This study provides Class II evidence that for children with perinatal stroke and hemiparetic cerebral palsy, the addition of tDCS to moderate-dose motor learning therapy does not significantly improve motor function as measured by the AHA.

IMPORTANCE Hemorrhage into the brain of term newborns often results in major injury and lifelong disability. The clinical epidemiology of neonatal hemorrhagic stroke (NHS) remains undefined, hindering the development of strategies to improve outcomes.OBJECTIVE To characterize the incidence, types, presentations, associated factors, and outcomes of neonatal hemorrhagic stroke. DESIGN, SETTING, AND PARTICIPANTS Population-based, nested case-control study. The Alberta Perinatal Stroke Project, a provincial registry, ascertained NHS cases using exhaustive diagnostic code searching (1992-2010, >2500 medical record reviews). Prospective cases were captured through the Calgary Pediatric Stroke Program (2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014). Participants included term neonates with magnetic resonance imaging-confirmed NHS including primary and secondary intracerebral hemorrhage, hemorrhagic transformation of ischemic injury, and presumed perinatal hemorrhagic stroke. Control infants with common data were recruited from a population-based study (4 to 1 ratio). MAIN OUTCOMES AND MEASURESInfants with NHS underwent structured medical record review using data-capture forms and blinded scoring of neuroimaging. Clinical risk factor common data elements were explored using logistic regression. Provincial live births were obtained from Statistics Canada. Outcomes were extrapolated to the Pediatric Stroke Outcome Measure. RESULTSWe identified 86 cases: 51 infants (59%) with NHS, of which 32 (67%) were idiopathic, 30 (35%) were hemorrhagic transformation of primary ischemic injuries (14 with neonatal cerebral sinovenous thrombosis, 11 with hypoxic ischemic encephalopathy, and 5 with neonatal arterial ischemic stroke), and 5 were presumed perinatal hemorrhagic stroke. Sixty-two percent were male. Incidence of pure NHS was 1 in 9500 live births and 1 in 6300 for all forms. Most presented in the first week of life with seizures and encephalopathy. Acute neurosurgical intervention was rare (3 of 86 total cases; 3.5%). Temporal lobe was the most common NHS location (16 of 51 pure NHS cases; 31%). A primary cause was evident in 19 of the 51 cases of non-hemorrhagic transformation NHS (37%). Idiopathic NHS was independently associated with lower maternal age (odds ratio [OR], 0.87; 95% CI, 0.78-0.94), primiparity (OR, 2.98; 95% CI, 1.18-7.50), prior spontaneous abortion (OR, 0.11; 95% CI, 0.02-0.53), difficult fetal transition (bradycardia [OR, 15.0; 95% CI,] and low Apgar [OR, 14.3; 95% CI, 2.77-73.5]), and small for gestational age (OR, 14.3; 95% CI, 1.62-126.1). Follow-up of 50 cases at a median of 37 months demonstrated poor neurological outcomes in 21 patients (44%). CONCLUSIONS AND RELEVANCENeonatal hemorrhagic stroke is more common than previously reported, occurring in at least 1 in 6300 live births. Etiologies are approximately equally distributed between idiopathic, secondary, and hemorrhagic transformation. Clinical associations do not suggest a common mechanism or predictability of NHS. Recurrence is rare. Outcomes a...

This study provides Class II evidence that combined rTMS and CIMT enhance therapy-induced functional motor gains in children with stroke-induced hemiparetic cerebral palsy.

