Background. There is growing interest to establish recovery biomarkers, especially neurological biomarkers, in order to develop new therapies and prediction models for the promotion of stroke rehabilitation and recovery. However, there is no consensus among the neurorehabilitation community about which biomarker(s) have the highest predictive value for motor recovery. Objective. To review the evidence and determine which neurological biomarker(s) meet the high evidence quality criteria for use in predicting motor recovery. Methods. We searched databases for prognostic neuroimaging/neurophysiological studies. Methodological quality of each study was assessed using a previously employed comprehensive 15-item rating system. Furthermore, we used the GRADE approach and ranked the overall evidence quality for each category of neurologic biomarker. Results. Seventy-one articles met our inclusion criteria; 5 categories of neurologic biomarkers were identified: diffusion tensor imaging (DTI), transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), conventional structural MRI (sMRI), and a combination of these biomarkers. Most studies were conducted with individuals after ischemic stroke in the acute and/or subacute stage (~70%). Less than one-third of the studies (21/71) were assessed with satisfactory methodological quality (80% or more of total quality score). Conventional structural MRI and the combination biomarker categories ranked “high” in overall evidence quality. Conclusions. There were 3 prevalent methodological limitations: (a) lack of cross-validation, (b) lack of minimal clinically important difference (MCID) for motor outcomes, and (c) small sample size. More high-quality studies are needed to establish which neurological biomarkers are the best predictors of motor recovery after stroke. Finally, the quarter-century old methodological quality tool used here should be updated by inclusion of more contemporary methods and statistical approaches.
There is growing interest in establishing stroke recovery biomarkers. Researchers define stroke recovery biomarkers as surrogate indicators of disease state that can have predictive value for recovery or treatment response.1 Specifically, previous studies have suggested that better understanding of neurological biomarkers, derived from brain imaging and neurophysiological assessments, is likely to move stroke rehabilitation research forward.1,2
Recovery biomarkers acquired during the acute and subacute phases (acute—within 1 week after onset; subacute—between 1 week and 3 months after onset) may be vital to set attainable neurorehabilitation goals and to choose proper therapeutic approaches based on the recovery capacity. Furthermore, motor recovery prediction using neurological biomarkers in the chronic phase (more than 3 months after onset) can be useful to determine whether an individual will benefit from specific therapeutic interventions applied after the normal period of rehabilitation has ended. Hence, use of recovery biomarkers is likely to improve customization of physical interventions for individual stroke survivors regarding their capacity for recovery, and to facilitate development of new neurorehabilitation approaches.
There have been fundamental changes in recovery biomarkers from simple clinical behavioral biomarkers to brain imaging and neurophysiological biomarkers. In particular, a number of recent studies have shown that neurologic biomarkers (ie, neuroimaging and/or neurophysiological measures of brain) are more predictive of motor recovery than clinical behavioral biomarkers.3–5
Although there is some evidence that neurological biomarkers are more valuable as predictors of motor recovery than clinical behavioral biomarkers, there are significant gaps between the published evidence and clinical usage. First, there is no consensus on which specific neurological biomarkers would be best for prediction models.4,6,7 Viable neurological biomarker of motor recovery have evolved from lesion size and location, prevalent in the early 1990s8 to more contemporary complex brain network analysis variables.9 Despite this evolution, there is a paucity of high-level evidence for determining the most critical neurological biomarkers of motor recovery. A number of literature reviews and systematic reviews of studies published since the 1990s aimed to identify the most appropriate biomarkers of motor recovery or functional independence.8,10–12 Among these reviews, only one by Schiemanck and colleagues8 assessed the evidence quality of neurologic biomarkers, while many focused on clinical measures (ie, clinical motor and/or functional measures).11 Their review was limited to only 13 studies that employed structural magnetic resonance imaging (sMRI) measures of lesion volume as neurologic biomarkers. Besides lesion volume derived from structural MRI, there are other viable neurological biomarkers of brain impairment. Therefore, this systematic review includes a broad set of relevant biomarkers for consideration as critical predictors for inclusion in motor recovery prediction models.
Furthermore, there is some evidence to suggest that multivariate prediction models that use neurological biomarkers in addition to clinical outcome measures are more accurate than those that use clinical outcome measures alone.2,13 However there is still no consensus about whether incorporating behavioral and neurological predictors in a multimodal prediction model is superior (ie, more accurate) to a univariate model that includes either behavioral or neurological predictors alone.
Taken together, this systematic review has 2 aims. The first is to conduct a critical and systematic comparison of selected studies to determine which neurological biomarker(s) is likely to have sufficient high-level evidence in order to render the most accurate prediction of motor recovery after stroke. The second aim is to identify whether adding clinical measures along with neurological biomarkers in the model improves the accuracy of the model compared to the models that use neurological biomarkers alone.