Restorative Neurology and Neuroscience

Purpose: Most pre-clinical stroke studies address the acute phase after injury, with less attention to long-term effects of injury, treatment, and experimental testing itself. We addressed these questions: 1) Will functional deficits persist up to 8 weeks following transient stroke in older animals? 2) Will functional deficits resolve spontaneously, with time and/or repeated behavioral testing?

Methods: Male Sprague-Dawley rats (12 months) were pre-trained on behavioral tasks to provide baseline data and then underwent transient middle artery occlusion (tMCAO) or sham surgery. We measured motor, sensory, cognitive and gait impairments over 8 weeks, and the extent of hemispheric brain infarction. One cohort underwent behavioral testing once at 8 weeks post-stroke (LT); a second cohort (RLT) was tested at 3, 6 and 8 weeks post-stroke.

Results: Significant deficits were exhibited in all functional outcomes in both cohorts after 8 weeks. We observed some recovery in some behavioral parameters in both cohorts at 8 weeks.

Conclusions: Deficits persist for at least 8 weeks after tMCAO. The greater spontaneous recovery seen in the RLT groups suggest that repeated testing did reduce the severity of these stroke-induced impairments. These findings have implications for designing future studies of agents to induce long-term functional recovery following stroke.

Background: Transcranial Electrical Stimulation (tES) methods have been shown to enhance performance across a range of cognitive tasks. It is thought that tES can be used to enhance the treatment-effects of cognitive training (CT), leading to lasting improvements in neurocognitive function. Recently, a small number of studies have investigated the effects of tES combined with CT in healthy and cognitively impaired subjects.

Objective: To evaluate the effects of tES + CT on both CT task performance and on non-trained cognitive outcomes.

Methods: A systematic review was conducted in accordance with PRISMA guidelines. Databases (PsycINFO, EMBASE, PubMed and Medline) were searched for all randomized, controlled and naturalistic prospective studies up until June 2014, combining tES and CT.

Results: 13 studies comprising 465 participants met the inclusion criteria. Findings indicated that tES + CT enhanced performance on the majority of CT tasks. The effects on non-trained tasks were mixed, with some evidence for improvements in working memory, cognitive control, approximate number sense and arithmetic processing.

Conclusions: tES + CT enhances performance on CT tasks across a range of cognitive functions. Preliminary evidence suggests that tES may also increase transfer effects to non-trained tasks in some domains. Recommendations for future studies are provided.

Purpose: Previous studies have shown brain reorganizations after early deprivation of auditory sensory. However, changes of grey matter connectivity have not been investigated in prelingually deaf adolescents yet. In the present study, we aimed to investigate changes of grey matter connectivity within and between auditory, language and visual systems in prelingually deaf adolescents.

Methods: We recruited 16 prelingually deaf adolescents and 16 age-and gender-matched normal controls, and extracted the grey matter volume as the structural characteristic from 14 regions of interest involved in auditory, language or visual processing to investigate the changes of grey matter connectivity within and between auditory, language and visual systems. Sparse inverse covariance estimation (SICE) was utilized to construct grey matter connectivity between these brain regions.

Results: The results show that prelingually deaf adolescents present weaker grey matter connectivity within auditory and visual systems, and connectivity between language and visual systems declined. Notably, significantly increased brain connectivity was found between auditory and visual systems in prelingually deaf adolescents.

Conclusions: Our results indicate “cross-modal” plasticity after deprivation of the auditory input in prelingually deaf adolescents, especially between auditory and visual systems. Besides, auditory deprivation and visual deficits might affect the connectivity pattern within language and visual systems in prelingually deaf adolescents.

Purpose: The aim of the present study was to explore the use of two-photon microscopy for investigating the therapeutic time window of methylprednisolone (MP) treatment after spinal cord injury (SCI).

Methods: Twenty-four YFP H-line mice were subjected to hemisection SCI and then divided into four groups. Group 1 received MP at 30 min post-injury; group 2 received MP at 8 h post-injury; group 3 received MP at 24 h post-injury; and group 4 received saline at 30 min post-injury. Post-injury axonal dieback was imaged in vivo using two-photon microscopy. After all imaging sessions, histological examination of the surviving neurons and microglial/macrophage accumulation was performed.

