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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    054—Ischemia: Recovery

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    54.07: Choosing the right rehabilitation paradigm: Enhancement and manipulation of forelimb motor function after stroke by combined application of Anti-Nogo immunotherapy and training

    Location: Halls B-H

    ">*A.-S. E. WAHL1, W. OMLOR1, S. MUSALL1, J. CHEN1, H. ZHENG2, A. SCHR÷TER3, M. GULLO1, H. KASPER1, B. OMMER2, F. HELMCHEN1, M. E. SCHWAB1;
    1Brain Res. Institute, Univ. and ETH Zurich, Zuerich, Switzerland; 2Computer Vision Group, Univ. of Heidelberg, Heidelberg Interdisciplinary Ctr. for Scientific Computing, Heidelberg, Germany; 3ETH, Inst. for Biomed. Imaging, Zurich, Switzerland

    Abstract Body: The adult nervous system reveals tremendous capacities by which neural networks can reorganize and reassemble in modified configuration to sustain behavioural recovery and compensation after stroke. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the external therapeutic interventions in accordance with defined plastic windows. Here we show that the timing, intensity and kind of the rehabilitation paradigm matters in terms of functional outcome: Four rehabilitative schedules were compared after a large unilateral stroke placed in the motor cortex of the hemisphere corresponding to the preferred side of adult rats. Anti-Nogo A or Ig G control antibodies were then infused intrathecally immediately after the stroke for 2 weeks and rats were trained in skilled forelimb tasks simultaneously to antibody administration or sequentially - 2 weeks after the immunotherapy. While rats receiving first the anti-Nogo A treatment followed by training afterwards showed excellent (up to >80%) functional restoration of skilled reaching, the opposite effect was detected in the group with simultaneous training and anti-Nogo A antibody treatment (recovery rate<15%). Grasping function of the early trained control group outreached the one of the delayed trained group. Anatomically, anti-Nogo-A antibodies induced large numbers of corticospinal tract (CST) fibres from the intact side to grow across the midline of the cervical spinal cord. The huge discrepancy in functional outcome depending on the early vs. late rehabilitation paradigms was reflected by distinct patterns of CST fibres in the denervated hemi-spinal cord as identified by machine learning algorithms for pattern recognition. Manipulation of these sprouted fibres using optogenetics indicates functional relevance of these newly formed corticospinal circuits when tested in both, the anesthetized and the awake, grasping animal.

    Lay Language Summary: Our research indicates that timing, dose and kind of rehabilitation matters for recovery of motor function after a large stroke: If applied in the right way, rehabilitative training in combination with nerve growth-promoting agents greatly enhances the recovery of lost functions. However, ‘wrong’ timing can have disastrous consequences, destroying the beneficial effects of the growth promoting or the rehabilitation therapy. These observations in animal models have obvious relevance for the optimal design of clinical rehabilitation.
    A stroke hits unexpectedly, leaving its victims behind with strong physical impairment affecting quality of life. The fulfilment of banal every day’s activities become an issue due to motor deficits, problems with speech and vision. For many years people have thought that the hardware of the brain is that ‘hard’, that once an incident such as stroke happens, brain areas and functions are lost forever. The adult brain seemed to be a stable and static structure, consisting of billions of nerve cells and circuits. Now, functional imaging data in stroke patients, microscopy in rodents and even genomic profiling reveals that the brain and spinal cord have great potential for re-organization and restoration of the functions lost due to the stroke. Clinically, the most successful therapy to further enhance this restoration of function is rehabilitative training. Nevertheless, the neurobiology of rehabilitation and the mechanisms on-going in the brain and spinal cord responsible for the increased recovery are still poorly understood.
    The current study examines the combination of rehabilitative training of skilled forelimb grasping in rats with the application of an antibody against the Nogo-A protein. Nogo-A is one of the most potent growth inhibitory proteins in the brain and spinal cord. This growth inhibitory function of Nogo-A can be suppressed by an antibody. The anti-Nogo-A antibody, which is already in clinical trials for spinal cord injury and MS, was shown to also magnify outgrowth of nerve fibres after stroke. We now combined this antibody treatment with intense rehabilitative therapy. Rats were either trained simultaneously to the anti-Nogo A application or afterwards. Surprisingly, these two different rehabilitation schedules resulted in completely diverse outcomes: While rats which first received the antibody followed by rehabilitative training showed an excellent restoration of forelimb function (>85% of forelimb function before stroke), the performance of rats in the group of simultaneous training and anti-Nogo remained poor (<15% of baseline function).
    Anatomical studies where we visualized the fibers coming from the motor forebrain cortex to the spinal cord revealed large numbers of fibers growing from the intact side across the midline in the cervical spinal cord in the animals treated with the anti-Nogo antibody. In the well recovered group of rats, these fibers formed a near normal branching and termination pattern. In contrast, the rats with early rehab and poor functional recovery showed overshooting fiber growth, aberrant branching and too high numbers of synapses, in part in wrong areas of the spinal cord.
    Our study shows the importance of carefully designing rehabilitation schedules after stroke, in particular if different therapeutic options such as training and growth enhancing agents are combined: A rehabilitative approach that supports the intrinsic potential of the brain and spinal cord to reinforce lost functions by boosting the growth of new fibres and by stabilizing the meaningful newly formed circuits may result in robustly enhanced recovery of motor function. In contrast, rehabilitative schedules may lose their beneficial character if applied at the wrong time and intensity. During an early phase after the injury, the brain seems to be in a particularly vulnerable state, and forced rehab therapies should therefore be applied with great caution during this period of circuit plasticity.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    054—Ischemia: Recovery

