Yeah, this is from Steven C. Cramer so you know it's going to be good, but come on, survivors want 100% recovery, not this tyranny of low expectations of 'improve' you're pushing on us. Will you be satisfied with not getting to 100% recovery when you're the 1 in 4 per WHO that has a stroke?
Interventions to improve stroke recovery
Steven C. Cramer
KEY POINTS
• Neural repair is a therapeutic strategy that is separate from acute stroke strategies such as reperfusion and neuroprotection, and has distinct biological targets, time windows for therapeutic efficacy, and issues to address in clinical trial design.• Many classes of therapy are under study to improve stroke recovery including small molecules, growth factors, monoclonal antibodies, stem cells, robotic devices, brain stimulation, activity-based therapies, telerehabilitation, and cognitive-based strategies.• Some repair-based therapies are introduced within days of stroke onset, in an attempt to amplify innate repair mechanisms, while other therapies are offered to patients from months to years after stroke onset, where the goal is to stimulate new forms of neural repair.• Restorative therapies improve behavioral outcomes on the basis of experience-dependent brain plasticity – a drug may galvanize the brain for repair, but behavioral reinforcement is also needed to achieve maximal gains. This is an important difference as compared to neuroprotective, reperfusion, and preventative stroke therapies, where the patient generally does not need to engage in any particular behavioral regimen to derive treatment benefit.• Several positive late-phase clinical trials of restorative therapies have been published, e.g., for activity-based therapies and for small molecules such as serotonergic drugs.
BIOLOGY OF STROKE RECOVERY SUGGESTS THERAPEUTICS TARGETS
A new stroke sets numerous biological pathways into motion. These include the ischemic cascade acutely, immunological events that evolve from pro-inflammatory systemic immuno-suppression,
1
and later a sequence of restorative events that support tissue repair and that also represent potential targets to improve stroke recovery. Animal studies indicate that an experimental stroke results in an ordered change in expression of numerous genes. Numer-ous growth-related events are seen, such as growth factor release, increased levels of growth inhibitors such as Nogo and MAG, capillary growth, axonal sprouting, synaptogenesis, glial cell activation, and changes in cortical excitability. These changes are seen both near and distant from injury, and gener-ally peak during the initial weeks post-stroke.
2–6
Studies of stroke recovery mechanisms in humans, informed by non-invasive neuroimaging and neurophysiolog-ical methods, are overall concordant with preclinical findings.
7
In parallel with behavioral improvement, cortical maps undergo reorganization.
8–10
compensatory changes in brain function and brain networks
11–13
arise, often bilaterally,
14–17
and are associated with changes in brain structure.
18,19
Un injured areas that are normally connected to the infarct region as part of a distributed network may show depressed function, a process known as diaschisis,
20,21
resolution of which may be linked with behavioral improvement. These restorative events represent potential therapeutic targets to promote brain repair.
22
Many classes of restorative therapy are under study, using many different strategies.
6,23–27
These are listed in Box 59-1, which emphasizes interventions that have reached the point of human trials. Some repair-based therapies are introduced within days, or perhaps weeks, of stroke onset in an attempt to amplify innate repair mechanisms. For some restorative therapies, a critical period exists, whereby introduction within a specific time window provides a therapeutic benefit that is lost when treatment is delayed.
28–30
This is one of the many parallels between stroke recovery and normal brain develop-ment.
7,31
Other repair-based therapies are less limited by a time window and that may be offered to patients in the chronic phase, from months to years after stroke onset. Advan-tages of this approach include availability of a large enroll-ment pool and a stable baseline that is helpful to interpret treatment effects.
KEY POINTS
• Neural repair is a therapeutic strategy that is separate from acute stroke strategies such as reperfusion and neuroprotection, and has distinct biological targets, time windows for therapeutic efficacy, and issues to address in clinical trial design.• Many classes of therapy are under study to improve stroke recovery including small molecules, growth factors, monoclonal antibodies, stem cells, robotic devices, brain stimulation, activity-based therapies, telerehabilitation, and cognitive-based strategies.• Some repair-based therapies are introduced within days of stroke onset, in an attempt to amplify innate repair mechanisms, while other therapies are offered to patients from months to years after stroke onset, where the goal is to stimulate new forms of neural repair.• Restorative therapies improve behavioral outcomes on the basis of experience-dependent brain plasticity – a drug may galvanize the brain for repair, but behavioral reinforcement is also needed to achieve maximal gains. This is an important difference as compared to neuroprotective, reperfusion, and preventative stroke therapies, where the patient generally does not need to engage in any particular behavioral regimen to derive treatment benefit.• Several positive late-phase clinical trials of restorative therapies have been published, e.g., for activity-based therapies and for small molecules such as serotonergic drugs.
BIOLOGY OF STROKE RECOVERY SUGGESTS THERAPEUTICS TARGETS
A new stroke sets numerous biological pathways into motion. These include the ischemic cascade acutely, immunological events that evolve from pro-inflammatory systemic immuno-suppression,
1
and later a sequence of restorative events that support tissue repair and that also represent potential targets to improve stroke recovery. Animal studies indicate that an experimental stroke results in an ordered change in expression of numerous genes. Numer-ous growth-related events are seen, such as growth factor release, increased levels of growth inhibitors such as Nogo and MAG, capillary growth, axonal sprouting, synaptogenesis, glial cell activation, and changes in cortical excitability. These changes are seen both near and distant from injury, and gener-ally peak during the initial weeks post-stroke.
2–6
Studies of stroke recovery mechanisms in humans, informed by non-invasive neuroimaging and neurophysiolog-ical methods, are overall concordant with preclinical findings.
7
In parallel with behavioral improvement, cortical maps undergo reorganization.
8–10
compensatory changes in brain function and brain networks
11–13
arise, often bilaterally,
14–17
and are associated with changes in brain structure.
18,19
Un injured areas that are normally connected to the infarct region as part of a distributed network may show depressed function, a process known as diaschisis,
20,21
resolution of which may be linked with behavioral improvement. These restorative events represent potential therapeutic targets to promote brain repair.
NEURAL REPAIR IS DISTINCT FROM NEUROPROTECTION
A clear distinction must be made between therapeutic targets related to neuroprotection and those related to repair. These are parallel treatment strategies that have temporally distinct targets – a neuroprotective therapy is initiated from minutes to hours after stroke onset to salvage threatened tissue, while a repair therapy is typically introduced days after stroke onset or later. Brain repair aims to improve function by restoring normal patterns of brain structure and function, e.g., regaining voluntary control of arm reaching; this is distinguished from compensation, which aims to improve function by substitut-ing new patterns, e.g, teaching a patient to reach by swinging his torso to propel a paretic arm.22
Many classes of restorative therapy are under study, using many different strategies.
6,23–27
These are listed in Box 59-1, which emphasizes interventions that have reached the point of human trials. Some repair-based therapies are introduced within days, or perhaps weeks, of stroke onset in an attempt to amplify innate repair mechanisms. For some restorative therapies, a critical period exists, whereby introduction within a specific time window provides a therapeutic benefit that is lost when treatment is delayed.
28–30
This is one of the many parallels between stroke recovery and normal brain develop-ment.
7,31
Other repair-based therapies are less limited by a time window and that may be offered to patients in the chronic phase, from months to years after stroke onset. Advan-tages of this approach include availability of a large enroll-ment pool and a stable baseline that is helpful to interpret treatment effects.
14 pages in total.
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