Results: Two-photon imaging revealed the degree of progressive axon damage after SCI. Group 1 exhibited a shorter axonal dieback distance and slower axonal dieback speed than groups 2, 3, and 4 (p <  0.01). MAP-2 staining revealed greater neuronal survival in group 1 than in groups 2, 3, and 4 (p <  0.05). F4/80 staining revealed greater microglial/macrophage density in groups 2, 3, and 4 than in group 1 (p <  0.05).

Conclusions: MP therapy may help attenuate progressive axon damage, reduce neuronal death, and inhibit microglial/macrophage accumulation, especially when initiated shortly after SCI.

Purpose: Several clinical trials have highlighted general favorable outcomes of intravenous tissue type plasminogen activator (rt-PA) in acute ischemic stroke using different measures including, National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). Findings from most of these measures indicate that the benefits of rt-PA are time dependent, thus, supporting intensive efforts to fast-track hospital thrombolytic treatment in patients with stroke. Despite the widespread benefits of rt-PA, the effectiveness of this therapy on specific functions such as ambulatory performance of the recovering stroke patient is not fully investigated. We aim to investigate this issue in the current study.

Methods: We analyzed data from a retrospective cohort of acute ischemic stroke patients admitted to Greenville Health System (GHS) between 2010-2013. We identified patients who received rt-PA within a 4.5 hour time frame following the onset of acute ischemic stroke symptoms. Our analysis compared ambulatory variables and hospital-level characteristics in proportions of patients receiving rt-PA with those not receiving rt-PA. This analysis determined whether early treatment with rt-PA is associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke.

Results: Among 663 patients with ischemic stroke who were eligible to receive rt-PA, 241 patients received rt-PA and 422 patients did not due to several risk factors. We found a statistically significant difference (P <  0.001) for changes in ambulation status from hospital admission to discharge between patients receiving rt-PA and patients who did not receive rt-PA. Among patients who received rt-PA, 27.8% improved in their ambulation status, 41.9% saw no change in their ambulation status, 0.4% worsened in their ambulation status, and 29.9% were unable to be determined. Of the patients who did not receive rt-PA, 20.1% improved in their ambulation status, 61.8% saw no change in their ambulation status, 1.4% worsened in their ambulation status, and 16.6% were unable to be determined.

Conclusion: Our current study indicates that early treatment with rt-PA may be associated with favorable changes in ambulatory status from admission to discharge following acute ischemic stroke.

Purpose: This study aimed to identify brain areas with white matter changes that contribute to motor recovery of affected limbs during acute to sub-acute phases of subcortical infarction.

Methods: Diffusion tensor imaging was performed 1, 4, and 12 weeks after stroke onset in 18 patients with acute subcortical infarct, and in 18 age- and risk factor-matched controls. Fugl-Meyer scale was used to assess levels of motor impairment, and Statistical Parametric Mapping was applied to determine fractional anisotropy (FA) changes for the entire brain in order to identify areas correlated with motor recovery.

Results: Fugl-Meyer scores of patients at 4 and 12 weeks were significantly higher than those at 1 week (all p <  0.01). Accompanying with the progressive decreases of FA in the corticospinal tract above and below the stroke lesion, progressive increases of FA in the contralesional medial frontal gyrus, and thalamocortical connections including projections to the somatosensory cortices, primary motor cortex, and premotor areas, were positively correlated with Fugl-Meyer scores (all p <  0.005) within 12 weeks following acute subcortical infarction.

Conclusions: Remodeling of white matter in contralesional brain regions related to motor, cognition, and sensory processing may facilitate early motor recovery in patients with an acute infarct.

Purpose: The present study was conducted to determine changes in the expression of voltage-gated sodium channels (VGSCs) α-subunits after nerve injury and their relation with development of neuropathic pain.

Methods: We used the crush injury model of regeneration of the sciatic nerve (Crush) and the spared nerve injury (SNI) model of neuropathic pain in the rat. Measurements of thermal and mechanical pain thresholds were performed until 3 months after injury. Real-time PCR and immunohistochemistry of VGSC α-subunits were used to evaluate the mRNA and protein expression in the DRG.