Background: Non-invasive brain stimulation is being increasingly used to interrogate neurophysiology and modulate brain function. Despite the high scientific and therapeutic potential of non-invasive brain stimulation, experience in the developing brain has been limited. Objective: To determine the safety and tolerability of non-invasive neurostimulation in children across diverse modalities of stimulation and pediatric populations. Methods: A non-invasive brain stimulation program was established in 2008 at our pediatric, academic institution. Multi-disciplinary neurophysiological studies included single-and paired-pulse Transcranial Magnetic Stimulation (TMS) methods. Motor mapping employed robotic TMS. Interventional trials included repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS). Standardized safety and tolerability measures were completed prospectively by all participants. Results: Over 10 years, 384 children underwent brain stimulation (median 13 years, range 0.8e18.0). Populations included typical development (n ¼ 118), perinatal stroke/cerebral palsy (n ¼ 101), mild traumatic brain injury (n ¼ 121) neuropsychiatric disorders (n ¼ 37), and other (n ¼ 7). No serious adverse events occurred. Drop-outs were rare (<1%). No seizures were reported despite >100 participants having brain injuries and/or epilepsy. Tolerability between single and paired-pulse TMS (542340 stimulations) and rTMS (3.0 million stimulations) was comparable and favourable. TMS-related headache was more common in perinatal stroke (40%) than healthy participants (13%) but was mild and self-limiting. Tolerability improved over time with side-effect frequency decreasing by >50%. Robotic TMS motor mapping was well-tolerated though neck pain was more common than with manual TMS (33% vs 3%). Across 612 tDCS sessions including 92 children, tolerability was favourable with mild itching/tingling reported in 37%. Conclusions: Standard non-invasive brain stimulation paradigms are safe and well-tolerated in children and should be considered minimal risk. Advancement of applications in the developing brain are warranted. A new and improved pediatric NIBS safety and tolerability form is included.

Perinatal stroke causes most hemiparetic cerebral palsy, resulting in lifelong disability. We have demonstrated the ability of robots to quantify sensory dysfunction in hemiparetic children but the relationship between such deficits and sensory tract structural connectivity has not been explored. It was aimed to characterize the relationship between the dorsal column medial lemniscus (DCML) pathway connectivity and proprioceptive dysfunction in children with perinatal stroke. Twenty-nine participants (6-19 years old) with MRI-classified, unilateral perinatal ischemic stroke (14 arterial, 15 venous), and upper extremity deficits were recruited from a population-based cohort and compared with 21 healthy controls. Diffusion tensor imaging (DTI) defined DCML tracts and five diffusion properties were quantified: fractional anisotropy (FA), mean, radial, and axial diffusivities (MD, RD, AD), and fiber count. A robotic exoskeleton (KINARM) tested upper limb proprioception in an augmented reality environment. Correlations between robotic measures and sensory tract diffusion parameters were evaluated. Lesioned hemisphere sensory tracts demonstrated lower FA and higher MD, RD, and AD compared with the non-dominant hemisphere of controls. Dominant (contralesional) hemisphere tracts were not different from controls. Both arterial and venous stroke groups demonstrated impairments in proprioception that correlated with lesioned hemisphere DCML tract diffusion properties. Sensory tract connectivity is altered in the lesioned hemisphere of hemiparetic children with perinatal stroke. A correlation between lesioned DCML tract diffusion properties and robotic proprioceptive measures suggests clinical relevance and a possible target for therapeutic intervention. Hum Brain Mapp 38:2424-2440, 2017. © 2017 Wiley Periodicals, Inc.

