Well, if they work; where are the protocols located so all 10 million yearly stroke survivors can find them and bring them to the attention of their stroke medical 'professionals'?
Non-invasive brain stimulation for functional recovery in animal models of stroke: A systematic review
Introduction
Stroke is a serious life-threatening cerebrovascular disease affecting 12 million individuals annually worldwide and is the second-leading cause of death (GBD 2019 Stroke Collaborators, 2021). Most stroke survivors experience severe motor and cognitive function impairments as a consequence of brain damage (Rathore et al., 2002). While some degree of spontaneous recovery occurs after a stroke, it is most pronounced within the first week and tends to stabilize around the fourth week post-stroke. Beyond this point, the likelihood of further spontaneous recovery diminishes (Stinear & Byblow, 2014). Unfortunately, this recovery process is generally incomplete, and current therapies fall short of fully restoring motor and cognitive function to pre-stroke levels (Dickstein, 2008, Mijajlović et al., 2017). Therefore, these disabilities often become permanent, severely compromising the quality of life for affected individuals. Moreover, the diminished functional capacity following a stroke leads to reduced physical activity, putting patients into a positive feedback loop of disability that exacerbates cerebrovascular disease and increases their susceptibility to subsequent strokes (Hankey et al., 2002, Ivey et al., 2006).
Recovery after stroke is mediated by cellular and molecular mechanisms, a process known as brain plasticity, which is responsible for the restoration of damaged neuronal networks (Kleim and Jones, 2008, Cramer et al., 2011). This form of plasticity typically involves axonal sprouting, the formation and strengthening of synapses, and the compensatory mechanisms to address the loss of functioning (Cirillo et al., 2020). Non-invasive brain stimulation (NIBS) constitutes a category of rehabilitative therapies with the potential for producing long-lasting effects capable of modulating brain plasticity (Dayan et al., 2013). Moreover, the effects of NIBS extend beyond the local target area and have the capacity to influence neural networks beyond the specific stimulation site (Shafi et al., 2012).
NIBS techniques primarily include transcranial magnetic stimulation (TMS) and transcranial electrical stimulation (tES). Within these categories, different variants have shown promising results in stroke patients, including repetitive TMS (rTMS), continuous theta-burst rTMS (cTBS), intermittent theta-burst rTMS (iTBS), transcranial direct (tDCS), transcranial random noise (tRNS), and transcranial alternating (tACS) current stimulations (Koch et al., 2012, Monti et al., 2013, Hatem et al., 2016, Inukai et al., 2016, Meinzer et al., 2016, Kondo et al., 2017, Bornheim et al., 2020, Chen et al., 2021, Schuhmann et al., 2022). Additionally, combination therapies are available, involving either a blend of electrical and magnetic stimulation protocols (Shin et al., 2008) or brain stimulation in conjunction with peripheral stimulation (Gao et al., 2020). Therefore, a wide range of NIBS therapies has been developed in an attempt to improve functional recovery after a stroke. Nonetheless, a better understanding of brain remodeling is needed to efficiently implement these therapies in clinical settings.
tDCS and rTMS stand out as the two most commonly employed forms of NIBS. Both methods safely and painlessly deliver low-intensity currents to specific regions of interest. In tDCS, this current is directly applied via two electrodes (anode and cathode) placed on the scalp, while in rTMS employs magnetic fields produced by an electromagnetic coil to induce the current. High frequencies (rTMS) and anodal stimulation (tDCS) are applied to promote neural activity, whereas low frequencies and cathodal stimulation inhibit such activity (Nitsche and Paulus, 2000, Sasaki et al., 2013). These therapies are mainly based on the concept of inter-hemispheric communication in the context of a stroke, which is currently explained by three main models: the inter-hemispheric competition model, the vicariation model, and the balance recovery bimodal model (Brancaccio et al., 2022). Briefly, the inter-hemispheric competition model suggests that the two hemispheres are constantly inhibiting each other via the corpus callosum (Cook, 1984, Bloom and Hynd, 2005). As a result, this dynamic leads to brain remodeling that impairs spontaneous recovery after stroke, a phenomenon referred to as maladaptive plasticity. According to this model, the contralesional hemisphere receives less inhibition from the ipsilesional hemisphere, and the ipsilesional hemisphere is both damaged and excessively inhibited by the contralesional hemisphere. Consequently, NIBS protocols based on this focus on increasing neural activity in the ipsilesional hemisphere or inhibiting activity in the contralesional hemisphere (Dodd et al., 2017).
Although the inter-hemispheric competition model serves as the foundational theory for standardized NIBS therapies in stroke patients, some studies have reported contrasting results. For example, one study found that suppressive cathodal tDCS applied to the contralesional hemisphere yielded different outcomes depending on the severity of the stroke, worsening stroke recovery in severe cases (Bradnam et al., 2012). In addition, another study reported a decline in motor function after applying high-frequency rTMS over the ipsilesional hemisphere (Ameli et al., 2009). Together, these findings prompted the emergence of the vicariation model. In contrast to the inter-hemispheric competition model, the vicariation model posits that the activity of the contralesional hemisphere may not be maladaptive but rather adaptive, potentially contributing to functional recovery by assuming the lost functions of the affected areas (Johansen-Berg et al., 2002). This effect is most prominent in severely affected patients, implying that this compensatory function gains significance as the damage to the affected hemisphere becomes more extensive. Finally, the balance recovery bimodal model postulated by Di Pino et al., (2014) integrates both theories with a focus on predicting optimal recovery. According to this model, inter-hemispheric competition is a more accurate predictor of recovery and should be favored in mild stroke patients with a high structural reserve, while vicariation should be considered in cases of severe stroke. However, despite the increasing number of stimulation protocols based on these three models, the utilization of NIBS therapies in clinical settings remains a controversial issue. Notably, a gold standard treatment protocol has yet to be established, but, more importantly, the underlying mechanisms of action of NIBS are not fully understood. Variables such as lesion severity should be further considered when determining the appropriate therapeutic approach. Moreover, adjusting stimulation intensity and duration is essential to ensure complete adaptive plasticity, which is further translated into more rapid motor and cognitive recovery.
The various mechanisms governing brain plasticity for functional recovery in humans are also identifiable in animal models (Murphy and Corbett, 2009, Caleo, 2015). Preclinical models play a crucial role in offering insights that are often unattainable through other means. For example, they enable the investigation of brain activity pre- and post-stroke in the same animal. Therefore, these approaches significantly enhance our understanding of neuroplasticity mechanisms, facilitate the exploration of potential clinical applications, and aid in the optimization of current rehabilitative therapies. The primary objectives of this systematic review were as follows: (a) to provide an overview of the studies employing various NIBS therapies to evaluate functional recovery (global neurological, motor and cognitive functions) in animal stroke models; (b) to analyze the most effective and promising stimulation protocols; and (c) to discuss their potential translation into clinical practice. In sum, this review aimed to serve as a guiding resource for future studies seeking to improve the therapeutic use of NIBS following stroke.
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