Multiple Sclerosis (MS) is a neurological disease that both reduces overall life expectancy and reduces the quality of life of those remaining years. The methodology of MS involves the immune system no longer recognizing myelin as a part of the host. The loss of this recognition results in the immune system attacking and damaging myelin. Losing specific sheathes of myelin is neurologically detrimental because myelin acts as an insulating element limiting the rate of leaking from neuronal electrical signals, most notably action potentials. During neuronal development myelin covered axons up-regulate fewer sodium and potassium channels because of the greater signal strength afforded by the myelin. When the myelin is lost these axons no longer have the ability to effectively conduct action potentials because the increased leaking weakens the potential below threshold before it can activate the next set of voltage gated channels in the series along the axon. These inefficiencies create interruptions in the depolarization networks that cause thoughts and action. Note that the term ‘white matter’ comes from myelinated neurons.
One of the biggest problems with MS is its idiopathic nature with the only real clue to a potential cause its strange regionality in that individuals who grow up in the Northern Hemisphere have a much higher rate of occurrence than those who grow up in the Southern Hemisphere. This lack of information pertaining to cause makes developing effective treatments even more important because preventative measures cannot be taken. Pertaining to treatments there are multiple types of MS where the first neurological dysfunction episode related to demyelination is categorized as clinically isolated syndrome (CIS).1 MS typically develops upon the recurrence of more demyelination events eventually resulting in one of four types:
1. Relapsing Remitting MS (RRMS) makes up a large percentage (75-90) of the MS cases and is characterized by unpredictable attacks that, depending on their length, could result in permanent damage followed by a period of time (a grace period representing the remitting aspect) with no new myelin or oligodendrocyte loss.1
2. Secondary Progressive MS is the “evolved” form of relapsing remitting MS, which is characterized by progressive neurological decline between acute attacks. In large part there is no remission period because of the ongoing neurological decline. Fortunately it takes an average of 19 years to move from relapsing remitting MS to secondary progressive.1
3. Primary Progressive MS describes an almost immediate transition from relapsing remitting to a condition of progressive neurological decline. Basically whereas secondary progressive takes 19 years to occur due to remission periods, primary progressive has zero remission periods after the onset of symptoms. Somewhat confusingly there can be small periods of remission upon the onset of primary progressive MS, but generally none afterwards.1
4. Progressive Relapsing MS is the most debilitating form with steady neurological decline upon the onset of initial symptoms and includes acute superimposed attacks increasing damage.1
The bigger problem in MS may be that the nature of myelin loss is prolonged not simply from the direct loss of myelin, but the loss of oligodendrocytes.2 Oligodendrocytes are one of the three types of glial cells and one of its principle responsibilities is to synthesis and maintain myelin. Therefore, not only is myelin damaged, but also the principle cell responsible for repair that damage is also diminished. An additional problem with this oligodendrocyte loss is that it is rather non-specific, apoptosis via caspase 3 pathway, phagocytosis of apoptotic oligodendrocytes, swelling with abnormal nuclei, complement deposition and lysis,2 which provide little help determining the pathway of injury and eventual cell death.
The most common current treatment for MS is either an immunomodulator (interferon beta-1a, interferon beta-1b, glatiramer acetate, natalizumab and fingolimod or teriflunomide) or mitoxantrone (an immunosuppressor).1,2 The idea behind these treatments is to reduce the activity of certain immune system elements in order to reduce the probability of these elements launching an attack against myelin. All of these treatments have some positive effects against RRMS, but mitoxantrone, natalizumab and fingolimod have shown the most promise (in that order) at reducing RRMS progression based on the frequency of relapses and the number of brain lesions developed.1
Unfortunately the side effects associated with these three drugs are significant and create problems for repetitive use. Therefore, interferons and/or glatiramer acetate are used as a “first line” of treatment and if they are not effective enough mitoxantrone, natalizumab or fingolimod is used as a “second line” of treatment. “Second line” of treatment agents are currently approved for and typically used as monotherapy. While the second line agents are able to effectively reduce the rate of progression in RRMS they are not currently able to cure RRMS and have and have little effect against the other three types of MS.
Another potential theoretical treatment has been to somehow increase the concentration of oligodendrocytes, which could better repair the damage done by the rouge immune cells maintaining the viability of the myelin sheaths eliminating the negative effects associated with MS. Techniques involving the surgical implantation of oligodendrocyte precursor cells (OPCs) into the CNS have shown some minor success in mice,3 but no solid evidence exists for humans. Cholinergic treatment, most notably acetylcholinesterase inhibitors, have had some positive benefits because it is thought that increased cholinergic stimulation stimulates oligodendrocyte activation aiding myelin repair.4 However, the rate of increase in repair is inconsistent alluding to other factors controlling the influence of cholinergic stimulations.5 Overall while direct injection of neuronal stem cells is not a feasible at this moment there may be an alternative strategy to recruit neuronal stem cells to better address MS.
Transcranial direct current stimulation (tDCS) is a type of neurostimulation that utilizes a constant and low current that is delivered directly to specific regions of the brain through small electrodes.6 When a positive stimulation is produced it increases the probability of neuronal depolarization in the affected area whereas a negative stimulation increases the probability of neuronal hyperpolarization in the affected area, which will inhibit spontaneous cell firing. The original purpose of tDCS was to aid in recovery after strokes and other focused brain injuries and later was discovered to have a beneficial influence on learning.7-9 However, another result from tDCS appears to be neuronal stem cell recruitment to the areas of stimulation.
