subsequently flows to neural tissue and generates another electric field (Chail et al., 2018). The mechanisms of TMS are rather complicated and poorly understood. However, the rationale for using TMS in stroke rehabilitation is that it can cause enhanced intracortical excitability of the stroke side and transcallosal inhibition of the healthy hemisphere, and this neuroplastic effects of TMS might be relevant with long-term potentiation (LTP) and long-term depression (LTD) (Fisicaro et al., 2019). One human study used the TMS to target the brain transcallosally. The study from this single-site clinical trial used TMS-evoked interhemispheric motor connectivity, enhanced corticomotor excitability, and reduced response time on a modified serial reaction time task as primary outcome measures to evaluate the therapeutic potential of this neuromodulation in promoting neural plasticity to enhance stroke recovery (Borich et al., 2018). The molecular and cellular-level mechanisms of the TMS in regard to neuroplasticity are investigated by several recent animal studies. For example, 15 Hz TMS was shown to promote neuroplastic processes within the brain. Stimulation of the mouse primary motor cortex led to increased dendritic arborization and spine density of pyramidal neurons in layers 2/3 (Cambiaghi et al., 2021). Another rodent study using repetitive TMS observed reduced DNA fragmentation and infarct volume, as well as increased angiogenesis, growth factors; and reduced inflammation and axonal sprouting related gene expressions in the animals that received treatment (Caglayan et al., 2019).

Paired associated stimulation

Paired associative stimulation refers to a paradigm consisting of repetitive peripheral nerve stimulation combined with transcranial magnetic stimulation over the contralateral motor cortex. This intervention aims to synchronize perisynaptic neuronal activity to elicit spike timing-dependent plasticity (Ting et al., 2021). Animal models have inherent advantages in the precise identification of the mechanisms and principles of plasticity. For instance, coincident stimulation of the descending corticospinal tract and spinal cord afferents in rats could induce sustained potentiation of corticospinal excitability (Mishra et al., 2017). In awake monkeys, paired associative stimulation within the sensorimotor cortex between implanted electrodes led to the induction of intra-cortical plasticity (Seeman et al., 2017).

The above non-invasive neuromodulation techniques have several common disadvantages despite the benefits of avoiding the risk of complications during surgery and the lower possibility of causing unintended injuries. Firstly, the precise mechanisms underlying these effects are poorly understood. Discrepancies in results remain due to the lack of consistency in stimulation parameters and high injury variability. Moreover, specific activation of certain neurons or selective neural circuits using these approaches is not possible.

Future Directions of Brain Stimulation For Stroke Rehabilitation

Optogenetic stimulation

Optogenetics is a biological technique using light for precise control of neuronal activity achieved by inducing single genes encoding light-activated ion conductance regulators or biochemical signaling proteins, such as channel rhodopsin 2, in target cells (Deisseroth, 2015). Specific cell types and circuits with high temporal resolution can be activated or inhibited by application of light pulses with specific wavelengths.

Optogenetic approaches have been successfully applied for stroke treatment in animal models. For instance, Cheng et al. (Cheng et al., 2014) reported that selective stimulation of cells with channel rhodopsin 2 expression in the ipsilesional primary motor cortex could promote stroke recovery and stimulated mice exhibited a significant increase in expression of plasticity marker growth-associated protein 43. Additional studies have shown that optogenetic stimulation in the striatum enhances neurogenesis and neurobehavioral recovery in stroke model mice (He et al., 2017; Jiang et al., 2017; Song et al., 2017). Our group’s recent investigation revealed a neuroprotective effect of gamma frequency stimulation of inhibitory neurons in the acute phase of stroke (Balbi et al., 2021). The efficacy of optogenetic stimulation treatment for stroke in promoting neural plasticity was recently validated (Lu et al., 2019). For example, utilization of optogenetic tools to evoke sleep slow waves in the penumbra of stroke-induced mice significantly improved fine motor movements of the limb and increased anatomic presynaptic and postsynaptic markers and axonal sprouting (Facchin et al., 2020). Specific targeting of the thalamocortical or corticospinal projections for optogenetic stimulation enhanced synaptic bouton formation and axonal sprouting and promoted sensorimotor abilities (Tennant et al., 2017).

While the requirement of gene alterations currently limits the clinical applications of optogenetics, owing to rapid advances in gene therapy, the use of optogenetics to modulate recovery pathways should be more easily translated from bench to clinic in the future.

Sensory stimulation

Sensory stimulation, such as visual stimuli, auditory stimuli and whisker movements, is a promising research direction for treating neural disorders. In a mouse model of Alzheimer’s disease, using a 40 Hz light flicker or multisensory stimulus (combining auditory with visual stimuli) drove gamma frequency neural activity, reduced amyloid levels in the brain, and improved spatial and recognition memory (Adaikkan et al., 2019; Martorell et al., 2019). Sensory stimulation techniques have also been implemented to improve motor recovery after stroke in animals. A recent animal study showed that rhythmic light flicker could rescue hippocampal neural activity and protect ischemic neurons by enhancing presynaptic plasticity (Zheng et al., 2020). Further research is necessary to fully elucidate the underlying mechanisms and effectiveness of sensory stimulation in stroke rehabilitation.

Concluding Remarks

Accumulating evidence supports an association of neuromodulation with induction of neural plasticity to promote stroke rehabilitation (Motolese et al., 2022). Fundamental research to date has enhanced our understanding of neural diseases and optimized treatment strategies, providing a solid foundation for clinical applications. Future directions include the clarification of the pathways of synaptic plasticity in the whole brain network following neuromodulation after stroke, and investigation of the different roles of distinctive cell populations in neural plasticity enhancement. Additional studies are essential for developing standard protocols in neuromodulation based on a better understanding of the molecular and cellular processes for the ultimate optimization of clinical efficacy. In this review, we focus on how neuronal plasticity facilitates stroke recovery, and one of the limitations of this review is that we did not cover all the processes which contribute to stroke recovery, such as neuroprotection or restoring the excitation-inhibition balance between hemispheres.[55]

Acknowledgments

I thank Matilde Balbi (University of British Columbia and University of Queensland) for the inspiration and comments on the manuscript.

Author contributions

CW conceived and visualized the manuscript, made the original draft and revision and approved the final manuscript for publication.

Conflicts of interest

The author declares no competing financial interests.

Editor note: CW is an Editorial Board member of Brain Network and Modulation. She was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and her research group.

Open access statement

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