    Saturday, November 09, 2013, 1:00 pm - 5:00 pm

    54.07: Choosing the right rehabilitation paradigm: Enhancement and manipulation of forelimb motor function after stroke by combined application of Anti-Nogo immunotherapy and training

    Location: Halls B-H

    ">*A.-S. E. WAHL1, W. OMLOR1, S. MUSALL1, J. CHEN1, H. ZHENG2, A. SCHR÷TER3, M. GULLO1, H. KASPER1, B. OMMER2, F. HELMCHEN1, M. E. SCHWAB1;
    1Brain Res. Institute, Univ. and ETH Zurich, Zuerich, Switzerland; 2Computer Vision Group, Univ. of Heidelberg, Heidelberg Interdisciplinary Ctr. for Scientific Computing, Heidelberg, Germany; 3ETH, Inst. for Biomed. Imaging, Zurich, Switzerland

    Abstract Body: The adult nervous system reveals tremendous capacities by which neural networks can reorganize and reassemble in modified configuration to sustain behavioural recovery and compensation after stroke. Finding optimal rehabilitation paradigms requires an optimal orchestration of the internal processes of re-organization and the external therapeutic interventions in accordance with defined plastic windows. Here we show that the timing, intensity and kind of the rehabilitation paradigm matters in terms of functional outcome: Four rehabilitative schedules were compared after a large unilateral stroke placed in the motor cortex of the hemisphere corresponding to the preferred side of adult rats. Anti-Nogo A or Ig G control antibodies were then infused intrathecally immediately after the stroke for 2 weeks and rats were trained in skilled forelimb tasks simultaneously to antibody administration or sequentially - 2 weeks after the immunotherapy. While rats receiving first the anti-Nogo A treatment followed by training afterwards showed excellent (up to >80%) functional restoration of skilled reaching, the opposite effect was detected in the group with simultaneous training and anti-Nogo A antibody treatment (recovery rate<15%). Grasping function of the early trained control group outreached the one of the delayed trained group. Anatomically, anti-Nogo-A antibodies induced large numbers of corticospinal tract (CST) fibres from the intact side to grow across the midline of the cervical spinal cord. The huge discrepancy in functional outcome depending on the early vs. late rehabilitation paradigms was reflected by distinct patterns of CST fibres in the denervated hemi-spinal cord as identified by machine learning algorithms for pattern recognition. Manipulation of these sprouted fibres using optogenetics indicates functional relevance of these newly formed corticospinal circuits when tested in both, the anesthetized and the awake, grasping animal.

    Lay Language Summary: Our research indicates that timing, dose and kind of rehabilitation matters for recovery of motor function after a large stroke: If applied in the right way, rehabilitative training in combination with nerve growth-promoting agents greatly enhances the recovery of lost functions. However, ‘wrong’ timing can have disastrous consequences, destroying the beneficial effects of the growth promoting or the rehabilitation therapy. These observations in animal models have obvious relevance for the optimal design of clinical rehabilitation.
    A stroke hits unexpectedly, leaving its victims behind with strong physical impairment affecting quality of life. The fulfilment of banal every day’s activities become an issue due to motor deficits, problems with speech and vision. For many years people have thought that the hardware of the brain is that ‘hard’, that once an incident such as stroke happens, brain areas and functions are lost forever. The adult brain seemed to be a stable and static structure, consisting of billions of nerve cells and circuits. Now, functional imaging data in stroke patients, microscopy in rodents and even genomic profiling reveals that the brain and spinal cord have great potential for re-organization and restoration of the functions lost due to the stroke. Clinically, the most successful therapy to further enhance this restoration of function is rehabilitative training. Nevertheless, the neurobiology of rehabilitation and the mechanisms on-going in the brain and spinal cord responsible for the increased recovery are still poorly understood.
    The current study examines the combination of rehabilitative training of skilled forelimb grasping in rats with the application of an antibody against the Nogo-A protein. Nogo-A is one of the most potent growth inhibitory proteins in the brain and spinal cord. This growth inhibitory function of Nogo-A can be suppressed by an antibody. The anti-Nogo-A antibody, which is already in clinical trials for spinal cord injury and MS, was shown to also magnify outgrowth of nerve fibres after stroke. We now combined this antibody treatment with intense rehabilitative therapy. Rats were either trained simultaneously to the anti-Nogo A application or afterwards. Surprisingly, these two different rehabilitation schedules resulted in completely diverse outcomes: While rats which first received the antibody followed by rehabilitative training showed an excellent restoration of forelimb function (>85% of forelimb function before stroke), the performance of rats in the group of simultaneous training and anti-Nogo remained poor (<15% of baseline function).
    Anatomical studies where we visualized the fibers coming from the motor forebrain cortex to the spinal cord revealed large numbers of fibers growing from the intact side across the midline in the cervical spinal cord in the animals treated with the anti-Nogo antibody. In the well recovered group of rats, these fibers formed a near normal branching and termination pattern. In contrast, the rats with early rehab and poor functional recovery showed overshooting fiber growth, aberrant branching and too high numbers of synapses, in part in wrong areas of the spinal cord.
    Our study shows the importance of carefully designing rehabilitation schedules after stroke, in particular if different therapeutic options such as training and growth enhancing agents are combined: A rehabilitative approach that supports the intrinsic potential of the brain and spinal cord to reinforce lost functions by boosting the growth of new fibres and by stabilizing the meaningful newly formed circuits may result in robustly enhanced recovery of motor function. In contrast, rehabilitative schedules may lose their beneficial character if applied at the wrong time and intensity. During an early phase after the injury, the brain seems to be in a particularly vulnerable state, and forced rehab therapies should therefore be applied with great caution during this period of circuit plasticity.