Restorative Neurology and Neuroscience - Volume 36, issue 4

Authors: Su, Diya | Li, Dezhi | Wang, Shiwei | Qiao, Hui | Li, Ping | Wang, Binbin | Wan, Hong | Schumacher, Michael | Liu, Song

Article Type: Research Article

Abstract: Background: Closed temporal bone fractures due to cranial trauma often result in facial nerve injury, frequently inducing incomplete facial paralysis. Conventional hypoglossal-facial nerve end-to-end neurorrhaphy may not be suitable for these injuries because sacrifice of the lesioned facial nerve for neurorrhaphy destroys the remnant axons and/or potential spontaneous innervation. Objective: we modified the classical method by hypoglossal-facial nerve “side-to-side” neurorrhaphy using an interpositional predegenerated nerve graft to treat these injuries. Methods: Five patients who experienced facial paralysis resulting from closed temporal bone fractures due to cranial trauma were treated with the “side-to-side” neurorrhaphy. An additional 4 …patients did not receive the neurorrhaphy and served as controls. Results: Before treatment, all patients had suffered House-Brackmann (H-B) grade V or VI facial paralysis for a mean of 5 months. During the 12–30 months of follow-up period, no further detectable deficits were observed, but an improvement in facial nerve function was evidenced over time in the 5 neurorrhaphy-treated patients. At the end of follow-up, the improved facial function reached H-B grade II in 3, grade III in 1 and grade IV in 1 of the 5 patients, consistent with the electrophysiological examinations. In the control group, two patients showed slightly spontaneous innervation with facial function improved from H-B grade VI to V, and the other patients remained unchanged at H-B grade V or VI. Conclusions: We concluded that the hypoglossal-facial nerve “side-to-side” neurorrhaphy can preserve the injured facial nerve and is suitable for treating significant incomplete facial paralysis resulting from closed temporal bone fractures, providing an evident beneficial effect. Moreover, this treatment may be performed earlier after the onset of facial paralysis in order to reduce the unfavorable changes to the injured facial nerve and atrophy of its target muscles due to long-term denervation and allow axonal regrowth in a rich supportive environment. Show more

Keywords: Facial nerve injury, House-Brackmann grade, nerve regeneration, innervation

DOI: 10.3233/RNN-170794

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 443-457, 2018

Authors: Portaro, Simona | Naro, Antonino | Bramanti, Alessia | Leo, Antonino | Manuli, Alfredo | Balletta, Tina | Trinchera, Antonia | Bramanti, Placido | Calabrò, Rocco Salvatore

Article Type: Research Article

Abstract: Background: The central nervous system involvement, in terms of a maladaptive sensory-motor plasticity, is well known in patients with dystrophic myotonias (DMs). To date, there are no data suggesting a central nervous system involvement in non-dystrophic myotonias (NDMs). Objective: To investigate sensory-motor plasticity in patients with Myotonia Congenita (MC) and Paramyotonia Congenita (PMC) with or without mexiletine. Methods: Twelve patients with a clinical, genetic, and electromyographic evidence of MC, fifteen with PMC, and 25 healthy controls (HC) were included in the study. TMS on both primary motor cortices (M1) and a rapid paired associative stimulation (rPAS) …paradigm were carried out to assess M1 excitability and sensory-motor plasticity. Results: patients showed a higher cortical excitability and a deterioration of the topographic specificity of rPAS aftereffects, as compared to HCs. There was no correlation among neurophysiological and clinical-demographic characteristics. Noteworthy, the patients who were under mexiletine showed a minor impairment of the topographic specificity of rPAS aftereffects as compared to those who did not take the drug. Conclusion: our findings could suggest the deterioration of cortical sensory-motor plasticity in patients with NDMs as a trait of the disease. Show more

Keywords: Non-dystrophic myotonias (NDMs), central nervous system, rTMS, cortical excitability, sensory-motor plasticity, mexiletine

