Effects of constraint-induced movement therapy on neurogenesis and functional recovery after early hypoxic-ischemic injury in mice

Aim: Constraint-induced movement therapy (CIMT) has emerged as a promising therapeutic strategy for improving affected upper limb function in children with hemiplegic cerebral palsy (CP). However, little is known about the changes in the brain that are induced by CIMT. This study was designed to investigate these changes and behavioural performance after CIMT intervention in mice with neonatal hypoxic-ischemic brain injury. Method: We utilized the neonatal hypoxic-ischemic brain injury model established in mice pups. Three weeks after the injury, the mice were randomly assigned to the following three groups: the control group (n=15), the enriched-environment group (n=17), and the CIMT with an enriched-environment group (CIMT-EE, n=15). 5-bromo-2-deoxyuridine (BrdU) was injected daily to label proliferating cells during the 2 weeks of intervention. Results: The CIMT-EE group showed better fall rate in the horizontal ladder rung walking test (mean 5.4%, SD 3.6%) than either the control (mean 14.3%, SD 7.3%; p=0.001) or enriched-environment (mean 12.4%, SD 7.7%; p=0.010) groups 2 weeks after the end of intervention. The CIMT-EE group also showed more neurogenesis (mean 7069 cells/mm³, SD 4017 cells/mm³) than either the control group (mean 1555 cells/mm³, SD 1422 cells/mm³; p<0.001) or enriched-environment group (mean 2994 cells/mm³, SD 3498 cells/mm³; p=0.001) in the subventricular zone. In the striatum, neurogenesis in the CIMT-EE group (mean 534 cells/mm³, SD 441 cells/mm³) was greater than in the control group (mean 95 cells/mm³, SD 133 cells/mm³; p=0.001). Interpretation: There was CIMT-EE enhanced neurogenesis in the brain along with functional benefits in mice after early hypoxic-ischemic brain injury. This is the first study to demonstrate the effects of CIMT on neurogenesis and functional recovery after experimental injury to an immature brain.