Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes.

Waxman, Stephen G.; Brill, Michael H.

doi:10.1136/jnnp.41.5.408

Cited by 171 publications

(72 citation statements)

References 26 publications

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“…Regulating g L could control axon excitability (synergistically with g Na ) in the course of demyelination and its sequalae (21,22). Although AD and bistability have been described in more complex systems (23,24), and other factors including impedance mismatch (itself related to local input resistance) contribute to excitability in a spatially extended model (25), our model demonstrates the sufficiency of g Na /g L (in the presence of g Nap ) to explain four excitability states that may underlie the positive and negative symptoms of demyelination. Furthermore, given that qualitative excitability changes can result from small changes in α, the intermittence of symptoms may reflect operation of the axon near one of its critical transition boundaries.…”

Section: Discussionmentioning

confidence: 99%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Fast axonal conduction of action potentials in mammals relies on myelin insulation. Demyelination can cause slowed, blocked, desynchronized, or paradoxically excessive spiking that underlies the symptoms observed in demyelination diseases. The diversity and timing of such symptoms are poorly understood, often intermittent, and uncorrelated with disease progress. We modeled the effects of demyelination (and secondary remodeling) on intrinsic axonal excitability using Hodgkin-Huxley and reduced Morris-Lecar models. Simulations and analysis suggested a simple explanation for the breadth of symptoms and revealed that the ratio of sodium to leak conductance, g Na /g L , acted as a four-way switch controlling excitability patterns that included spike failure, single spike transmission, afterdischarge, and spontaneous spiking. Failure occurred when this ratio fell below a threshold value. Afterdischarge occurred at g Na /g L just below the threshold for spontaneous spiking and required a slow inward current that allowed for two stable attractor states, one corresponding to quiescence and the other to repetitive spiking. A neuron prone to afterdischarge could function normally unless it was switched to its "pathological" attractor state; thus, although the underlying pathology may develop slowly by continuous changes in membrane conductances, a discontinuous change in axonal excitability can occur and lead to paroxysmal symptoms. We conclude that tonic and paroxysmal positive symptoms as well as negative symptoms may be a consequence of varying degrees of imbalance between g Na and g L after demyelination. The KCNK family of g L potassium channels may be an important target for new drugs to treat the symptoms of demyelination. O ligodendrocytes and Schwann cells tightly wrap axons at regular intervals to form the myelin sheath that allows for rapid axonal conduction. Neuropathies involving axonal demyelination are characterized by the unraveling of this insulation and can affect both the central nervous system, as in the case of multiple sclerosis (MS), and the peripheral nervous system, as in Guillain-Barré syndrome.Causes of demyelination include immunologic disease processes, as well as lesions such as traumatic nerve damage, nonpenetrating spinal cord injuries, and chronic nerve compression (1-4). Regardless of the precise etiology, clinical presentation often involves negative (loss-of-function) symptoms, including loss of motor control (i.e., paresis) and sensory deficits such as blindness and numbness, as well as positive (gain-of-function) symptoms, including muscle spasms, tactile allodynia, and chronic pain that is constant or paroxysmal (1, 4-7). Which muscles or sensory modalities are affected depends on where in the nervous system the demyelinating lesions develop, but changes in conduction velocity alone are clearly insufficient to explain the breadth of symptoms observed, especially the positive ones. In particular, MS often produces confounding symptoms that can present intermittently, resolving and retu...

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Section: Discussionmentioning

confidence: 99%

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Coggan

Prescott

Bartol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, although the axonal path is roughly perpendicular to cortical gray matter, although obviously not completely, and has significant branching (41). At the transition from myelinated to unmyelinated axon, there may also be a delay because of impedance mismatch (42). These factors could also contribute to the long conduction time in the cortex.…”

Section: Discussionmentioning

confidence: 99%

Change of conduction velocity by regional myelination yields constant latency irrespective of distance between thalamus and cortex