The recruitment is aided by the ability of tDCS to facilitate cortical changes after the completion of the stimulation. Not surprisingly this residual influence is dependent on the duration and intensity of the stimulation. tDCS exerts its influence through modifications to intracellular cAMP and calcium levels10 in addition to influencing NMDA receptor plasticity and actually modulating cerebral blood flow in a specific manner (neuro-vascular coupling).11 These influences also augment long term potentiation (LTP) and long term depression (LTD) depending on the type of current and its length. This influence is most likely how tDCS has such a significant effect on learning. Overall the recommended administration methodology for tDCS is to wait at least 48 to 168 hours between stimulations with a stimulation time of 20 minutes.11
Some of the most interesting results for tDCS have come recently with evidence that supports the idea of glial cell recruitment and activation over only neuronal activation. Previous evidence demonstrated electric field induced cell migration (galvanotaxis).12 Numerous cell types experience galvanotaxis including fibroblasts, granulocytes, keratinocytes and perhaps most importantly rodent neuronal progenitor cells, endogenous tri-potential neural stem cells (eNSCs), human embryonic stem (ES) cells and human ES-cell derived neural stem cells.13-18
Recruitment of neural stem cells and their derived associates could involve a transient tDCS derived pro-inflammatory effect on the cathodal side creating a polarity-specific migratory aspect to the recruitment.19 This pro-inflammatory effect also involves microglia recruitment with associated T-helper cell involvement to promote neurogenesis and stem cell recruitment.19 Some argue that the extent of stem cell recruitment is similar to the recruitment through Notch receptor activation.20 This recruitment has shown to be effective at improving neurological function and recovery in stroke victims and could see repeated benefit through tDCS.21,22
While tDCS has demonstrated some therapeutic effects for stroke victims, the recruitment of eNSCs also suggests that tDCS may also have a therapeutic effect for MS. ENSCs exist in the adult spinal cord, predominately the white matter tracts, and have a general pathway differentiation fate into oligodendrocytes and astrocytes.23 The neuronal spiking activity, which also occurs from tDCS, appears to aid in the differentiation rate of eNSCs to oligodendrocytes through the development of oligodendrocytic precursor cells (OPCs) with the most important neuron group those on the corticospinal tract.23 Newly differentiated oligodendrocytes have a full ability to myelinate appropriate neurons.24,25
The pathway converting OPCs into oligodendrocytes first involves glutamate phosphorylating cAMP response element binding protein (CREB) on OPC after binding to AMPA/kainite receptors leading to eventual OPC mitosis.26 Next corticospinal tract neurons release mitogens that stimulate astrocytes to release OPC platelet-derived growth factor (PDGF), which releases bi-potential glial progenitors.27 Finally ATP and adenosine act on their appropriate receptors releasing intracellular calcium resulting in OPC differentiation to oligodendrocytes.25
During the initial stages of MS the body is able to facilitate remyelination in many MS lesions, but this process begins to fail as time passes. Overall remyelination appears to occur in two different steps. The first step involves OPCs colonizing lesions and the second step is the differentiation of the OPCs into oligodendrocytes that contact demyelinated axons to wrap those axons with new functional myelin sheaths.27 Therefore, increasing the recruitment rate of OPCs and their differentiation into oligodendrocytes should provide a useful boost to facilitating remyelination.
There is evidence to suggest two types of OPCs. One type expresses voltage-gated sodium and potassium channels, which are down-regulated when OPCs differentiate into oligodendrocytes28,29 and another type which fail to express these voltage-gated channels.30 While perinatal OPCs can differentiate into oligodendrocytes and astrocytes postnatal OPCs only appear to differentiate into oligodendrocytes and neurons.31-33 OPCs with voltage-gated channels can depolarize after receiving input from glutaminergic and GABAergic neurons.34-36 This depolarization appears to promote proliferation and eventual differentiation as inhibiting depolarization reduces myelination rates.23,37 This proliferation and differentiation promotion supposedly comes from depolarization releasing platelet-derived growth factor (PDGF).27,38,39 Thus facilitating the former type of OPC would be superior over the latter.
Among the five PDGF isoforms PDGF-A appears to be the most important pertaining to myelination. PDGF-A significantly increases the rate of oligodendrocyte proliferation to the point where the elimination of PDGF-A nearly eliminates all myelin in the brain.40 Basically in normal environments PDGF is the limiting factor in oligodendrocyte proliferation both for fetuses and adults.39,40 Due to oligodendrocyte efficiency myelination is not severely reduced even in PDGF-A limited environments, thus increased oligodendrocyte densities provide little myelination advantage.41 However, in MS the accelerated demyelination and loss of oligodendrocytes increase the necessity of replenishing both the myelin and oligodendrocytes through the differentiation and proliferation of new oligodendrocytes. Experiments with electrical stimulation of arterial walls enhanced gene expression of PDGF-A chain, PDGF-B chain and PDGF-beta receptor (beta r),12 thus the same phenomenon is more than likely occurring in the brain during tDCS.
One outstanding question that remains with remyelination is whether or not the synthesized myelin is of similar quality to myelin synthesized during development? Basically are there any developmental specific mitogens that enhance the quality of myelin where these mitogens are not available during periods of remyelination in adults? While there is no reason to suspect a differential agent, knowing the answer to this question would be useful in estimating the length of treatment to address various types of MS.
Overall tDCS originally came into prominence in the research community as a technique designed to ease permanent damage inflicted upon stroke victims. However, it has gained popular prominence as a potential intelligence augmentation tool. While creating shortcuts in learning is viewed by the press as a more sexy application for this technique the discussion above hints at an even more useful possible application for tDCS, a new method for long-term treatment and even potential neutralization of MS. At first glance there do not appear to be any long-term detriments associated with the application of tDCS as a treatment strategy for MS and evidence exists that tDCS could augment oligodendrocyte concentrations in the brain, which would counter-act the demyelination influences of the compromised immune system. With no viable cure for MS, the application of tDCS could prove to be most effective treatment yet.
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