Brain Plasticity

Myelination by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system is essential for nervous system function and health. Despite its importance, we have a relatively poor understanding of the molecular and cellular mechanisms that regulate myelination in the living animal, particularly in the CNS. This is partly due to the fact that myelination commences around birth in mammals, by which time the CNS is complex and largely inaccessible, and thus very difficult to image live in its intact form. As a consequence, in recent years much effort has been invested in the use of smaller, simpler, transparent model organisms to investigate mechanisms of myelination in vivo. Although the majority of such studies have employed zebrafish, the Xenopus tadpole also represents an important complementary system with advantages for investigating myelin biology in vivo. Here we review how the natural features of zebrafish embryos and larvae and Xenopus tadpoles make them ideal systems for experimentally interrogating myelination by live imaging. We outline common transgenic technologies used to generate zebrafish and Xenopus that express fluorescent reporters, which can be used to image myelination. We also provide an extensive overview of the imaging modalities most commonly employed to date to image the nervous system in these transparent systems, and also emerging technologies that we anticipate will become widely used in studies of zebrafish and Xenopus myelination in the near future.

Purpose of review: Highly coordinated cellular interactions occur in the healthy or pathologic adult rodent central nervous system (CNS). Until recently, technical challenges have restricted the analysis of these events to largely static modes of study such as immuno-fluorescence and electron microscopy on fixed tissues. The development of intravital imaging with subcellular resolution is required to probe the dynamics of these events in their natural context, the living brain.

Recent findings: This review focuses on the recently developed live non-linear optical imaging modalities, the core principles involved, the identified technical challenges that limit their use and the scope of their applications. We highlight some practical applications for these modalities with a specific attention given to Experimental Autoimmune Encephalomyelitis (EAE), a rodent model of a chronic inflammatory disease of the CNS characterized by the formation of disseminated demyelinating lesions accompanied by axonal degeneration.

Summary: We conclude that label-free nonlinear optical imaging combined to two photon imaging will continue to contribute richly to comprehend brain function and pathogenesis and to develop effective therapeutic strategies.

Already during the last trimester of gestation, functional responses are recorded in foetuses and preterm newborns, attesting an already complex cerebral architecture. Then throughout childhood, anatomical connections are further refined but at different rates and over asynchronous periods across functional networks. Concurrently, infants gradually achieve new psychomotor and cognitive skills. Only the recent use of non-invasive techniques such as magnetic resonance imaging (MRI) and magneto- and electroencephalography (M/EEG) has opened the possibility to understand the relationships between brain maturation and skills development in vivo. In this review, we describe how these techniques have been applied to study the white matter maturation. At the structural level, the early architecture and myelination of bundles have been assessed with diffusion and relaxometry MRI, recently integrated in multi-compartment models and multi-parametric approaches. Nevertheless, technical limitations prevent us to map major developmental mechanisms such as fibers growth and pruning, and the progressive maturation at the bundle scale in case of mixing trajectories. At the functional level, M/EEG have been used to record different visual, somatosensory and auditory evoked responses. Because the conduction velocity of neural impulses increases with the myelination of connections, major changes in the components latency are observed throughout development. But so far, only a few studies have related structural and functional markers of white matter myelination. Such multi-modal approaches will be a major challenge in future research, not only to understand normal development, but also to characterize early mechanisms of pathologies and the influence of fetal and perinatal interventions on later outcome.

Myelin is critical for healthy brain function. An accurate in vivo measure of myelin content has important implications for understanding brain plasticity and neurodegenerative diseases. Myelin water imaging is a magnetic resonance imaging method which can be used to visualize myelination in the brain and spinal cord in vivo. This review presents an overview of myelin water imaging data acquisition and analysis, post-mortem validation work, findings in both animal and human studies and a brief discussion about other MR techniques purported to provide in vivo myelin content. Multi-echo T₂ relaxation approaches continue to undergo development and whole-brain imaging time now takes less than 10 minutes; the standard analysis method for this type of data acquisition is a non-negative least squares approach. Alternate methods including the multi-flip angle gradient echo mcDESPOT are also being used for myelin water imaging. Histological validation studies in animal and human brain and spinal cord tissue demonstrate high specificity of myelin water imaging for myelin. Potential confounding factors for in vivo myelin water fraction measurement include the presence of myelin debris and magnetization exchange processes. Myelin water imaging has successfully been used to study animal models of injury, applied in healthy human controls and can be used to assess damage and injury in conditions such as multiple sclerosis, neuromyelitis optica, schizophrenia, phenylketonuria, neurofibromatosis, niemann pick’s disease, stroke and concussion. Other quantitative magnetic resonance approaches that are sensitive to, but not specific for, myelin exist including magnetization transfer, diffusion tensor imaging and T₁ weighted imaging.

Positron Emission Tomography (PET), an imaging technique based on the injection of radiotracers directed against specific biological targets within brain tissues, within brain tissues, is a specific and sensitive technique which offers the unique opportunity to quantify myelin dynamics in the central nervous system. Several stilbene and benzothiazole derivatives have been repurposed to image myelin by PET. In demyelinating and dysmyelinating models, selected radiotracers were shown to reliably quantify demyelination and remyelination, allowing a translational approach in humans. A pilot study in subjects with active relapsing MS using PET and the most available benzothiazole derivative, [¹¹C]PIB, supported the hypothesis that this technique is able to quantify myelin content in multiple sclerosis (MS) lesions and to capture dynamic demyelination and remyelination over time. This study highlighted for the first time in vivo the prognostic value of individual profiles of remyelination on the disease course. In future, the clinical application of myelin PET will be pushed forward thanks to the availability of novel fluorinated tracers for myelin, together with the setting up of non invasive quantification procedures and the use of powerful PET-MR systems. This will enable to address in vivo critical unanswered questions about the pathogenesis of remyelination, and to measure the efficacy of emerging promyelinating drugs in early-phase therapeutic trials.

For a long time, although the functional anatomy of human cortex has extensively been studied, subcortical white matter tracts have received little consideration. Recent advances in tractography have opened the door to a non-invasive investigation of the subcortical fibers in vivo. However, this method cannot study directly the function of the bundles. Interestingly, for the first time in the history of cognitive neurosciences, direct axonal electrostimulation (DES) mapping of the neural pathways offers the unique opportunity to investigate the function of the connectomal anatomy. Indeed, this technique is able to perform real-time anatomo-functional correlations in awake patients who undergo brain surgery, especially at the level of the subcortical fibers. Here, the aim is to review original data issued from DES of myelinated tracts in adults, with regard to the functional connectivity mediating the sensorimotor, visuo-spatial, language, cognitive and emotional functions, as well as the interactions between these different sub-networks, leading ultimately to explore consciousness. Therefore, axonal stimulation is a valuable tool in the field of connectomics, that is, the map of neural connections, in order to switch from the traditional localizationist view of brain processing to a networking model in which cerebral functions are underpinned by the dynamic interactions of large-scale distributed and parallel sub-circuits. Such connectomal account should integrate the anatomic constraint represented by the subcortical fascicles. Indeed, post-lesional neuroplasticity is possible only on the condition that the white matter fibers are preserved, to allow communication and temporal synchronization among delocalized inter-connected networks.