Abstract
The impact of rehabilitation on post-stroke motor recovery and its dependency on the patient’s chronicity remain unclear. The field has widely accepted the notion of a proportional recovery rule with a “critical window for recovery” within the first 3–6 mo poststroke. This hypothesis justifies the general cessation of physical therapy at chronic stages. However, the limits of this critical window have, so far, been poorly defined. In this analysis, we address this question, and we further explore the temporal structure of motor recovery using individual patient data from a homogeneous sample of 219 individuals with mild to moderate upper-limb hemiparesis. We observed that improvement in body function and structure was possible even at late chronic stages. A bootstrapping analysis revealed a gradient of enhanced sensitivity to treatment that extended beyond 12 mo poststroke. Clinical guidelines for rehabilitation should be revised in the context of this temporal structure.
NEW & NOTEWORTHY Previous studies in humans suggest that there is a 3- to 6-mo “critical window” of heightened neuroplasticity poststroke. We analyze the temporal structure of recovery in patients with hemiparesis and uncover a precise gradient of enhanced sensitivity to treatment that expands far beyond the limits of the so-called critical window. These findings highlight the need for providing therapy to patients at the chronic and late chronic stages.
INTRODUCTION
The absolute incidence of stroke will continue to rise globally with a predicted 12 million stroke deaths in 2030 and 60 million stroke survivors worldwide (Eilers 2003). Stroke leads to focal lesions in the brain due to cell death following hypoxia and inflammation, affecting both gray and white matter tracts (Corbetta et al. 2015). After a stroke, a wide range of deficits can occur with varying onset latencies such as hemiparesis, abnormal posture, spatial hemineglect, aphasia, and spasticity, along with affective and cognitive deficits, chronic pain, and depression (Teasell et al. 2003). Due to improved treatment procedures during the acute stage of stroke (e.g., thrombolysis and thrombectomy), the associated reduction in stroke mortality has led to a greater proportion of patients facing impairments and needing long-term care and rehabilitation. However, prevention, diagnostics, rehabilitation, and prognostics of stroke recovery have not kept pace (Veerbeek et al. 2014).
Motor recovery after stroke has been widely operationalized as the individual’s change in two domains: 1) body function and structure (WHO 2001), whose improvement has been called “true recovery” (Bernhardt et al. 2017) and refers to the restitution of a movement repertoire that the individual had before the injury; and 2) the ability to successfully perform the activities of daily living (Levin et al. 2009). While the former is mainly due to the interaction of poststroke plasticity mechanisms and sensorimotor training, the latter is also influenced by the use of explicit and implicit compensatory strategies (Bernhardt et al. 2017; Kwakkel et al. 2017). The most accepted measure for recovery of body function and structure is the change in the Fugl-Meyer Assessment of the upper extremity (UE-FM) scores (Kwakkel et al. 2017), while other clinical scales focus on the assessment of activities, such as the Chedoke Arm and Hand Activity Inventory (CAHAI) (Barreca et al. 2005) or the Barthel Index for Activities of Daily Living (BI) (Granger et al. 1979).
Poststroke motor recovery mostly follows a nonlinear trajectory that reaches asymptotic levels a few months after the injury (Kwakkel et al. 2004). This model suggests the existence of a period of heightened plasticity in which the patient seems to be more responsive to treatment, the so-called “critical window” for recovery. Aiming at characterizing the temporal structure of recovery, animal models and clinical research have identified a combination of mechanisms underlying neurological repair that seems to be unique to the injured brain, including neurogenesis, gliogenesis, axonal sprouting, and the rebalancing of excitation and inhibition in cortical networks (Ward 2017). This state of enhanced plasticity seems to be transient and interacts closely with sensorimotor training to facilitate the recovery of motor function (Zeiler et al. 2016). However, there is no clear evidence of the exact temporal structure of enhanced responsiveness to treatment in humans, and as a result the optimal timing and intensity of treatment remain unclear. A systematic review of 14 studies suggested that, on average, recovery reaches a plateau at 15 wk poststroke for patients with severe hemiparesis and at 6.5 wk for patients with mild hemiparesis (Hendricks et al. 2002). This study however failed to conduct a meta-analysis due to substantial heterogeneity of the sample and protocols. Currently, an ongoing clinical trial is investigating the existence and the duration of a critical window of enhanced neuroplasticity in humans following ischemic stroke (McDonnell et al. 2015). Based on the assumption of the existence of this critical period, the SMARTS 2 trial (NCT02292251) (Krakauer and Cortés 2018) is currently investigating the effect of early and intensive therapy on upper extremity motor recovery. Sharing the same research question, the Critical Periods After Stroke Study (CPASS) is a large ongoing randomized controlled trial that focuses on determining the optimal time after stroke for intensive motor training (Dromerick et al. 2015). To contribute to the delineation of a temporal structure of stroke recovery in humans, we performed an analysis of individual patient clinical data from 219 subjects with upper-limb hemiparesis, who followed occupational therapy (OT) or a virtual reality (VR)-based training protocol using the Rehabilitation Gaming System (RGS) (Cameirão et al. 2010) (Fig. S1 in Supplemental Material; all Supplemental material is available at https://doi.org/10.5281/zenodo.3246368). We show that physical therapy has a significant impact on the function of the upper extremity (UE) at all periods poststroke considered, uncovering a gradient of responsiveness to treatment that extends >12 mo poststroke.[…]
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TBI Rehabilitation 