Original ArticleDevelopmental Remodelling of the Motor Cortex in Hemiparetic Children With Perinatal Stroke
Introduction
Perinatal stroke is the leading cause of hemiparetic cerebral palsy (HCP), resulting in lifelong motor disability for millions globally.1 Despite its common occurrence, there are no established prevention strategies, suggesting that the burden of perinatal stroke-induced HCP will persist. This situation necessitates a better understanding of the developmental neuroplastic mechanisms that determine motor outcomes to improve rehabilitative strategies.
Perinatal stroke-induced HCP involves contralateral motor impairment, often predominently affecting the upper extremity. Two dominant subtypes of perinatal stroke exist varying by the timing and location of injury. Periventricular venous infarcts (PVI) refer to germinal matrix hemorrhage occurring at less than 34 weeks’ gestation and causing secondary medullary venous infarction of the periventricular white matter.2,3 This isolated deep white matter injury often damages the corticospinal tracts directly while sparing the cortex and basal ganglia. In contrast, arterial ischemic strokes (AIS) occur proximate to term birth and most often involve the occlusion of the middle cerebral artery, damaging both cortical and subcortical motor components.4 As a unilateral, focal, and temporally defined injury in an otherwise healthy brain, perinatal stroke is an excellent human model of developmental motor plasticity, but subsequent motor system re-organization is not well understood.
Motor deficits after perinatal stroke may reflect altered organization of the descending corticospinal tracts and cortical motor areas. In normal motor development, each primary motor cortex (M1) initially has robust bilateral corticospinal connections projecting to the spinal cord. Contralateral projections decussate at the medulla before terminating on the synaptic targets, whereas ipsilateral fibers remain uncrossed. By 20 weeks’ gestation, spinal synaptic connections refine in an activity-dependent manner as contralateral fibers become increasingly strengthened and ipsilateral fibers gradually retract.5,6 Unilateral perinatal brain lesions may hinder the ability of the contralateral fibers to compete for their intended lower motor neuron targets, allowing more ipsilateral connections to persist.7,8 As a result, the paretic limb is often controlled by retained ipsilateral fibers from the intact primary motor cortex (M1′). Ipsilateral arrangements have been associated with worse functional outcomes.9, 10, 11 However, this is not always the case, and where both the lesional and intact primary motor cortices develop, it may be key to understanding clinical function.
The adult motor system is capable of reorganizing after stroke. Previous observations include local remapping of the lesioned M1,12, 13, 14, 15 an increased reliance on non-M1 motor areas in the lesioned hemisphere,13 and recruitment of motor structures in the intact hemisphere.16, 17, 18 It is unknown whether reorganization in the mature brain translates to developmental organization following perinatal injury. Motor system topography in children with perinatal stroke can be explored using task-based functional magnetic resonance imaging (fMRI) where unilateral hand movements reliably elicit measurable blood oxygen level-dependent (BOLD) changes in the contralateral M1.19,20 Other areas may also shape motor control after perinatal injury. For instance, the supplementary motor area (SMA) is capable of initiating motor actions autonomously from M121 and may compensate for M1 dysfunction poststroke in adults.20,22 In our population, motor system topography of M1, M1′, and SMA have not been systematically assessed across specific perinatal stroke disease states. Defining the precise location of cortical motor targets is required to advance personalized rehabilitation, including recent positive neuromodulation trials in HCP.23, 24, 25 Transcranial magnetic stimulation (TMS) is another noninvasive modality that can delineate the cortical representations of the paretic and unaffected hand.26, 27, 28 TMS has the potential to unveil motor topography in a “top-down” approach whereby directing a stimulus over the lesional M1 and M1′ in the intact hemisphere produces a muscle contraction in the paretic hand, albeit with a low functional resolution of ∼7 mm.29 By combining TMS mapping techniques with the superior spatial resolution of fMRI mapping (∼3-4 mm), we aim to validate motor cortex topography in these populations.
In the present study, we characterized bilateral motor cortex topography in children with HCP secondary to perinatal stroke using task-based fMRI. We hypothesized that M1 in the lesioned hemisphere, M1′ in the intact hemisphere, and SMA representations would be altered during paretic hand tapping. We furthermore predicted that the magnitude of lesional M1 displacement would correlate with clinical measures of motor impairment.
Section snippets
Population
Participants with perinatal stroke were recruited through the Alberta Perinatal Stroke Project, a population-based research cohort.30 Inclusion criteria were (1) symptomatic HCP, (2) MRI-confirmed unilateral perinatal ischemic stroke (PVI or AIS), (3) age six to 19 years, and (4) written informed consent/assent. Typically developing volunteers were recruited from our Healthy Infants and Children Clinical Research Program (HICCUP, www.hiccupkids.ca) and were right-handed by self-report, aged six
Population characteristics
Sixty-nine participants were recruited (18 PVI, 22 AIS, 29 controls). Twenty (four PVI, nine AIS, seven controls) were excluded due to excessive motion (n = 12) or incomplete data sets (n = 8). The final population comprised 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). Motor outcomes were similar between PVI and AIS. Population characteristics are outlined in Table 1. Mean values for excluded cases did not differ from included cases with the
Discussion
We demonstrate that motor topography is displaced in perinatal stroke disease states. The retention of ipsilateral projections in the nonlesioned hemisphere appears to influence the displacement of contralateral M1 activations in the same hemisphere. In children with arterial stroke, SMA activity was shifted from the canonical location, suggesting that plasticity is not limited to M1. That displacement measures were not highly correlated with upper extremity function suggests additional
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Cited by (0)
Conflicts of interest: The authors declare no conflicts of interest.
Funding: We thank the Heart and Stroke Foundation of Canada, the Canadian Institutes for Health Research and the Queen Elizabeth II Graduate Scholarship for financially supporting this work.