ROLE OF MYELIN PLASTICITY IN OSCILLATIONS AND SYNCHRONY OF NEURONAL ACTIVITY S. PAJEVIC, a P. J. BASSER b AND R. D. FIELDS c * a Mathematical and Statistical Computing Laboratory, Division of Computational Bioscience, Center for Information Technology, NIH, USA b Section on Tissue Biophysics and Biomimetics, Program on Pediatric Imaging and Tissue Sciences, NICHD, USA c Nervous System Development and Plasticity Section, National Institute of Child Health and Human Development, NIH, USA Abstract—Conduction time is typically ignored in computa- tional models of neural network function. Here we consider the eﬀects of conduction delays on the synchrony of neuronal activity and neural oscillators, and evaluate the consequences of allowing conduction velocity (CV) to be regulated adaptively. We propose that CV variation, medi- ated by myelin, could provide an important mechanism of activity-dependent nervous system plasticity. Even small changes in CV, resulting from small changes in myelin thick- ness or nodal structure, could have profound eﬀects on neuronal network function in terms of spike-time arrival, oscillation frequency, oscillator coupling, and propagation of brain waves. For example, a conduction delay of 5 ms could change interactions of two coupled oscillators at the upper end of the gamma frequency range (100 Hz) from constructive to destructive interference; delays smaller than 1 ms could change the phase by 30°, signiﬁcantly aﬀecting signal amplitude. Myelin plasticity, as another form of activity-dependent plasticity, is relevant not only to nervous system development but also to complex information processing tasks that involve coupling and synchrony among diﬀerent brain rhythms. We use coupled oscillator models with time delays to explore the importance of adaptive time delays and adaptive synaptic strengths. The impairment of activity-dependent myelination and the loss of adaptive time delays may contribute to disorders where hyper- and hypo-synchrony of neuronal ﬁring leads to dysfunction (e.g., dyslexia, schizophrenia, epilepsy). This article is part of a Special Issue entitled: ‘‘SI: The CNS White Matter’’. Published by Elsevier Ltd. on behalf of IBRO. Key words: activity-dependent myelination, white matter plasticity, synchronization, oscillations, conduction velocity and delays, coupled oscillators. INTRODUCTION The functional and evolutionary signiﬁcance of myelin is typically interpreted in terms of the increased conduction velocity (CV) it confers through the mechanism of saltatory conduction (Tasaki, 1939). However, faster is not always better, as many aspects of brain function require precise temporal relationships among the signals originating from distant brain areas and, thus, a proper distribution of the CVs. In the vertebrate nervous system, CVs range from a small fraction of a m/s to hundreds of m/s in diﬀerent axons. The speed of conduction is largely dependent on the thickness of myelin, axon diameter, and the spacing and width of nodes of Ranvier. Glial cells form myelin and inﬂuence the spacing of nodes, and in the PNS at least, aﬀect axon diameter as well (de Waegh et al., 1992; Garcia et al., 2003). In order to mediate proper spike-time arrival among axons of diﬀerent lengths converging onto a common target, these axonal parameters are crucial to establish proper conduction delays. It is commonly assumed that the transmission speeds and delays are genetically speciﬁed and ﬁxed at the developmental stage, and the changes in degree of myelination in an adult brain are only considered in cases of pathology (e.g., demyelination and dysmyelination). This view is changing, and there is growing evidence that neurotransmitters mediate communication between axons and myelinating glia (Kukley et al., 2007; Ziskin et al., 2007; Bakiri et al., 2009), and that myelination is a dynamical, activity-dependent process (Fields, 2010). Two principal mechanisms for changing CV are altering axon diameter and myelination (in vertebrates), the latter being the most eﬀective means of increasing the CV. Enlarging axon diameter only is much less eﬀective because CV increases in proportion to the square root of the axon diameter in unmyelinated ﬁbers (Tasaki, 2004), while it increases linearly with the diameter of myelinated axons (Hursh, 1939). Additionally, the enlargement of axon caliber is metabolically and anatomically less feasible as a means of activity-dependent regulation of conduction delays. There is ample evidence now that the functional activity and action potentials inﬂuence proper development of myelin sheaths (Fields, 2013 for review). For example, in the experiments with the development of barrel cortex in mice (Barrera et al., 2013) sensory deprivation (removal of whiskers on one side), while not changing the onset of myelination relative to the controls, does signiﬁcantly decrease the amount of myelin ensheathing each axon in 0306-4522/13 $36.00 Published by Elsevier Ltd. on behalf of IBRO. http://dx.doi.org/10.1016/j.neuroscience.2013.11.007 * Corresponding author. Address: National Institutes of Health, Building 35, Room 2A211, MSC 3713, Bethesda, MD 20892, USA. Tel: +1-(301)-480-3209. E-mail address: ﬁeldsd@mail.nih.gov (R. D. Fields). Abbreviations: CV, conduction velocity; CO, coupled oscillators; ITD, interaural time diﬀerence; PFC, prefrontal cortex; STDP, spike-time- dependent plasticity; VB, ventrobasal nucleus; WM, white matter. Neuroscience xxx (2014) xxx–xxx Please cite this article in press as: Pajevic S et al. Role of myelin plasticity in oscillations and synchrony of neuronal activity. Neuroscience (2014), http:// dx.doi.org/10.1016/j.neuroscience.2013.11.007 1