DOI: 10.3233/RNN-170796

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 459-467, 2018

Authors: Li, Rong | Sahu, Sudhanshu | Schachner, Melitta

Article Type: Research Article

Abstract: Background: Neural cell adhesion molecule L1 contributes to nervous system development and maintenance by promoting neuronal survival, neuritogenesis, axonal regrowth/sprouting, myelination, and synapse formation and plasticity. L1 also enhances recovery after spinal cord injury and ameliorates neurodegenerative processes in experimental rodent models. Aiming for clinical translation of L1 into therapy we screened for and functionally characterized in vitro the small organic molecule phenelzine, which mimics characteristic L1 functions. Objective: The present study was designed to evaluate the potential of this compound in vivo in a mouse model of spinal cord injury. Methods and Results: …In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice. Phenelzine application upregulated L1 expression in the spinal cord and stimulated the cognate L1-mediated intracellular signaling cascades in the spinal cord tissue. Phenelzine-treated mice showed decreased levels of pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the injured spinal cord during the acute phase of inflammation. Conclusions: This study provides new insights into the role of phenelzine in L1-mediated neural functions and modulation of inflammation. The combined results raise hopes that phenelzine may develop into a therapeutic agent for nervous system injuries. Show more

Keywords: L1, phenelzine, mouse, spinal cord injury, inflammation, regeneration

DOI: 10.3233/RNN-170808

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 469-483, 2018

Authors: Ndode-Ekane, Xavier Ekolle | Matthiesen, Liz | Bañuelos-Cabrera, Ivette | Palminha, Cátia Alexandra Pêgas | Pitkänen, Asla

Article Type: Research Article

Abstract: Background: T-lymphocyte (T-cell) invasion into the brain parenchyma is a major consequence of traumatic brain injury (TBI). However, the role of T-cells in the post-TBI functional outcome and secondary inflammatory processes is unknown. We explored the dynamics of T-cell infiltration into the cortex after TBI to establish whether the infiltration relates to post-injury functional impairment/recovery and progression of the secondary injury. Method: TBI was induced in rats by lateral fluid-percussion injury, and the acute functional impairment was assessed using the neuroscore. Animals were killed between 1–90 d post-TBI for immunohistochemical analysis of T-cell infiltration (CD3), chronic macrophage/microglial reaction …(CD68), blood-brain barrier (BBB) dysfunction (IgG), and endophenotype of the cortical injury. Furthermore, the occurrence of spontaneous seizures and spike-and-wave discharges were assessed using video-electroencephalography. Results: The number of T-cells peaked at 2-d post-TBI, and then dramatically decreased by 7-d post-TBI (5% of 2-d value). Unexpectedly, chronic T-cell infiltration at 1 or 3 months post-TBI did not correlate with the severity of chronic inflammation (p  > 0.05) or BBB dysfunction (p  > 0.05). Multiple regression analysis indicated that inflammation and BBB dysfunction is associated with 48% of the perilesional T-cell infiltration even at the chronic time-point (r  = 0.695, F = 6.54, p  < 0.05). The magnitude of T-cell infiltration did not predict the pathologic endophenotype of cortical injury, but the higher the number of T-cells in the cortex, the poorer the recovery index based on the neuroscore (r  = – 0.538, p  < 0.05). T-cell infiltration was not associated with the number or duration of age-related spike-and-wave discharges (SWD). Nevertheless, the higher the number of SWD, the poorer the recovery index (r  = – 0.767, p  < 0.5). Conclusions: These findings suggest that acute infiltration of T-cells into the brain parenchyma after TBI is a contributing factor to poor post-injury recovery. Show more

Keywords: Fluid-percussion brain injury, functional impairment, inflammation, T-lymphocytes, traumatic brain injury

DOI: 10.3233/RNN-170811

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 485-501, 2018

Authors: Szaflarski, Jerzy P. | Griffis, Joseph | Vannest, Jennifer | Allendorfer, Jane B. | Nenert, Rodolphe | Amara, Amy W. | Sung, Victor | Walker, Harrison C. | Martin, Amber N. | Mark, Victor W. | Zhou, Xiaohua

