The role of brain oscillations in post-stroke motor recovery: An overview

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The role of brain oscillations in post-stroke motor recovery: An overview

Giulia Leonardi¹, Rosella Ciurleo², Francesca Cucinotta², Bartolo Fonti², Daniele Borzelli³, Lara Costa⁴, Adriana Tisano⁴, Simona Portaro¹ and Angelo Alito^3*

• ¹Department of Physical and Rehabilitation Medicine and Sports Medicine, Policlinico “G. Martino,” Messina, Italy
• ²IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy
• ³Department of Biomedical, Dental Sciences and Morphological and Functional Images, University of Messina, Messina, Italy
• ⁴Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

Stroke is the second cause of disability and death worldwide, highly impacting patient’s quality of life. Several changes in brain architecture and function led by stroke can be disclosed by neurophysiological techniques. Specifically, electroencephalogram (EEG) can disclose brain oscillatory rhythms, which can be considered as a possible outcome measure for stroke recovery, and potentially shaped by neuromodulation techniques. We performed a review of randomized controlled trials on the role of brain oscillations in patients with post-stroke searching the following databases: Pubmed, Scopus, and the Web of Science, from 2012 to 2022. Thirteen studies involving 346 patients in total were included. Patients in the control groups received various treatments (sham or different stimulation modalities) in different post-stroke phases. This review describes the state of the art in the existing randomized controlled trials evaluating post-stroke motor function recovery after conventional rehabilitation treatment associated with neuromodulation techniques. Moreover, the role of brain pattern rhythms to modulate cortical excitability has been analyzed. To date, neuromodulation approaches could be considered a valid tool to improve stroke rehabilitation outcomes, despite more high-quality, and homogeneous randomized clinical trials are needed to determine to which extent motor functional impairment after stroke can be improved by neuromodulation approaches and which one could provide better functional outcomes. However, the high reproducibility of brain oscillatory rhythms could be considered a promising predictive outcome measure applicable to evaluate patients with stroke recovery after rehabilitation.

Introduction

A stroke is defined as a sudden onset of signs and symptoms related to focal or global cerebral deficits of brain function, lasting more than 24 h, not attributable to any apparent cause other than cerebral vasculopathy (Sacco et al., 2013). Six months post-stroke, nearly 50% of survivors have some residual motor deficits (Benjamin et al., 2017). Advances in acute stroke therapeutic management (intravenous thrombolysis, mechanical thrombectomy) have improved the prevention possibilities of long-term disability (Tong et al., 2012). Being the second cause of disability and death worldwide (GBD 2016 Stroke Collaborators, 2019), stroke has high relevance to a patient’s quality of life and significant impact on health care costs. Functional impairment, resulting in poor performance in activities of daily living, is common (Benjamin et al., 2017). Environmental conditions are required for post-stroke motor recovery (Power et al., 2011; Wenger et al., 2017). Internal processes combinations such as functional undamaged neural structures recovery and/or brain network remapping could promote impaired functions spontaneous restoration (Gazzaniga, 2005). The phenomenon behind these recovery processes is lifetime—continuous motor system neuroplasticity (Power et al., 2011; Remsik et al., 2016). Traditional rehabilitation techniques enhance motor function recovery (Kollen et al., 2006; Fleet et al., 2014; Laver et al., 2015) leveraging this motor learning circuitry, thus improving patient outcomes (Thakor, 2013). The relationship between brain activity and movements is important for motor learning, thus integrating motor system modulation and rehabilitation techniques in treatment settings could aid stroke recovery (Pfurtscheller et al., 2005; Felton et al., 2007; Schalk et al., 2008). Several neurological disorders (i.e., stroke) are associated with altered electroencephalogram (EEG) brain rhythms, which sustain motor, cognitive, and perceptive functions (Muralidharan et al., 2011; Ortner et al., 2012). EEG signal oscillations detectable in sensorimotor areas, especially in the mu (8–13 Hz) and beta (13–30 Hz) bands, present characteristic modulation during motor tasks. Interestingly, alpha and beta rhythms modulations caused by sensory stimulation, a motor act or motor imagery, are correlated with a decrease or increase in the underlying neuronal population’s synchrony (McFarland et al., 2000; Pfurtscheller et al., 2006; Nicolas-Alonso and Gomez-Gil, 2012). Modulations of sensorimotor rhythms resulting from sensory stimulation, motor act, or its imagination can be of two types, namely, event-related desynchronization (ERD) and event-related synchronization (ERS) of mu and beta rhythms (Jeannerod, 1995; Pfurtscheller and Neuper, 2001). Specifically, ERDs consist of a decrease in the amplitude of rhythms, while ERS is an increase in the amplitude of rhythms (Felton et al., 2007). Alpha (mu) and beta oscillations can be used as control rhythms for a “brain–computer interface” (BCI) system (Schalk et al., 2004). BCI systems can transform brain activity into control signals for external devices (Schalk et al., 2004; McFarland and Wolpaw, 2011; Lee et al., 2020), and can be used for tasks that require users to activate or deactivate specific brain regions (Rathee et al., 2019). Therefore, non-invasive BCI systems can facilitate recovery in patients with chronic post-stroke by linking brain activity with distal motor effectors in the peripheral nervous system (Song et al., 2014). Feedback-regulated motor imagination could be used to improve functional recovery, enhancing antagonistic ERD/ERS patterns, and, consequently, supporting stroke-affected hemisphere activation and contralateral unaffected hemisphere inhibition (Pfurtscheller and Neuper, 2006). Therefore, in the BCI system, brain activity can be transformed into control signals for external devices including “functional electrical stimulation” (FES) (McFarland and Wolpaw, 2011). Thus, non-invasive EEG-BCI-FES systems may facilitate recovery in patients with chronic post-stroke by linking brain activity with distal motor peripheral nervous system effectors and may be used as biomarkers to predict rehabilitation outcomes (Song et al., 2014, 2015).

