Restorative Neurology and Neuroscience

Purpose: Recovery of the most basic shoulder-flexion/elbow-extension components of functional reach is critical for effective arm function following stroke. In order to understand the mechanisms of motor recovery, it is important to characterize the pattern of brain activation during the reach task. Methods: We evaluated 11 controls and 23 moderately to severely impaired chronic stroke survivors (>6 months), with impaired shoulder flexion and elbow extension. Measures were acquired for Arm Motor Ability Test (AMAT) and functional Magnetic Resonance Imaging (fMRI) during the basic shoulder/elbow reach. Results: First, in controls, lateralization of fMRI signal during the reach task was less pronounced in comparison to other tasks, and even further diminished after stroke (p < 0.05). Second, for the stroke group, centroid locations, for specific ipsilesional (contralateral to working limb) motor-sensory regions and for contralesional (ipsilateral to working arm) somatosensory and SMA regions, were significantly more distant from the centroid location of average healthy controls (p < 0.05). Third, both greater activation volume and greater degree of signal intensity were correlated with better motor function in stroke survivors. Conclusions: These findings can be useful in guiding the development of more targeted brain training methods for recovery of impaired reach coordination.

Purpose: Cognitive impairment is one of the most disabling symptoms of multiple sclerosis (MS), affecting a large proportion of patients and having a severe impact on their quality of life. Nevertheless, there exists a large variability in the neuropsychological profiles of MS patients and some of them appear to withstand better than others the MS-related brain pathology before showing cognitive decline. In recent years, many studies have made use of concepts such as cognitive reserve and brain reserve to take account of the inter-individual discrepancy between cognitive impairment and MS pathology. Critically, these studies have left open the fundamental issue of the clinical implications of this research for the treatment of cognitive dysfunction in MS. Methods and Results: We provide an updated and extensive overview of the studies that have explored cognitive and brain reserve in MS and discuss their implications for non-pharmacological therapeutic strategies aimed at potentiating patients' reserve. In particular, the possible utility of integrated approaches based on mind-body techniques such as mindfulness-meditation is considered. Conclusions: We conclude that these techniques represent challenging mental enriching activities that may help cultivating cognitive reserve and more systematic research on their efficacy to protect against cognitive degradation in MS is encouraged.

Purpose: The mechanism underlying forced limb-use -induced structural plasticity remains to be studied. We examined whether the cyclic adenosine monophosphate (cAMP)–mediated signal transduction pathway was involved in brain plasticity and promoted behavioral recovery induced by forced limb-use after stroke. Methods: Adult rats were divided into a sham group, an ischemia group, an ischemia group with forced limb-use, and an ischemia group with forced limb-use and infusion of N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H89). Forced limb-use began on post-stroke day 7. Biotinylated dextran amine (BDA) was injected into the sensorimotor cortex on post-stroke day 14. Behavioral recovery was evaluated on post-stroke days 29 to 32, and the levels of cAMP, PKA C-α, phosphorylated CREB (pCREB), synaptophysin, PSD-95, BDA, and BrdU/NeuN were measured. Results: The number of midline-crossing axons and the expression levels of synaptophysin and PSD-95 were increased after forced limb-use. Forced limb-use enhanced the survival of the newborn neurons and increased the levels of cAMP, PKA C-α and pCREB. These were significantly suppressed by H89. Behavioral performance improved with forced limb-use and was reversed with H89. Conclusions: Enhanced structural plasticity and the behavioral recovery promoted by post-stroke forced limb-use are suggested to be mediated through the cAMP/PKA/CREB signal transduction pathway.

Purpose: The illusory ownership of a fake hand as part the body follows synchronous tactile stimulation over a visible rubber hand and a covered hand. Whether brain plasticity mechanisms after sensory and motor disconnection modulates this illusion remain unexplored. Methods: We tested a tetraplegic man after synchronous and asynchronous stimulation of the hand and face. Results: The illusory ownership of the fake hand was tested four times in separate days and always reported. To verify whether this ownership feeling generalized also to object not resembling the human body we tested this illusion with a plastic bottle and a rubber hand. The illusionary perception of owning an external object using the rubber hand paradigm showed that the temporally matched tactile stimulation on a fake hand and visual capture mechanism create the illusionary feeling that the rubber hand was part of his body. Conclusions: Despite lesions that dramatically disconnect the access to sensory inputs and motor outputs our data suggests a strong visual capture of a rubber hand and a possible remapping of hand-face representations after the spinal lesion. We suggest that vision and brain plasticity may represent a supportive tool for motor rehabilitation in patients with sensory deficits.