Article Type: Research Article

Abstract: Purpose: The purpose of this feasibility study was to assess whether combined intermittent theta burst suppression (iTBS) applied to the ipsilesional hemisphere and modified constraint-induced aphasia therapy (mCIAT) are safe and logistically feasible within the time interval associated with iTBS induced long-term potentiation in patients with post-stroke aphasia. We also wanted to determine whether combining priming with iTBS and CIAT improves language functions after treatment. Methods: Twelve participants received fMRI (semantic decision/tone decision task) and neuropsychological testing of language skills at three time points – before starting the iTBS/mCIAT intervention (T1), immediately after completing 2-week long course of …intervention (T2), and at 3-months follow-up (T3). ITBS was applied to the individually determined fMRI language “hot spot” located in the left fronto-temporal regions. Results: There were no serious adverse events, and all mCIAT group therapy sessions (3–4 subjects each) were initiated within 30 minutes of the first group subject receiving iTBS. Neuropsychological assessments of language showed a significant effect of session on Western Aphasia Battery aphasia quotient (WAB-AQ; p  = 0.04) and spontaneously correct responses on Boston Naming Test (BNT; p  = 0.002), with improvement noted at T2 (p  = 0.002) and T3 (p  = 0.05) versus T1. FMRI showed significant changes between all timepoints. Post-hoc correlations showed associations between improvements in WAB-AQ from T2 to T3 and decreased BOLD signal in left inferior parietal lobe, and improvements in BNT from T1 to T3 with decreased signal in right inferior frontal gyrus. Conclusion: This study shows feasibility and safety for combining behavioral and neurostimulation interventions for chronic post-stroke aphasia. Observed changes in linguistic measures were relatively small. However, they were statistically significant and associated with parallel changes observed in the neuroimaging. Our findings support further development and testing of the combined mCIAT and iTBS protocol and comparisons to either CIAT/mCIAT or iTBS applied alone for the treatment of post-stroke aphasia. Show more

Keywords: Aphasia, fMRI, iTBS, rTMS, rehabilitation, CIAT, WAB-AQ

DOI: 10.3233/RNN-180812

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 503-518, 2018

Authors: Zhao, Chuansheng | Könönen, Mervi | Vanninen, Ritva | Pitkänen, Kauko | Hiekkala, Sinikka | Jolkkonen, Jukka

Article Type: Research Article

Abstract: Recent advances in basic research have revealed the complex structural plasticity associated with the spontaneous motor recovery after stroke. Various rehabilitative interventions seem to act through the same repair mechanisms to further enhance recovery processes. In this review, we first summarize the current understanding on brain plasticity and repair after stroke. We then outline experimental approaches for studying stroke rehabilitation in rodents and review current rehabilitative practices in stroke patients. Although experimental approaches are valuable in providing details regarding mechanisms and proof-of-concept data, relatively modest treatment effects in stroke patients highlight the translational gap. Further studies will be needed to …find optimal treatment paradigms through emerging knowledge of brain repair, whilst appreciating the important differences between rodent and patient studies that complicate the translation of experimental data. Show more

Keywords: Stroke, brain plasticity, recovery, rehabilitation, translational research

DOI: 10.3233/RNN-180814

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 519-533, 2018

Authors: Levy-Tzedek, Shelly | Arbelle, Dan | Forman, Dan | Zlotnik, Yair

Article Type: Research Article

Abstract: Background: The symptoms of patients with Parkinson’s disease (PD) have been shown to improve when they perform fast-paced rhythmic cycling movements with their lower limbs. Objective: Our goal in this pilot experiment was to test the feasibility and the benefits of a short exercise program involving fast-paced rhythmic movements of the upper limb for patients with PD. Methods: We used an experimental procedure that elicits large, fast-paced movements by the participants without the direct instructions to do so by the experimenter. Ten participants with PD (71.0±6.5 years old) performed a 50-min fast-paced rhythmic exercise of the …upper limb after withdrawal from PD medication for at least 12 hours. Results: Participants improved their kinematic performance, in terms of accuracy and combined speed and amplitude (p  < 0.02), as well as their upper-limb MDS-UPDRS motor scores (p  = 0.023). Conclusions: The results demonstrate the feasibility of using the described apparatus to perform an exercise session of approximately 50 min with both arms, and give a preliminary indication of the potential benefit of such an exercise program. Show more