To modulate and explore brain function, non-invasive brain stimulation (NIBS) could be applied. To date, there are different NIBS protocols with therapeutic applications, reflecting synaptic mechanisms of long-term potentiation (LTP) or long-term depression (LTD), even in stroke rehabilitation (Terranova et al., 2019). The NIBS after effects are short lasting (∼30–120 min) in humans (Abraham and Williams, 2003), but other mechanisms are also involved [i.e., post-tetanic potentiation (PSP) and short-term potentiation (STP)] (Ugawa, 2012). The most applied NIBS are transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS) (Paulus, 2011; Terranova et al., 2019). TMS motor-evoked potentials are obtained from the contralateral muscles of the stimulated hemisphere (Barker et al., 1985). TMS can modulate cortical excitability in different ways: (i) Inducing electrical field causing local effects immediately under the coil and/or remote effects (i.e., excitatory and inhibitory effects) (Rothwell et al., 1999) and (ii) applying a transient weak current to the brain through a pair of saline-sponged electrodes (Nitsche et al., 2008) and changing the polarity of the current. Repetitive transcranial magnetic stimulation (rTMS) produces long-term changes, reducing cortical excitability at low frequency (≤ 1 Hz), and boosting it up at high frequency (≥ 5 Hz) (Maeda et al., 2000; Siebner and Rothwell, 2003; Quartarone et al., 2005). However, it has been shown that continuous 5 Hz rTMS decreases instead of increasing corticospinal excitability (Rothkegel et al., 2010). When rTMS is administered in a complex burst pattern, i.e., theta burst stimulation, it produces more reliable effects than conventional rTMS (Huang et al., 2005; Hamada et al., 2008; Suppa et al., 2016). Another rTMS approach, namely, theta burst stimulation (TBS) (intermittent or continuous), uses 5 Hz short bursts at a repetitive high frequency mimicking the brain’s natural firing patterns (Oberman et al., 2011; Hoy et al., 2016). Compared to rTMS, intermittent TBS (iTBS) may be applied to induce greater and longer-lasting motor cortical effects on cortical excitability (Huang et al., 2005; Di Lazzaro et al., 2008). It is applied using biphasic stimulus pulses that induce an initial posterior-anterior current through M1 (Huang et al., 2005). The use of short 5-Hz high-frequency repetitive bursts that mimic the brain’s natural firing patterns would result in greater neuromodulatory potential than the standard approach. Thus, the effects on the functional brain network of patients with stroke would be greater and longer lasting in regions remote from the stimulated site (Oberman et al., 2011; Hoy et al., 2016; Suppa et al., 2016). Continuous TBS (cTBS) decreases cortical excitability, while intermittent TBS has a booster-up effect (Hamada et al., 2008). However, tDCS is mainly applied in clinical practice, while tACS and tRNS are more used in a research context (Paulus, 2011). Anodal tDCS modulates the cortical excitability of depolarizing neurons, whereas cathodal tDCS reduces the excitability of hyperpolarizing neurons (Antal et al., 2004). In 1–2 mA tDCS, electrical current is delivered over the skull through sponge electrodes, changing neurons firing frequency (Paulus, 2011); anodal stimulation induces cortical facilitation, whereas cathodal stimulation has an opposite effect (Paulus, 2011). However, despite TMS and tDCS having different mechanisms of action (acting TMS as neurostimulator and tDCS as neuromodulator), they both induce cortical excitability long-term after effects, which engage neural plasticity mechanisms (Fregni et al., 2005; Khedr et al., 2010). Transcranial alternating current stimulation (tACS) is a variant of TMS at a predetermined frequency (Alekseichuk et al., 2016). Transcranial random noise stimulation (tRNS) is another NIBS technique using a low-intensity biphasic randomly alternating current at a variable frequency (Fertonani et al., 2011). While researchers are still debating over the functional meaning of these synchronization and de-synchronization patterns of rhythmic activity, practical applications based on the accumulated knowledge are already emerging. On such a basis, this review aims to evaluate the role of brain oscillatory activity on motor function recovery in patients with post-stroke undergoing conventional rehabilitation treatment integrated with different NIBS.

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