There are currently multiple strategies being developed to increase the recovery of patients following a stroke. Approaches used in the hours following the lesion generally try to limit the extent of damage and prevent further cell death. For example, intervention targeting the vascular system, such as tissue plasminogen activator (t-PA) administration, applied in the first few hours following the lesion can decrease lesion size and disability (Lansberg et al., 2009a
). Similarly, approaches to decrease hyperthermia (Colbourne et al., 2000
; Corbett et al., 2000
) or the inflammatory response (Patel et al., 1993
; Yrjanheikki et al., 1998
) initiated within the first few hours following the lesion have shown to increase the neural survival and to decrease the motor deficits in rodent models of stroke.
In the subsequent days, patients go through the acute and subacute phases of recovery. Most of the behavioral improvements occur in this period that is considered to last about 3 months (Duncan, 1998
). Rehabilitation, traditionally based on neurofacilitation or functional retraining, usually takes place within these 3 months and aims at increasing adaptive plasticity in the tissue that survived the lesion (Nudo and Dancause, 2007
; Shumway-Cook and Woollacoot, 2001
). The demonstration in animals and humans that cortical maps are malleable as a function of experience in both normal and brain-injured individuals has contributed to the rapid development of new rehabilitative approaches based on experience-dependent plasticity mechanisms.
More recently, the use of CIMT was shown to increase motor function in stroke patients in the chronic phase of recovery (Taub et al., 1999
). CIMT was developed on the basis of pioneering animal studies by Taub and colleagues (Taub, 1980
; Taub and Morris, 2001
). Due to the extensive amount of research that was conducted to test the efficacy of CIMT, it has arguably become the most mature approach among rehabilitative treatments. CIMT consists of (a) constraint of the less-affected upper extremity, typically with a sling or glove and (b) either shaping or task practice with the impaired upper limb. Shaping includes immediate feedback concerning movements, individualized tasks, prompting and cueing, and progressive increase in the difficulty of the tasks. Task practice consists of repetitive practice of a single individualized task in specified blocks without feedback prompting or cueing. While it is generally thought that the sensory-motor experience with the impaired limb is most important, the differential contributions of constraint and the type of practice (shaping or task practice) are confounded (Uswatte et al., 2006
). Interestingly, in the nonhuman primate studies that examined map plasticity in the peri-infarct motor cortex and demonstrated a positive effect of rehabilitative training, the behavioral paradigm was a combination of shaping and task practice principles, since the monkeys repeated a single task (pellet retrieval from small wells) in blocks of trials, but the task was made progressively harder by decreasing well diameter (Nudo et al., 1996b
A series of experiments to evaluate the presence of cortical representation changes, paralleling the behavioral changes resulting from CIMT therapy, has also been performed in humans (Liepert et al., 1998
; Taub et al., 2003
, Wittenberg et al., 2003
). These studies reported increased cortical representations of the affected arm following treatment, an upper limb representational map size that was similar in both affected and less-affected hemispheres at a 6 months follow-up and shifts of the center of the output map, suggesting recruitment of adjacent brain areas.
Recently, efficacy of CIMT for stroke recovery was tested in a multisite randomized controlled trial in 222 stroke survivors, called EXCITE (extremity constraint-induced therapy evaluation; Wolf et al., 2006
). This trial demonstrated improvements in upper extremity functional endpoints compared with control groups up to 2 years after treatment. This is despite the fact that individuals were enrolled in the chronic period after stroke. Several details regarding the optimum protocol still remain. The two most critical factors: duration and intensity of treatment (dosage), and the time of onset for the treatment after stroke are still unresolved. A recent trial in 52 stroke survivors suggested that early treatment (enrollment within 9 days after stroke) with CIMT and at higher doses resulted in less improvement (Dromerick et al., 2009
). Whether this clinical trial result is due to early excitotoxic effects of intense use remains to be established (Kozlowski et al., 1996
In the past few years, several other novel approaches have been explored to increase the adaptive plasticity in the subacute stage of recovery, where much of the neural reorganization supporting the recovery is expected to occur. Often, these approaches are used as adjuncts to conventional rehabilitation. For example, the use of pharmacological manipulation to increase arousal and learning during training (Barbay and Nudo, 2009
; Feeney et al., 1982
; Gladstone and Black, 2000
; Papadopoulos et al., 2009
), and the use of pharmacological agents to increase sprouting and anatomical plasticity (Fang et al., 2010
; Tsai et al., 2007
) are currently being investigated by several groups.
Restoration of function in the peri-infarct area can be aided by pharmacologic treatment. It has long been known that amphetamine paired with training can enhance recovery after lesions (Feeney et al., 1982
). In addition, the pairing of amphetamine with training enhances expression of GAP-43 and synaptophysin in both the intact and damaged hemispheres, presumably indicative of synaptogenesis and axonal sprouting (Stroemer et al., 1998
). A significant new finding by Carmichael and colleagues (Clarkson et al., 2010
) sheds more light on the early events after focal stroke and suggests potential new targets for therapy. These investigators found excessive tonic inhibition in the peri-infarct zone after a stroke-like injury in the cortex of mice. The inhibition is mediated by extrasynaptic GABAa receptors. The novel approach in this study was to administer a benzodiazepine inverse agonist specific for a subset of the GABAa receptors at various times after stroke. This treatment resulted in sustained, improved motor function. Further, genetically altering the same subset of GABAa receptors also improved poststroke recovery. Thus, it may be possible to substantially improve the effect of poststroke rehabilitative interventions by pharmacologically manipulating tonic inhibition in very specific subsets of receptor types.
Another strategy under intensive investigation is the use of cortical stimulation to increase or decrease the activity of targeted brain areas. Recently, the use of both invasive and noninvasive stimulation techniques to favor recovery from stroke has been the focus of extensive research. The use of stimulation has the potential advantages of manipulating the function of specific targeted areas to favor recovery with few, if any, side effects. The following sections will focus on the development of this approach in stroke and review both the literature from animal models as well as the current state of our efforts in humans.