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Since the discovery in the 1960s that remyelination can occur in the damaged central nervous system (CNS) (Bunge et al. 1961), there has been much progress in understanding the cellular and molecular biology of oligodendroglia and the factors that regulate their propagation, migration, differentiation, maturation, and ability to myelinate nerve axons. More recently, greater understanding of disease states and the role of oligodendrocytes in remyelination have sparked tremendous interest in this once obscure field. Although the explosion of information is being hampered by adherence to commonly held beliefs based on empirical evidence, novel molecular and cellular tools are allowing scientists to address age-old assumptions. It is now recognized that, as well as promoting salutatory conduction along axons, oligodendroglia are important near-term clinical targets for restoring function after CNS injury, particularly spinal cord injury. Thus, remyelination appears to be one of the most feasible restoration strategies. This review focuses on concepts that are important for developing strategies of repair. The brightest young scientists will be attracted into this exciting field by its near-term potential for human application.

Resting-state functional MRI (rs-fMRI) permits study of the brain’s functional networks without requiring participants to perform tasks. Robust changes in such resting state networks (RSNs) have been observed in neurologic disorders, and rs-fMRI outcome measures are candidate biomarkers for monitoring clinical trials, including trials of extended therapeutic interventions for rehabilitation of patients with chronic conditions. In this study, we aim to present a unique longitudinal dataset reporting on a healthy adult subject scanned weekly over 3.5 years and identify rs-fMRI outcome measures appropriate for clinical trials. Accordingly, we assessed the reproducibility, and characterized the temporal structure of, rs-fMRI outcome measures derived using independent component analysis (ICA). Data was compared to a 21-person dataset acquired on the same scanner in order to confirm that the values of the single-subject RSN measures were within the expected range as assessed from the multi-participant dataset. Fourteen RSNs were identified, and the inter-session reproducibility of outcome measures—network spatial map, temporal signal fluctuation magnitude, and between-network connectivity (BNC)–was high, with executive RSNs showing the highest reproducibility. Analysis of the weekly outcome measures also showed that many rs-fMRI outcome measures had a significant linear trend, annual periodicity, and persistence. Such temporal structure was most prominent in spatial map similarity, and least prominent in BNC. High reproducibility supports the candidacy of rs-fMRI outcome measures as biomarkers, but the presence of significant temporal structure needs to be taken into account when such outcome measures are considered as biomarkers for rehabilitation-style therapeutic interventions in chronic conditions.

Axon demyelination contributes to the loss of sensory and motor function following injury or disease in the central nervous system. Numerous reports have demonstrated that myelination can be achieved in neuron/oligodendrocyte co-cultures. However, the ability to selectively treat neuron or oligodendrocyte (OL) cell bodies in co-cultures improves the value of these systems when designing mechanism-based therapeutics. We have developed a microfluidic-based compartmentalized culture system to achieve segregation of neuron and OL cell bodies while simultaneously allowing the formation of myelin sheaths. Our microfluidic platform allows for a high replicate number, minimal leakage, and high flexibility. Using a custom built lid, fit with platinum electrodes for electrical stimulation (10-Hz pulses at a constant 3 V with ~190 kΩ impedance), we employed the microfluidic platform to achieve activity-dependent myelin segment formation. Electrical stimulation of dorsal root ganglia resulted in a fivefold increase in the number of myelinated segments/mm² when compared to unstimulated controls (19.6 ± 3.0 vs. 3.6 ± 2.3 MBP+ segments/mm²). This work describes the modification of a microfluidic, multi-chamber system so that electrical stimulation can be used to achieve increased levels of myelination while maintaining control of the cell culture microenvironment.

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)-and magnetization transfer (MT)-derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column-specific parallel (λ || ) and perpendicular (λ ⊥ ) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT-weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time-points separated by more than 1 week. Cross-sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ || : 2.13 ±0.14 and 2.14 ±0.11 μm 2 /ms; λ ⊥ : 0.67 ±0.16 and 0.61 ±0.09 μm 2 /ms; MD: 1.15 ±0.15 and 1.12 ±0.08 μm 2 / ms; FA: 0.68 ±0.06 and 0.68 ±0.05; MTCSF: 0.52 ±0.05 and 0.50 ±0.05. We examined the variability and interrater and test-retest reliability for each metric. These column-specific MR measurements are expected to enhance understanding of the intimate structure-function relationship in the cervical spinal cord and may be useful for the assessment of disease progression.