Keywords: Parkinson’s disease, motor control, behavioral approach, exercise, UPDRS III

DOI: 10.3233/RNN-180818

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 535-545, 2018

Authors: Berenpas, Frank | Schiemanck, Sven | Beelen, Anita | Nollet, Frans | Weerdesteyn, Vivian | Geurts, Alexander

Article Type: Research Article

Abstract: Background: Contralesional ‘drop foot’ after stroke is usually treated with an ankle-foot orthosis (AFO). However, AFOs may hamper ankle motion during stance. Peroneal functional electrical stimulation (FES) is an alternative treatment that provides active dorsiflexion and allows normal ankle motion. Despite this theoretical advantage of FES, the kinematic and kinetic differences between AFO and FES have been scarcely investigated. Objective: To test whether walking with implanted FES leads to improvements in stance stability, propulsion, and swing initiation compared to AFO. Methods: A 4-channel peroneal nerve stimulator (ActiGait ® ) was implanted in 22 chronic patients after stroke. …Instrumented gait analyses were performed during comfortable walking up to 26 weeks (n  = 10) or 52 weeks (n  = 12) after FES-system activation. Kinematics of knee and ankle (stance and swing phase) and kinetics (stance phase) of gait were determined, besides spatiotemporal parameters. Finally, we determined whether differences between devices regarding late stance kine(ma)tics correlated with those regarding the swing phase. Results: In mid-stance, knee stability improved as the peak knee extension velocity was lower with FES (β = 18.1°/s, p  = 0.007), while peak ankle plantarflexion velocity (β = –29.2°/s, p  = 0.006) and peak ankle plantarflexion power (β = –0.2 W/kg, p  = 0.018) were higher with FES compared to AFO. With FES, the ground reaction force (GRF) vector at peak ankle power (i.e., ‘propulsion’) was oriented more anteriorly (β = –1.1°, p  = 0.001). Similarly, the horizontal GRF (β = –0.8% body mass, p  = 0.003) and gait speed (β = 0.03 m/s, p  = 0.015) were higher. An increase in peak ankle plantarflexion velocity and a more forward oriented GRF angle during late stance were moderately associated with an increase in hip flexion velocity during initial swing (rs  = 0.502, p  = 0.029 and rs  = 0.504, p  = 0.028, respectively). Conclusions: This study substantiates the evidence that implantable peroneal FES as a treatment for post-stroke drop foot may be superior over AFO in terms of knee stability, ankle plantarflexion power, and propulsion. Show more

Keywords: Functional electrical stimulation, peroneal nerve, ankle-foot orthosis, stroke, gait, rehabilitation

DOI: 10.3233/RNN-180822

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 547-558, 2018

Authors: Sama, Diana M. | Carlson, Shaun W. | Joseph, Binoy | Saenger, Stefanie | Metzger, Friedrich | Saatman, Kathryn E.