BACKGROUND: Perinatal stroke encompasses multiple disease-specific cerebrovascular syndromes that cause lifelong neurodevelopmental morbidity for millions worldwide. Acute presentations include neonatal arterial ischemic stroke (NAIS), neonatal cerebral sinovenous thrombosis, and neonatal hemorrhagic stroke (NHS). Delayed presentations include arterial presumed perinatal ischemic stroke, periventricular venous infarction, and presumed perinatal hemorrhagic stroke. Our objective was to define the birth prevalence of all subtypes of perinatal stroke by using a population-based cohort. METHODS: The Alberta Perinatal Stroke Project is a research cohort established in 2008 in southern Alberta, Canada, with prospective (2008–2017) and retrospective (1990–2008) enrollment leveraging universal health care at a single tertiary care pediatric center. The primary outcome was the estimated birth prevalence of each perinatal stroke syndrome, secondary outcomes were birth prevalence over time, sex ratios, and change in age at diagnosis. Analysis included Poisson regression, Wilcoxon rank test, and Fisher exact test. RESULTS: The overall estimated birth prevalence of term-born perinatal stroke was 1:1100. The estimated birth prevalence was 1:3000 for NAIS, 1:7900 for arterial presumed perinatal ischemic stroke, 1:6000 for periventricular venous infarction, 1:9100 for cerebral sinovenous thrombosis, 1:6800 for NHS, and 1:65000 for presumed perinatal hemorrhagic stroke. The apparent birth prevalence of NAIS and NHS increased over time. There were more males affected than females. The age at diagnosis decreased for late-presenting stroke types. CONCLUSIONS: The estimated birth prevalence of term perinatal stroke is higher than previous estimates, which may be explained by population-based sampling of disease-specific states. This emphasizes the need for further studies to better understand the disease-specific pathophysiology to improve treatment and prevention strategies.

Perinatal stroke is the leading cause of hemiparetic cerebral palsy (CP), resulting in life-long disability. In this study, we examined the relationship between robotic upper extremity motor impairment and corticospinal tract (CST) diffusion properties. Thirty-three children with unilateral perinatal ischemic stroke (17 arterial, 16 venous) and hemiparesis were recruited from a population-based research cohort. Bilateral CSTs were defined using diffusion tensor imaging (DTI) and four diffusion metrics were quantified: fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivities. Participants completed a visually guided reaching task using the KINARM robot to define 10 movement parameters including movement time and maximum speed. Twenty-six typically developing children underwent the same evaluations. Partial correlations assessed the relationship between robotic reaching and CST diffusion parameters. All diffusion properties of the lesioned CST differed from controls in the arterial group, whereas only FA was reduced in the venous group. Non-lesioned CST diffusion measures were similar between stroke groups and controls. Both stroke groups demonstrated impaired reaching performance. Multiple reaching parameters of the affected limb correlated with lesioned CST diffusion properties. Lower FA and higher MD were associated with greater movement time. Few correlations were observed between non-lesioned CST diffusion and unaffected limb function though FA was associated with reaction time (R = -0.39, p < .01). Diffusion properties of the lesioned CST are altered after perinatal stroke, the degree of which correlates with specific elements of visually guided reaching performance, suggesting specific relevance of CST structural connectivity to clinical motor function in hemiparetic children.

BackgroundPerinatal stroke is the most common cause of unilateral cerebral palsy. Mechanisms of post-stroke developmental plasticity in children are poorly understood. To better understand the relationship between functional connectivity and disability, we used resting-state fMRI to compare sensorimotor connectivity with clinical dysfunction.MethodsSchool-aged children with periventricular venous infarction (PVI) and unilateral cerebral palsy were compared to controls. Resting-state BOLD signal was acquired on 3 T MRI and analyzed using CONN in SPM12. Functional connectivity was computed between S1, M1, supplementary motor area (SMA), and thalamus of the left/non-lesioned and right/lesioned hemisphere. Primary outcome was connectivity expressed as a Fisher-transformed correlation coefficient. Motor function was measured using the Assisting Hand Assessment (AHA), and Melbourne Assessment (MA). Proprioceptive function was measured using a robotic position matching task (VarXY).ResultsParticipants included 15 PVI and 21 controls. AHA and MA in stroke patients were negatively correlated with connectivity (increased connectivity = poorer performance). Position sense was inversely correlated with connectivity (increased connectivity = improved performance) between the non-lesioned S1 and thalamus/SMA. In controls, VarXY was positively correlated with connectivity between the thalamus and bilateral sensorimotor regions.ConclusionsResting state fMRI measures of sensorimotor connectivity are associated with clinical sensorimotor function in children with unilateral cerebral palsy secondary to PVI. Greater insight into understanding reorganization of brain networks following perinatal stroke may facilitate personalized rehabilitation.