Neurological recovery in patients with severe spinal cord injury (SCI) is extremely rare. We have identified a patient with chronic cervical traumatic SCI, who suffered a complete loss of motor and sensory function below the injury for 6 weeks after the injury, but experienced a progressive neurological recovery that continued for 17 years. The extent of the patient's recovery from the severe trauma-induced paralysis is rare and remarkable. A detailed study of this patient using diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and resting state fMRI (rs-fMRI) revealed structural and functional changes in the central nervous system that may be associated with the neurological recovery. Sixty-two percent cervical cord white matter atrophy was observed. DTI-derived quantities, more sensitive to axons, demonstrated focal changes, while MTI-derived quantity, more sensitive to myelin, showed a diffuse change. No significant cortical structural changes were observed, while rs-fMRI revealed increased brain functional connectivity between sensorimotor and visual networks. The study provides comprehensive description of the structural and functional changes in the patient using advanced MR imaging technique. This multimodal MR imaging study also shows the potential of rs-fMRI to measure the extent of cortical plasticity.

BackgroundWe sought to investigate the effects of co-grafting neural stem cells (NSCs) with olfactory ensheathing cells (OECs) on neurological behavior in rats subjected to traumatic brain injury (TBI) and explore underlying molecular mechanisms.MethodsTBI was established by percussion device made through a weight drop (50 g) from a 30 cm height. Cultured NSCs and OECs isolated from rats were labeled by Hoechst 33342 (blue) and chloromethyl-benzamidodialkyl carbocyanine (CM-Dil) (red), respectively. Then, NSCs and/or OECs, separately or combined, were transplanted into the area surrounding the injury site. Fourteen days after transplantation, neurological severity score (NSS) were recorded. The brain tissue was harvested and processed for immunocytochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reverse transcription-polymerase chain reaction (RT-PCR).ResultsSignificant neurological function improvement was observed in the three transplant groups, compared to the TBI group, and co-transplantation gave rise to the best improvement. Morphological evaluation showed that the number of neurons in cortex from combination implantation was more than for other groups (P <0.05); conversely, the number of apoptotic cells showed a significant decrease by TUNEL staining. Transplanted NSCs and OECs could survive and migrate in the brain, and the number of neurons differentiating from NSCs in the co-transplantation group was significantly greater than in the NSCs group. At the molecular level, the expressions of IL-6 and BAD in the co-graft group were found to be down regulated significantly, when compared to either the NSC or OEC alone groups.ConclusionThe present study demonstrates for the first time the optimal effects of co-grafting NSCs and OECs as a new strategy for the treatment of TBI via an anti-inflammation mechanism.

Introduction: Spinal cord injury (SCI) causes partial or complete damage to sensory and motor pathways and induces immediate changes in cortical function. Current rehabilitative strategies do not address this early alteration, therefore impacting the degree of neuroplasticity and subsequent recovery. The following study aims to test if a non-invasive brain stimulation technique such as repetitive transcranial magnetic stimulation (rTMS) is effective in promoting plasticity and rehabilitation, and can be used as an early intervention strategy in a rat model of SCI. Methods: A contusion SCI was induced at segment T9 in adult rats. An rTMS coil was positioned over the brain to deliver high frequency stimulation. Behavior, motor and sensory functions were tested in three groups: SCI rats that received high-frequency (20 Hz) rTMS within 10 min post-injury (acute-TMS; n = 7); SCI rats that received TMS starting 2 weeks post-injury (chronic-TMS; n = 5), and SCI rats that received sham TMS (no-TMS, n = 5). Locomotion was evaluated by the Basso, Beattie, and Bresnahan (BBB) and gridwalk tests. Motor evoked potentials (MEP) were recorded from the forepaw across all groups to measure integrity of motor pathways. Functional MRI (fMRI) responses to contralateral tactile hindlimb stimulation were measured in an 11.7T horizontal bore small-animal scanner. Results: The acute-TMS group demonstrated the fastest improvements in locomotor performance in both the BBB and gridwalk tests compared to chronic and no-TMS groups. MEP responses from forepaw showed significantly greater difference in the inter-peak latency between acute-TMS and no-TMS groups, suggesting increases in motor function. Finally, the acute-TMS group showed increased fMRI-evoked responses to hindlimb stimulation over the right and left hindlimb (LHL) primary somatosensory representations (S1), respectively; the chronic-TMS group showed moderate sensory responses in comparison, and the no-TMS group exhibited the lowest sensory responses to both hindlimbs. Conclusion: The results suggest that rTMS therapy beginning in the acute phase after SCI promotes neuroplasticity and is an effective rehabilitative approach in a rat model of SCI.