Salami

Itami

Tsumoto

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

269

201

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The widely spanning sensory cortex receives inputs from the disproportionately smaller nucleus of the thalamus, which results in a wide variety of travelling distance among thalamic afferents. Yet, latency from the thalamus to a cortical cell is remarkably constant across the cortex (typically, Ϸ2 ms). Here, we found a mechanism that produces invariability of latency among thalamocortical afferents, irrespective of the variability of travelling distances. The conduction velocity (CV) was calculated from excitatory postsynaptic currents recorded from layer IV cells in mouse thalamocortical slices by stimulating the ventrobasal nucleus of the thalamus (VB) and white matter (WM). In adults, the obtained CV for VB to WM (CVVB-WM; 3.28 ؎ 0.11 m͞s) was Ϸ10 times faster than that of WM to layer IV cells (CVWM-IV; 0.33 ؎ 0.05 m͞s). The CVVB-WM was confirmed by recording antidromic single-unit responses from VB cells by stimulating WM. Exclusion of synaptic delay from CVWM-IV did not account for the 10-fold difference of CV. By histochemical staining, it was revealed that VB to WM was heavily myelinated, whereas in the cortex staining became substantially weaker. We also found that such morphological and physiological characteristics developed in parallel and were accomplished around postnatal week 4. Considering that VB to WM is longer and more variable in length among afferents than is the intracortical region, such an enormous difference of CV makes conduction time heavily dependent on the length of intracortical region, which is relatively constant. Our finding may well provide a general strategy of connecting multiple sites irrespective of distances in the brain.T he timing of synaptic inputs onto postsynaptic neurons is of great importance, not only in the information processing (1-6) but also in the subsequent plasticity of the input (7-10). Yet, the expanse of cortex, in contrast with the disproportionately smaller nucleus of the thalamus (11, 12), makes the thalamocortical afferent trajectory crooked, resulting in a variety of travelling distances among the afferents. Nevertheless, a spike in thalamic cells arrives in cortical cells within a narrow window of time that peaks Ϸ2 ms (range: Ϸ1-4 ms), and this timing window seems well preserved, in some cases, even across the modality (visual, auditory, and somatosensory; refs. 2 and 13-16). This observation raises the following question: how is the timing of input (latency) kept within a narrow window of time, irrespective of travelling distances? Interestingly, white matter (WM) stimulation evokes monosynaptic responses in the cortex, whose latency falls in a window of time similar to that of thalamic stimulation, although the travelling distance is less than half. We therefore systematically examined the conduction velocity (CV) of thalamocortical fibers and found that the CV along this axon is not homogeneous. Instead, the CV of thalamus to WM was 10ϫ faster than the rest of the afferents, because of a selective myelination. We also found that, in newborn anima...

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“…These two properties, frequency-related conduction failure and increased conduction latency, are also features of acute and chronically demyelinated axons (Waxman 1977;Waxman and Brill, 1978;Utzschneider et al 1994;McDonald and Ron, 1999). We used confocal microscopy to determine whether the axons that had regenerated into the white matter rostral to the injury site were myelinated.…”

Section: The Lack Of Myelin May Account For the Pathophysiological Stmentioning

confidence: 99%

Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

Tan

Petruska

Mendell

et al. 2007

Experimental Neurology

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Axon regeneration after experimental spinal cord injury (SCI) can be promoted by combinatorial treatments that increase the intrinsic growth capacity of the damaged neurons and reduce environmental factors that inhibit axon growth. A prior peripheral nerve conditioning lesion is a well established means of increasing the intrinsic growth state of sensory neurons whose axons project within the dorsal columns of the spinal cord. Combining such a prior peripheral nerve conditioning lesion with the infusion of antibodies that neutralize the growth-inhibitory effects of the NG2 chondroitin sulfate proteoglycan promotes sensory axon growth through the glial scar and into the white matter of the dorsal columns. The physiological properties of these regenerated axons, particularly in the chronic SCI phase, have not been established. Here we examined the functional status of regenerated sensory afferents in the dorsal columns after SCI. Six months post-injury, we located and electrically mapped functional sensory axons that had regenerated beyond the injury site. The regenerated axons had reduced conduction velocity, decreased frequency-following ability, and increasing latency to repetitive stimuli. Many of the axons that had regenerated into the dorsal columns rostral to the injury site were chronically demyelinated. These results demonstrate that regenerated sensory axons remain in a chronic pathophysiological state and emphasize the need to restore normal conduction properties to regenerated axons after spinal cord injury.

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Conduction through demyelinated plaques in multiple sclerosis: computer simulations of facilitation by short internodes.

Cited by 171 publications

References 26 publications

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Imbalance of ionic conductances contributes to diverse symptoms of demyelination

Change of conduction velocity by regional myelination yields constant latency irrespective of distance between thalamus and cortex

Sensory afferents regenerated into dorsal columns after spinal cord injury remain in a chronic pathophysiological state

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