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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Giulia Leonardi
Rosella Ciurleo
Francesca Cucinotta
Bartolo Fonti
Daniele Borzelli
Lara Costa
Adriana Tisano
Simona Portaro
Angelo Alito
Sven Storch
Montana Samantzis
Matilde Balbi