Removing the brakes on post-stroke plasticity drives recovery from the intact hemisphere and spinal cord

The existence of bilaterally redundant corticospinal pathways suggests a potential means of recovery after unilateral injury such as stroke. However, in the adult brain, plasticity is kept in check by inhibitory factors that provide the stability necessary in neuronal networks to encode memories and retain learned actions. In the current issue of Brain, Nicolas Lindau and colleagues use antibodies that block Nogo-A functioning to unlock plasticity within the adult injured brain, leading to a structural and functional re-routing of corticospinal signals to exploit circuit redundancy (Lindau et al., 2014). After a large motor cortex stroke, there is evidence that the intact hemisphere can control the impaired hand and thus facilitate behavioural recovery (Grefkes and Ward, 2014). However, hemiparesis remains a common deficit after stroke, indicating a need for therapies that augment spontaneous recovery. Lindau et al. (2014) show that, in rats, promoting axonal sprouting by blocking the growth-inhibitor protein Nogo-A facilitates the emergence of motor pathways that allow the intact hemisphere to drive motor output to the impaired forelimb. Although only 10% of corticospinal projections terminated in the ipsilateral spinal cord before injury, anti-Nogo-A therapy induced the generation of additional ipsilateral motor projections and produced substantial recovery of forelimb function. During the development and refinement of the nervous system there is extensive axonal sprouting. To curb ebullient outgrowth in the adult, various inhibitory molecules such as Nogo-A keep the system in check. Over the years, the Schwab group has systematically examined the therapeutic potential of inhibiting Nogo-A in a number of disease models, including stroke. Initial efforts were aimed at enhancing sprouting at the cortical level through the expression of Nogo-A antibodies in peri-infarct tissue (Emerick et al., 2003). To evaluate a more clinically accessible approach to treatment, Lindau et al. (2014) delivered a Nogo-A inhibitor intrathecally to the lumbar spinal cord. This method builds on previous studies providing proof of principle that intrathecal anti-Nogo-A treatment promotes recovery after cortical injury (Tsai et al., 2007). Following unilateral stroke, Lindau et al. (2014) observed a remarkable sprouting of axons and rewiring of limb pathways within the spinal cord to take advantage of the spared hemisphere. Widespread switching of corticospinal projections has been observed after injury in more plastic juveniles, which may have lower levels of sprouting inhibitors than adults. Recent evidence suggests that several molecular mediators of plasticity are temporarily upregulated in the spinal cord after cortical stroke (Sist et al., 2014) and may therefore act in concert with anti-Nogo-A treatment to promote recovery. Although a spinal site of action is likely based on the data presented, Nogo-A antibodies would also have access to the peri-infarct cortex where other inhibitors of outgrowth such as ephrin-A5 have been shown to act (Overman et al., 2012). Lindau et al. (2014) use a multi-pronged approach ranging from detailed kinematic assessment of forelimb movements to tracing of axonal crossings within the spinal cord. Intracortical microstimulation (ICMS) was performed to confirm the contribution of specific cortical sites to motor output and the presence of an enhanced uncrossed functional corticospinal pathway following stroke in anti-Nogo-A treated animals. The anatomical tracing experiments revealed that anti-Nogo-A treatment promoted contralaterally projecting fibres from the uninjured hemisphere to recross at the level of the cervical spinal cord and replace connections lost after stroke. The treatment also produced a 2-fold increase in the number of ipsilaterally projecting fibres from the rostral forelimb area of the uninjured hemisphere. These anatomical changes correlated with significant behavioural recovery and an increase in ICMS evoked motor output from the intact hemisphere to the ipsilateral forelimb in anti-Nogo-A treated animals. To demonstrate that the corticospinal tract from the intact hemisphere was mediating behavioural recovery, the authors severed the tract from the uninjured hemisphere in recovered animals and showed that the deficits re-emerged. This large body of work supports evidence that the intact hemisphere assumes control after a relatively large stroke that leaves little spared sensory-motor cortex (Murphy and Corbett, 2009). Although the ipsilateral hemisphere is involved in forelimb movements in uninjured animals (Ganguly et al., 2009), this means of recovery was not observed in the absence of anti-Nogo-A treatment as there was little spontaneous reorganization. Given the magnitude of the behavioural recovery and apparent axonal sprouting from the intact hemisphere following anti-Nogo-A treatment, it is possible that the normal function of this cortical tissue (controlling the unimpaired paw) is negatively impacted by such reorganization. Although Lindau et al. (2014) did not directly evaluate the function of the ipsilesional limb, the single pellet reaching task used likely requires significant bimanual coordination. The non-reaching limb supports and aligns the body while executing the reach, and the kinematic analysis performed by the authors is sensitive to impairments in body posture. Reaches by treated animals resembled the normal reaching pattern more closely than those of untreated animals, suggesting that the intact hemisphere is able to drive output to both forelimbs without producing a gross motor deficit in the ipsilesional limb. In a series of related experiments, Theresa Jones’ lab found that engaging the intact hemisphere after stroke by reach-training with the ipsilesional limb blocked all recovery in the contralesional forelimb (Jones et al., 2013). One explanation for these seemingly contradictory effects is that the intact hemisphere has limited plasticity after injury, and the allocation of this limited plasticity is a key determinant of functional outcome. Using up plasticity by training the ipsilesional forelimb results in poor recovery of the contralesional forepaw; removing the brakes on plasticity through anti-Nogo-A inhibitors facilitates the recruitment of the intact hemisphere to drive motor output to the contralesional forelimb through ipsilateral projections. One critical test of this hypothesis would be to reversibly silence the intact hemisphere either optogenetically or chemically and determine whether this reinstates the deficit in anti-Nogo-A treated animals. Cortical muscimol infusion was recently used to demonstrate the importance of ipsilateral pathways that emerged after chronic electrical stimulation of the intact hemisphere (Carmel et al., 2014). The impressive efficacy of this treatment in a rat model of stroke opens up the possibility that growth-inhibitor blockade could one day be developed as a treatment for humans with motor cortex stroke. Although the current study provides clear evidence in favour of pursuing this approach, future experiments should assess the impact of stroke risk factors such as age and cerebrovascular health on treatment efficacy. The current study focused on motor pathways, but the treatment may also induce functionally relevant plasticity in fibres mediating sensory processing. Removing key inhibitors of plasticity during a limited time window after stroke offers new hope for unlocking potential plasticity in the adult nervous system, and could provide a powerful intervention when combined with current rehabilitative strategies. Timothy H. Murphy is funded by a CIHR operating grant MOP-111009 and a Grant in Aid from the Heart and Stroke Foundation of Canada. Both Timothy H. Murphy and Gergely Silasi receive funding from the Canadian Partnership for Stroke Recovery.

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