Translating concepts of neural repair after stroke: Structural and functional targets for recovery

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Stroke is among the commonest causes of adult disability worldwide (GBD 2016 Stroke Collaborators, 2019; Murray & Lopez, 2013; Regenhardt, Biseko et al., 2019). Furthermore, there has been an epidemiological shift of its disease burden towards that of a long-term condition, suggesting that the number of patients with stroke will continue to rise (Crichton, Bray, McKevitt, Rudd, & Wolfe, 2016). Therefore, the development of approaches to enhance recovery and augment neural repair after stroke will be critical. Herein, we provide a narrative review for clinicians broadly summarizing recovery after stroke, basic elements of neural repair, and ongoing work to augment repair. To devise novel interventions, an understanding of the spontaneous repair processes that occur in the brain after stroke is essential. Ongoing work builds on mounting data to identify strategies to improve the brain’s capacity to repair itself, through pharmacological, rehabilitative, and neurotechnological means.

Many factors make the clinical translation of therapies a challenging task. Stroke is a heterogeneous disease. Repair and recovery are highly dependent upon the brain regions involved (Minnerup et al., 2018) and the time point after stroke through a biphasic progression as damaged brain transitions from injury into repair (E. H. Lo, 2008). Interventions that target repair are unique compared to acute reperfusion and neuroprotection strategies. Those that target repair have a different timeline (weeks to months versus hours to days) and different target (augmenting the function of surviving tissue rather than saving dying tissue) (Cramer, 2018). Unlike acute therapies to “save” brain, repair-focused therapies emphasize repairing, replacing, and “re-wiring” damaged brain (i.e. plasticity) (Corbett, Nguemeni, & Gomez-Smith, 2014; Cramer et al., 2011; Regenhardt et al., 2017; Regenhardt et al., 2018). In the weeks to months after stroke, spontaneous changes are seen in areas surrounding the infarct and those with network connections to the infarct (Cramer & Chopp, 2000; Hermann & Chopp, 2012; Nudo, 2011; Overman & Carmichael, 2014). These changes are interrelated and occur at both the structural (molecular, cellular, and tissue) and functional levels (excitability, cortical maps, and networks).

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At the level of the individual patient, recovery after stroke can be variable and difficult to predict (Ward, 2017). While both reflect functional improvement, a distinction should be made between compensation and true recovery (J. W. Krakauer, Carmichael, Corbett, & Wittenberg, 2012). Compensation is the use of alternative strategies to accomplish a task or goal, such as the use of the unaffected limb. In contrast, true recovery occurs through neural repair, when brain regions regain function or when undamaged brain regions are recruited to generate commands to the same muscles that were used before injury. Complicating our understanding of recovery, many early trials failed to measure true recovery directly and instead measured global outcomes.

Different symptoms after stroke, including motor weakness, aphasia, neglect, and apraxia, spontaneously recover at different rates (Cassidy, Lewis, & Gray, 1998; Desmond, Moroney, Sano, & Stern, 1996; Hier, Mondlock, & Caplan, 1983; Lazar et al., 2010; Nijboer, Kollen, & Kwakkel, 2013; Pedersen, Jorgensen, Nakayama, Raaschou, & Olsen, 1995; Sunderland, Tinson, & Bradley, 1994; Wade, Parker, & Langton Hewer, 1986). The most data exist for motor recovery as it is amenable to more objective measurement (Duncan, Goldstein, Matchar, Divine, & Feussner, 1992). The dominant predictive factor is the initial severity of impairment (Coupar, Pollock, Rowe, Weir, & Langhorne, 2012), where milder deficits recover faster and achieve higher levels of function (Cramer, 2008). One classic study showed that arm function achieved maximum recovery in 95% of patients within 9 weeks (Nakayama, Jorgensen, Raaschou, & Olsen, 1994). More recently, the proportional recovery rule has been described for upper limb motor impairment: at 3 months, patients with mild to moderate initial impairments achieve approximately 70% of their maximum potential for recovery (Byblow, Stinear, Barber, Petoe, & Ackerley, 2015; J. W. Krakauer & Marshall, 2015; Prabhakaran et al., 2008; Winters, van Wegen, Daffertshofer, & Kwakkel, 2015; Zarahn et al., 2011). This “rule” has come under controversy recently (Hawe, Scott, & Dukelow, 2018; Hope et al., 2019; Senesh & Reinkensmeyer, 2019). Nevertheless, two themes hold for spontaneous recovery after stroke. First, most recovery occurs in the first weeks after stroke and involves stereotyped biological processes (as described below). Second, there is a substantial amount of individual variation in recovery after stroke that likely involves personal, genetic, and environmental factors. Ongoing research aims to identify other prognostic biomarkers, such as corticospinal tract lesion extent and prediction tools based on clinical variables; there has been progress predicting ultimate limb motor impairment, walking, and swallowing (Stinear, Smith, & Byblow, 2019).

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About the Author: Tung Chi