Purpose: Fifty percent of patients with Multiple Sclerosis (MS) are estimated to have cognitive impairments leading to considerable decline in productivity and quality of life. Cognitive intervention has been considered to complement pharmacological treatments. However, a lack of agreement concerning the efficacy of cognitive interventions in MS still exists. A systematic review and meta-analysis was conducted to assess the effects of cognitive interventions in MS. Methods: To overcome limitations of previous meta-analyses, several databases were searched only for Randomized Clinical Trials (RCTs) with low risk of bias. Results: Five studies (total of 139 participants) met our eligibility criteria. Although good completion and adherence rates were evident, we found no evidence of intervention effects on cognition or mood in post-intervention or follow-up assessments. Conclusions: This is the first meta-analysis assessing the effects of cognitive intervention in MS including only RCTs with comparable conditions. Research regarding efficacy, cost-effectiveness and feasibility is still in its infancy. Caution is advised when interpreting these results due to the small number of RCTs meeting the inclusion criteria. Considering the costs of disease, good completion and adherence rates of this approach, further research is warranted. Recommendations concerning improved research practices in the field are presented as well.

Purpose: In this study we investigated in observers with low myopia: (i) the pattern of lateral interactions between stimuli activating early cortical analyzers and its modulation by perceptual learning (PL), and (ii) whether PL transferred to untrained stimuli and tasks and whether it exhibits interocular transfer. Method: Participants (seven adults with low myopia) performed 12 training sessions. Participants were trained on a contrast detection task of a central Gabor target flanked by two co-oriented and co-aligned high contrast Gabor patches. Target-to-flankers separation along the vertical axis was varied from 2 wavelengths (λ) to 8λ. Results: The results showed that before PL facilitatory lateral interactions in the myopic eye were reduced in strength, but PL increased contrast sensitivity and improved facilitatory lateral interactions. However, PL did not transfer to different local/global orientations and lower spatial frequencies. On the other hand, PL resulted in an enhancement of the contrast sensitivity function (CSF) and of the uncorrected visual acuity (UCVA) both in the trained and untrained eye. Conclusions: Such improvements seem to be associated to a modulation of lateral interactions between target and flankers and it is likely to take place at a level in which the inputs from the two eyes converge.

Purpose: There is no consensus as to the optimum treatment for traumatic optic neuropathy (TON). The decision to intervene medically or surgically, or simply observe was recommended to be on an individual basis. The purpose of this study is to test whether optic nerve sheath fenestration (ONSF) could improve vision in patients with traumatic optic nerve sheath meningocele, although it was reported to be effective in patients with traumatic optic nerve sheath hematoma. Methods: ONSF was performed on two traumatic patients with dilated optic nerve sheath from MRI. Results: Both patients initially suspected as traumatic optic nerve sheath hematoma were diagnosed as traumatic optic nerve sheath meningocele by intraoperative findings of the enlarged optic nerve sheath and clear fluid drained without evidence of blood in the subdural space. Moreover, significant orbit/head pain resolution and visual improvement within a week after ONSF was found. Conclusions: When TON presents with an enlarged optic nerve/sheath on CT or MRI with visual loss, an optic nerve sheath meningocele should be considered with the consideration that ONSF may benefit both visual acuity and post-traumatic pain, if present.

Purpose: Peripheral vestibular dysfunction following vestibular neuritis (VN) often persists but functional recovery of balance can be variable. The authors compared structural changes in the brain before and after post-VN compensation and related it to the functional recovery. Methods: Nine patients diagnosed with unilateral VN were included. Brain MRI and clinical observation were performed within 2 days of acute VN diagnosis and were repeated 3 months after the first exam. Voxel-based morphometry (VBM) analysis for longitudinal data was performed using VBM8 toolbox running within SPM8. Changes in local grey matter volume (GMV) were examined using a paired t-test and clinical relevance was tested using correlation analyses with functional improvement. Results: Significant increases in GMV were observed in the vestibular cortex, bilateral hippocampus, visual cortices and the cerebellum. GMV decreased in cerebellar regions, including the vermis, and in the prefrontal cortex. Increases in GMV in visual cortices and cerebellum were associated with the poorest recovery of balance, which might be explained by functional substitution. Conclusions: The structural layout of vestibular compensation suggests that memory and motor planning are closely related to this process. Vision seems to be a major source of functional substitution, as has been previously demonstrated. This study, however, is the first longitudinal analysis of brain structural changes associated with recovery of balance following unilateral VN.