Results: Both nerve injuries induced similar alterations in the VGSCs expression at 7 dpi, with upregulation of Nav1.3, and downregulation of Nav1.7, Nav1.8 and Nav1.9. These changes persisted until 28 days, when hyperalgesia was still present in SNI but not in Crush rats. At 90 days, mRNA expression of all analyzed α-subunits returned to basal levels in the Crush group. However, SNI rats still showed altered expression of VGSCs, and neuropathic pain responses. Immunohistochemical staining revealed that Nav1.8 and Nav1.9 were widely expressed in IB4-positive neurons of the DRG, relevant in pain processing. The population of neurons coexpressing each α-subunit and IB4 was also affected by the injury, more markedly after the Crush.

Conclusion: Shifts in VGSCs expression occur in parallel to neuropathic pain behavior in rats early after injury, while at later times they appear to be more related to sensory nerve degeneration and regeneration processes.

Purpose: Theory of mind (ToM) deficits are common consequences of severe Traumatic Brain Injury (sTBI), but little is known about their impact on patients’ and their caregivers’ quality of life. This study aimed (i) to examine the presence of ToM difficulties in individuals with sTBI and adequate levels of self-awareness (SA); (ii) to investigate their relationship with perceived Health Related Quality of Life (HRQoL) in patients and their caregivers.

Methods: Twenty individuals with sTBI and adequate levels of SA, and 20 healthy controls (HCs) were recruited. ToM was examined by the Faux-pas Recognition paradigm. The QOLIBRI questionnaire was administered to patients and their caregivers to assess their HRQoL. Cognitive functioning and psychopathology were evaluated.

Results: Individuals with sTBI were less accurate than HCs on the Faux-pas Recognition paradigm. Patients’ satisfaction of HRQoL was related to their performance on the Wisconsin Card Sorting Test. Caregivers’ satisfaction was significantly predicted by patients’ score on the Faux-pas paradigm.

Conclusions: ToM is impaired in individuals with sTBI and adequate levels of SA. Moreover, their ToM performance predicted HRQoL in the caregivers. From a clinical perspective, these results provide understanding of the potential impact of ToM impairment in subjects with sTBI and their social system.

Purpose: We describe a technique for independently differentiating neocortical and mesencephalic dopaminergic (mDA) neurons from a single human pluripotent stem cell (hPSC) line, and subsequently allowing the two cell types to interact and form connections.

Methods: Dopaminergic and neocortical progenitors were differentiated in separate vessels, then separately seeded into the inner and outer compartments of specialized cell culture vessels designed for in vitro studies of wound healing. Cells were further differentiated using dopamine-specific and neocortex-specific trophic factors, respectively. The barrier was then removed, and differentiation was continued for three weeks in the presence of BDNF.

Results: After three weeks of differentiation, neocortical and mDA cell bodies largely remained in the areas into which they had been seeded, and the gap between the mDA and neocortical neuron populations could still be discerned. Abundant tyrosine hydroxylase (TH)-positive projections had extended from the area of the inner chamber to the outer chamber neocortical area.

Conclusions: We have developed a hPSC-based system for producing connections between neurons from two brain regions, neocortex and midbrain. Future experiments could employ modifications of this method to examine connections between any two brain regions or neuronal subtypes that can be produced from hPSCs in vitro.

Purpose: Preliminary evidence has shown no additional effects of transcranial direct current stimulation (tDCS) on robotic gait training in chronic stroke, probably due to the neural organization of locomotion involving cortical and spinal control. Our aim was to compare the combined effects of tDCS and transcutaneous spinal direct current stimulation (tsDCS) on robotic gait training in chronic stroke.

Methods: Thirty chronic stroke patients received ten 20-minute robot-assisted gait training sessions, five days a week, for 2 consecutive weeks combined with anodal tDCS + sham tsDCS (group 1; n = 10) or sham tDCS + cathodal tsDCS (group 2; n = 10) or tDCS + cathodal tsDCS (group 3; n = 10). The primary outcome was the 6-minute walk test (6MWT) performed before, after, 2 weeks and 4 weeks post-treatment.

