title: Forced arm use is superior to voluntary training for motor recovery and brain plasticity after cortical ischemia in rats.
abstract: OBJECTIVE
  Both the immobilization of the unaffected arm combined with physical therapy (forced arm use, FAU) and voluntary exercise (VE) as model for enriched environment are promising approaches to enhance recovery after stroke. The genomic mechanisms involved in long-term plasticity changes after different means of rehabilitative training post-stroke are largely unexplored. The present investigation explored the effects of these physical therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia.
  
  
  METHODS
  42 Wistar rats were randomly treated with either forced arm use (FAU, 1-sleeve plaster cast onto unaffected limb at 8/10 days), voluntary exercise (VE, connection of a freely accessible running wheel to cage), or controls with no access to a running wheel for 10 days starting at 48 hours after photothrombotic stroke of the sensorimotor cortex. Functional outcome was measured using sensorimotor test before ischemia, after ischemia, after the training period of 10 days, at 3 and 4 weeks after ischemia. Global gene expression changes were assessed from the ipsi- and contralateral cortex and the hippocampus.
  
  
  RESULTS
  FAU-treated animals demonstrated significantly improved functional recovery compared to the VE-treated group. Both were superior to cage control. A large number of genes are altered by both training paradigms in the ipsi- and contralateral cortex and the hippocampus. Overall, the extent of changes observed correlated well with the functional recovery obtained. One category of genes overrepresented in the gene set is linked to neuronal plasticity processes, containing marker genes such as the NMDA 2a receptor, PKC ζ, NTRK2, or MAP 1b.
  
  
  CONCLUSIONS
  We show that physical training after photothrombotic stroke significantly and permanently improves functional recovery after stroke, and that forced arm training is clearly superior to voluntary running training. The behavioral outcomes seen correlate with patterns and extent of gene expression changes in all brain areas examined. We propose that physical training induces a fundamental change in plasticity-relevant gene expression in several brain regions that enables recovery processes. These results contribute to the debate on optimal rehabilitation strategies, and provide a valuable source of molecular entry points for future pharmacological enhancement of recovery.
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Armin
authors: A
authors: Schneider
authors: Neurology Department Bethel EVKB Bielefeld and Dept. of Neurology, University of Muenster, Muenster, Germany.
authors: Andreas
authors: A
authors: Rogalewski
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Oliver
authors: O
authors: Wafzig
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Friederike
authors: F
authors: Kirsch
authors: Ctr. for Med. Res., Fac. for Clin. Medicine, University of Heidelberg, Mannheim, Germany.
authors: Norbert
authors: N
authors: Gretz
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Carola
authors: C
authors: Krüger
authors: Neurology Department Bethel EVKB Bielefeld and Dept. of Neurology, University of Muenster, Muenster, Germany.
authors: Kai
authors: K
authors: Diederich
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Claudia
authors: C
authors: Pitzer
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Rico
authors: R
authors: Laage
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Christian
authors: C
authors: Plaas
authors: SYGNIS Bioscience, Heidelberg, Germany.
authors: Gerhard
authors: G
authors: Vogt
authors: Neurology Department Bethel EVKB Bielefeld and Dept. of Neurology, University of Muenster, Muenster, Germany.
authors: Jens
authors: J
authors: Minnerup
authors: Neurology Department Bethel EVKB Bielefeld and Dept. of Neurology, University of Muenster, Muenster, Germany.
authors: Wolf-Rüdiger
authors: WR
authors: Schäbitz