Functional connectivity drives stroke recovery: shifting the paradigm from correlation to causation

Stroke is a leading cause of disability, with deficits encompassing multiple functional domains. The heterogeneity underlying stroke poses significant challenges in the prediction of post-stroke recovery, prompting the development of neuroimaging-based biomarkers. Structural neuroimaging measurements, particularly those reflecting corticospinal tract injury, are well-documented in the literature as potential biomarker candidates of post-stroke motor recovery. Consistent with the view of stroke as a 'circuitopathy', functional neuroimaging measures probing functional connectivity may also prove informative in post-stroke recovery. An important step in the development of biomarkers based on functional neural network connectivity is the establishment of causality between connectivity and post-stroke recovery. Current evidence predominantly involves statistical correlations between connectivity measures and post-stroke behavioural status, either cross-sectionally or serially over time. However, the advancement of functional connectivity application in stroke depends on devising experiments that infer causality. In 1965, Sir Austin Bradford Hill introduced nine viewpoints to consider when determining the causality of an association: (i) strength; (ii) consistency; (iii) specificity; (iv) temporality; (v) biological gradient; (vi) plausibility; (vii) coherence; (viii) experiment; and (ix) analogy. Collectively referred to as the Bradford Hill Criteria, these points have been widely adopted in epidemiology. In this review, we assert the value of implementing Bradford Hill's framework to stroke rehabilitation and neuroimaging. We focus on the role of neural network connectivity measurements acquired from task-oriented and resting-state functional MRI, EEG, magnetoencephalography and functional near-infrared spectroscopy in describing and predicting post-stroke behavioural status and recovery. We also identify research opportunities within each Bradford Hill tenet to shift the experimental paradigm from correlation to causation.