Results: Significant differences in the 6MWT distance were noted between group 3 and group 1 at the post-treatment and 2-week follow-up evaluations (post-treatment P = 0.015; 2-week follow-up P = 0.001) and between group 3 and group 2 (post-treatment P = 0.010; 2-week follow-up P = 0.015). No difference was found between group 2 and group 1.

Conclusions: Our preliminary findings support the hypothesis that anodal tDCS combined with cathodal tsDCS may be useful to improve the effects of robotic gait training in chronic stroke.

Purpose: Limb remote ischemic per-conditioning or post-conditioning has been shown to be neuroprotective after cerebral ischemic stroke. However, the effect of combining remote per-conditioning with post-conditioning on ischemic/reperfusion injury as well as the underlying mechanisms are largely unexplored.

Methods: Here, adult male Sprague Dawley rats were subjected to middle cerebral artery occlusion (MCAO). The limb ischemic stimulus was immediately applied after onset of focal ischemia (per-conditioning), followed by repeated short episodes of remote ischemia 24 hr after reperfusion (post-conditioning). The infarct volume, motor function, and the expression of neuroglobin (Ngb) were measured at different durations after reperfusion.

Results: We found that a single episode of limb remote per-conditioning afforded short-term protection, but combining repeated remote post-conditioning during the 14 days after reperfusion significantly ameliorated cerebral ischemia/reperfusion injury. Interestingly, we also found that ischemic per- and post-conditioning significantly increased expression of Ngb, an oxygen-binding globin protein that has been demonstrated to be neuroprotective against stroke, at peri-infarct regions from day 1 to day 14 following ischemia/reperfusion.

Conclusion: Our results suggest that the conventional per-conditioning combined with post-conditioning may be used as a novel neuroprotective strategy against ischemia-reperfusion injury, and Ngb seems to be one of the important players in limb remote ischemia-mediated neuroprotection.

Purpose: Several recent studies have demonstrated that following short-term monocular deprivation in normal adults, the patched eye, rather than the unpatched eye, becomes stronger in subsequent binocular viewing. However, little is known about the site and nature of the underlying processes. In this study, we examine the underlying mechanisms by measuring steady-state visual evoked potentials (SSVEPs) as an index of the neural contrast response in early visual areas.

Methods: The experiment consisted of three consecutive stages: a pre-patching EEG recording (14 minutes), a monocular patching stage (2.5 hours) and a post-patching EEG recording (14 minutes; started immediately after the removal of the patch). During the patching stage, a diffuser (transmits light but not pattern) was placed in front of one randomly selected eye. During the EEG recording stage, contrast response functions for each eye were measured.

Results: The neural responses from the patched eye increased after the removal of the patch, whilst the responses from the unpatched eye remained the same. Such phenomena occurred under both monocular and dichoptic viewing conditions.

Conclusions: We interpret this eye dominance plasticity in adult human visual cortex as homeostatic intrinsic plasticity regulated by an increase of contrast-gain in the patched eye.

Purpose: Motor and cognitive impairments are common and often coexist in patients with stroke. Although evidence is emerging about specific relationships between cognitive deficits and upper-limb motor recovery, the practical implication of these relationships for rehabilitation is unclear. Using a structured review and meta-analyses, we examined the nature and strength of the associations between cognitive deficits and upper-limb motor recovery in studies of patients with stroke.

Methods: Motor recovery was defined using measures of upper limb motor impairment and/or activity limitations. Studies were included if they reported on at least one measure of cognitive function and one measure of upper limb motor impairment or function.

Results: Six studies met the selection criteria. There was a moderate association (r = 0.43; confidence interval; CI:0.09– 0.68, p = 0.014) between cognition and overall arm motor recovery. Separate meta-analyses showed a moderately strong association between executive function and motor recovery (r = 0.48; CI:0.26– 0.65; p <  0.001), a weak positive correlation between attention and motor recovery (r = 0.25; CI:0.04– 0.45; p = 0.023), and no correlation between memory and motor recovery (r = 0.42; CI:0.16– 0.79; p = 0.14).

Conclusion: These results imply that information on the presence of cognitive deficits should be considered while planning interventions for clients in order to design more personalized interventions tailored to the individual for maximizing upper-limb recovery.