Article Type: Research Article

Abstract: Background: Traumatic brain injury can result in lasting cognitive dysfunction due to degeneration of mature hippocampal neurons as well as the loss of immature neurons within the dentate gyrus. While endogenous neurogenesis affords a partial recovery of the immature neuron population, hippocampal neurogenesis may be enhanced through therapeutic intervention. Insulin-like growth factor-1 (IGF-1) has the potential to improve cognitive function and promote neurogenesis after TBI, but its short half-life in the systemic circulation makes it difficult to maintain a therapeutic concentration. IGF-1 modified with a polyethylene glycol moiety (PEG-IGF-1) exhibits improved stability and half-life while retaining its ability to enter …the brain from the periphery, increasing its viability as a translational approach. Objective: The goal of this study was to evaluate the ability of systemic PEG-IGF-1 administration to attenuate acute neuronal loss and stimulate the recovery of hippocampal immature neurons in brain-injured mice. Methods: In a series of studies utilizing a well-established contusion brain injury model, PEG-IGF-1 was administered subcutaneously after injury. Serum levels of PEG were verified using ELISA and histological staining was used to investigate numbers of degenerating neurons and cortical contusion size at 24 h after injury. Immunofluorescent staining was used to evaluate numbers of immature neurons at 10 d after injury. Results: Although subcutaneous injections of PEG-IGF-1 increased serum IGF-1 levels in a dose-dependent manner, no effects were observed on cortical contusion size, neurodegeneration within the dentate gyrus, or recovery of hippocampal immature neuron numbers. Conclusions: In contrast to its efficacy in rodent models of neurodegenerative diseases, PEG- IGF-1 was not effective in ameliorating early neuronal loss after contusion brain trauma. Show more

Keywords: Contusion, doublecortin, hippocampus, insulin-like growth factor-1, neurogenesis, neuroprotection, PEGylation

DOI: 10.3233/RNN-180831

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 559-569, 2018

Authors: Kalantarian, Giti | Ziamajidi, Nasrin | Mahjub, Reza | Goodarzi, Mohammad Taghi | Saidijam, Massoud | Soleimani Asl, Sara | Abbasalipourkabir, Roghayeh

Article Type: Research Article

Abstract: Background: Subcutaneous injection of insulin can lead to problems such as hypoglycemia and edema. Objective: The purpose of this research was to evaluate the effect of oral insulin-coated trimethyl chitosan nanoparticles on control of glycemic status, IGF-1 and IGF-2 levels, and apoptosis in the hippocampus of rats with diabetes mellitus. Methods: Insulin-coated trimethyl chitosan nanoparticles were prepared by the polyelectrolyte complex method (PEC) method. Insulin loading content, loading efficiency, quantity and quality of particle size were evaluated. In vivo study was performed in different treatment groups of male Wistar rats with diabetes mellitus by insulin-coated …trimethyl chitosan nanoparticles or subcutaneous injection of trade insulin. The duration of diabetes was eight weeks and the treatment was started after that time and continued for another two weeks. Body weight, fasting blood glucose (FBS), hippocampal apoptosis, and immunohistochemical (IHC) protein levels of IGF-1 and IGF-2 were assessed at the end of the experiments. Results: The size and polydispersity indexes were 533 nanometers and 0.533, respectively. Insulin coated trimethyl chitosan nanoparticles showed high loading efficiency (97.67% ) and loading content (48.83% ). The spherical shape of nanoparticle was confirmed by transmission electron microscopic (TEM). The amine, amide, ether and aliphatic groups were evaluated using FT-IR spectrophotometer which represented the correctness of the insulin coated trimethyl chitosan nanoparticles. Although the apoptotic index was not changed either by insulin-coated nano-particles or commercial insulin, in vivo results showed the efficacy of insulin-coated nanoparticles as well as commercial insulin in compensated weight loss, FBS and protein levels of IGF-1 and IGF-2. Conclusions: The present study showed the efficacy of insulin coated nanoparticle in oral route manner that can be tested in Phase I– III clinical trials. However, a behavioral study could reveal the efficacy of insulin-loaded nanoparticles in the improvement of cognitive changes through the modulation of IGF-1 and IGF-2 levels in the hippocampus. Show more

Keywords: Diabetes mellitus, IGF-1, IGF-2, insulin, nanoparticles

DOI: 10.3233/RNN-170807

Citation: Restorative Neurology and Neuroscience, vol. 36, no. 4, pp. 571-581, 2018