Purpose: Despite advances towards potential clinically viable therapies there has been only limited success in improving functional recovery following traumatic brain injury (TBI). In rats, exposure to an enriched environment (EE) improves learning and fosters motor skill development. Induced pluripotent stem cells (iPSC) have been shown to survive transplantation and influence the recovery process. The current study evaluated EE and iPSC as a polytherapy for remediating cognitive deficits following medial frontal cortex (mFC) controlled cortical impact (CCI) injury. Methods: Sixty adult male rats received a midline mFC CCI or sham injury and were randomly placed in either EE or standard environment (SE). Seven days post-injury rats received bilateral transplantation of iPSCs or media. Behavioral measures were conducted throughout the remainder of the study. Following behavioral analysis, brains were extracted and prepared for histological analysis. Results: Open-field data revealed that combined therapy resulted in typical Sham/EE activity rearing patterns by the conclusion of the study. On the Vermicelli Handling task, rats with EE/iPSC polytherapy performed better than media-treated rats. Furthermore, rats treated with polytherapy performed equivalently to Sham/EE rats on the Morris water maze. Proficiency on the Rotarod was consistently better in EE when compared to SE counterparts. Confocal microscopy confirmed that iPSCs survived and migrated away from the transplantation site. Conclusions: Overall, EE or iPSC therapy improved cognition and motor performance, however, full cognitive restoration was seen only with the EE/iPSC treatment. These data suggest that EE/iPSC therapy should be explored as a potential, clinically relevant, treatment for TBI.

Purpose: The present study clarified the effects of repetitive transcranial magnetic stimulation (rTMS) in rats with vascular dementia (VaD) and explored the underlying mechanisms. Methods: Two-vessel occlusion was used as a VaD model. Two weeks after carotid artery occlusion, high (5 Hz) or low (1 Hz) frequency rTMS were applied for 10 days. Spatial learning and memory abilities were tested with a Morris water maze. Hippocampal CA1 neurons were histologically examined. The expressions of mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E (eIF-4E) in CA1 were detected by western blot, and immunohistochemistry. Results: Unlike unlesioned control animals, VaD rats had an impaired morphology of CA1 neurons and a reduced ability of spatial memory. rTMS significantly improved both, the morphology and the learning and memory abilities of VaD rats compared to untreated lesioned rats. Protein expressions of mTOR and eIF-4E in CA1 of VaD rats were lower than in control rats but rTMS significantly increased the expression compared to untreated VaD rats. Conclusions: rTMS promotes recovery of learning and memory abilities of VaD rats. Molecular analysis suggests that the beneficial effect of rTMS may be partly induced by upregulation of protein expressions of mTOR and eIF-4E in CA1.

Purpose: Anxiety-like (ANX) and depression-like (DEP) symptoms are common consequences of traumatic brain injury (TBI). Environmental enrichment (EE) attenuates many deficits, though its impact on ANX and DEP symptoms has yet to be described. Methods: Adult male Long-Evans rats were subject to a medial frontal cortex (mFC) cortical impact injury or sham preparation, then placed into EE or standard housing (SE). ANX symptoms were analyzed using the open field test (OFT) and elevated plus maze (EPM). The forced swim task (FST) and sucrose consumption task (SCT) were used to quantify DEP symptoms. In order to measure changes in spatial learning and motor performance, the Barnes maze (BM) and rotor rod (RR) were utilized. Results: Damage to the mFC resulted in functional losses in motor and cognitive behavior and an increase in ANX and DEP symptoms. Placement of injured rats into the EE improves motor functioning after TBI and resulted in an decreased latency to locate the escape box in the BM. Though the application of an EE attenuated deficits in BM and RR performance, the ANX and DEP behavioral symptoms persisted. Conclusions: Additional therapeutic approaches paired with EE may be necessary to address all functional changes post-TBI. Additionally, no single behavioral assessment appears to clearly identify symptoms of ANX or DEP in rats following TBI, however utilizing multiple tests can be potentially confounding.

Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in mice. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day post-injury), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.