recovery of motor function
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Human behavior requires interregional crosstalk to employ the sensorimotor processes in the brain. Although some external neuromodulation tools have been used to manipulate interhemispheric sensorimotor activity, a central controversy concerns whether this activity can be volitionally controlled. Experimental tools lack the power to up- or down-regulate the state of the targeted hemisphere over a large dynamic range and, therefore, cannot evaluate the possible volitional control of the activity. We overcame this difficulty by using the recently developed method of spatially bivariate electroencephalography (EEG)-neurofeedback to systematically enable participants to manipulate their bilateral sensorimotor activities. Herein, we report that bi-directional changes in ipsilateral excitability to the imagined hand (conditioning hemisphere) affect interhemispheric inhibition (IHI) assessed by paired-pulse transcranial magnetic stimulation paradigm. In addition, participants were able to robustly manipulate the IHI magnitudes. Further physiological analyses revealed that the self-manipulation of IHI magnitude reflected interhemispheric connectivity in EEG and TMS, which was accompanied by intrinsic bilateral cortical oscillatory activities. Our results provide clear neuroscientific evidence regarding the inhibitory interhemispheric sensorimotor activity and IHI manipulator, thereby challenging the current theoretical concept of recovery of motor function for neurorehabilitation.

Abstract Background Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. Methods Male Sprague–Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. Results PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. Conclusion Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.

AbstractVagus nerve stimulation (VNS) paired with rehabilitation training is emerging as a potential treatment for improving recovery of motor function following stroke. In rats, VNS paired with skilled forelimb training results in significant reorganization of the somatotopic cortical motor map; however, the mechanisms underlying this form of VNS-dependent plasticity remain unclear. Recent studies have shown that VNS-driven cortical plasticity is dependent on noradrenergic innervation of the neocortex. In the central nervous system, noradrenergic α2 receptors (α2-ARs) are widely expressed in the motor cortex and have been critically implicated in synaptic communication and plasticity. In current study, we examined whether activation of cortical α2-ARs is necessary for VNS-driven motor cortical reorganization to occur. Consistent with previous studies, we found that VNS paired with motor training enlarges the map representation of task-relevant musculature in the motor cortex. Infusion of α2-AR antagonists into M1 blocked VNS-driven motor map reorganization from occurring. Our results suggest that local α2-AR activation is required for VNS-induced cortical reorganization to occur, providing insight into the mechanisms that may underlie the neuroplastic effects of VNS therapy.

Abstract BackgroundIn situ microglia and astrocytes begin to activate and participate in neuroinflammation after spinal cord injury (SCI), and the high expression of lipocalin 2 (Lcn2) and the activation of the Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway promote the polarization of activated microglia and astrocytes towards the neurotoxic phenotype (M1 microglia and A1 astrocytes). We previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but the mechanism of PBM on the microglia and astrocytes involved is still unclear. Therefore, the purpose of this study was to explore the role of the Lcn2 and JAK2-STAT3 pathways in the activation of M1 and A1 and the mechanism by which PBM may play a therapeutic role.MethodsPBM intervention was performed every day after the SCI model was established, and the activation of microglia and astrocytes was observed at different time points post injury (1, 3, 7, 14, 28 dpi). The level of tissue apoptosis, the number of surviving neurons, the recovery of motor function, the level of Lcn2 and the activation of JAK2-STAT3 were evaluated in the PBM group and the vehicle group. M1 and A1 cells were irradiated with PBM in vitro, and the JAK2-STAT3 pathway inhibitor cucurbitacin I, adenovirus transfection and recombinant Lcn2 protein were cotreated with PBM to explore the mechanism of the activation of M1 and A1 and the underlying effect of PBM.ResultsPBM inhibited the activation of neurotoxic microglia and astrocytes, decreased secondary inflammation and tissue apoptosis, increased the number of neurons retained, and promoted the recovery of motor function after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also proved that PBM can inhibit the activation of M1 microglia and A1 astrocytes, and the effect is related to the level of Lcn2 and the activation of the JAK2-STAT3 pathway.ConclusionThe crosstalk of Lcn2/JAK2-STAT3 is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be alleviated by PBM.

Background Motor recovery after stroke in humans and in rodent models is time sensitive. Recovery in patients is a result of biological spontaneous recovery via endogenous repair mechanisms and is likely improved by enhancing the synaptic plasticity required for endogenous repair. Cerebrolysin is a polypeptide preparation known to enhance neuroplasticity and may improve recovery in patients. In mice, we tested the hypothesis that Cerebrolysin can act poststroke to enhance both spontaneous and training-associated motor recovery. Methods Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task in the presence or absence of Cerebrolysin after a 2-day or 8-day delay. Mice received daily intraperitoneal Cerebrolysin or saline injections starting poststroke day 1 or poststroke day 7. Results Prior studies showed that poststroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice receive daily Cerebrolysin administration starting on poststroke day 1 or on poststroke day 8. When Cerebrolysin is given on poststroke day 1, recovery occurred even in the absence of training. Stroke volumes were similar across groups. Conclusions Poststroke Cerebrolysin administration leads to recovery of motor function independent of rehabilitative training without a protective effect on stroke volume. This is one of the first demonstrations of training-independent motor recovery in rodent stroke models.