In this series of articles, I am investigating the impact that temporomandibular joint dysfunction (TMJD) can have on the physical & physiological wellbeing of an athlete, as well as how we can manage TMJD.
In the last article, I introduced the anatomy of the joint, in addition to how that can have an influence on balance, proprioception & skeletal alignment throughout the body. What I will discuss today is whether or not TMJD could impact recovery from concussion, skill acquisition & the refinement of neural pathways.
That’s a fairly controversial discussion to have & a big hypothesis to test but stay with me & maybe you will agree that it is not as far fetched a proposition as you might first think.
My reasoning behind the idea is related to the link between TMJD, the trigeminal nerve & glial cell activity. To understand this better, I am going to work backwards, starting with glial cells, what they are, what they do & how they can misbehave if they are pathologically activated, for example, when the trigeminal nerve is damaged & hyper-sensitised.
Much of my recent knowledge on glial cells has been gleaned by a fantastic paper by Barres (2008) that was published in the “Neuron" journal.
Glial cells make up around half the volume of the human brain…a staggering fact to start with. There are three types of glial cells: astrocytes, oligodendrocytes & microglial cells, the phenotypes of which are altered in instances of brain injury & disease.
If we look at astrocytes first, they are divided into two main classes, depending upon morphology, antigenic expression & location.
There are protoplasmic astrocytes, found in the grey matter, whose membranous protrusions branch off the star-shaped cell, to ensheath synapses & blood vessels. Fibrillary astrocytes, in contrast, are found in the white matter & relate with nodes of Ranvier (gaps in the myelin sheath) & blood vessels.
At synapses, the astrocytes help to control the levels of ions, such as K ions, as well as neurotransmitters in the intracellular space. The exact manner in which they do this is, however, not yet well understood.
It is proposed that this locus of control helps manage the development & function of synapses, blood vessel flow & neuronal survival.
Pfreiger & Barres (1997) demonstrated massive increases in synaptic activity when retinal ganglion cells were cultured with astrocytes in comparison to when the same cells were cultured with other cells types, such as fibroblasts or oligodendrocytes.
Ullian et al (2001) attributed this increase in synaptic activity to both an increase in the number of synapses, in addition to the enhancement of both pre- & post-synaptic function.
Ullian, E.M. et al. Control of synapse number by glia. Science, 2001; 291: pp 657-661
Beyond promoting synaptogenesis, an important aspect of brain plasticity is the removal of inappropriate synaptic connections. Boulanger & Shatz (2004) demonstrated that astrocytes were also involved in this process.
Not only do astrocytes secrete synaptogenesis-promoting proteins, but they also secrete many other neuroactive substances, including astrocyte-derived cholesterol, ATP & D-serine, which are involved in synaptic control.
Junctions between astrocytes vary but Houades et al (2006) suggested that glial cells form circuits, with the junctions facilitating the removal of ions & toxin metabolites from the synapses &/or the delivery of nutrients.
Several studies have demonstrated that astrocytes influence microvascular control, releasing either vaso-constrictors or vasodilators depending on the context (Zonta et al, 2003 & Metea & Newman, 2006)
Astrocytes have been shown to release neurotrophic signals that promote CNS neural survival, although the mechanism is another of those that is yet to be fully understood (Banker, 1980).
So, that is a fairly extensive account of how astrocytes act on synapses & at neural junctions, now we need to look at what influence they have on blood vessels. When you consider the role of vascular cells in the brain, there are three key roles they play:
Firstly, they guide axonal development (Makita et al, 2008), secondly they provide trophic support & differentiation signals to neurons & stem cells (Dugas et al, 2008) & finally, they provide a niche for neural stem cells (Tavazoie et al, 2008).
When you then look at the injured brain, astrocytes have been shown to seal the blood brain barrier (Bush et al, 1999), which has lead some to argue a role in maintaining the blood brain barriers in the healthy brain (Cahoy et al, 2008).
In an acute neurological injury, such as a traumatic brain injury, astrocytes are seen to swell dramatically, which is very harmful & may be linked to the compromise of the blood brain barrier that is observed. Furthermore, reactive astrocytosis is observed in every neurological disease state.
When cells are disturbed in these manners, it increases the risk of mutations occurring & mutations of astrocyte genes can cause demyelinating diseases & epilepsy.
Other effects of reactive astrocytosis are that whilst the action helps to seal the blood brain barrier when encapsulating infections or reacting to trauma, the astrocytes can release a neurotoxic signal that kills motor neurons & the resultant scarring of the cells contributes to the inhibition of axon regeneration (Silver & Miller, 2004).
Silver, J. & Miller, J.H. Regeneration beyond the glial scar. Nat Rev Neurosci, 2004; 5: pp 146-156
Furthermore, whilst reactive astrocytes up-regulate synapse-inducing genes to help repair the brain, they may also induce pathological synapses that can cause epilepsy or neuropathic pain (Boroujerdi et al, 2008).
If you’re still with me, we then need to start addressing the role of the other glial cells & next up are the oligodendrocytes.
The oligodendrocytes wrap their membranous processes around axons to form myelin & help determine the axonal structure by controlling the diameter & spacing/clustering of ion channels at the nodes of Ranvier & paranodes.
The Schwann cells are also involved in axonal development, promoting their regeneration, as well as the formation & function of the synapses at the neuromuscular junction.
Meanwhile, the last of the glial cells, the microglia, are immune system cells, which make up about 10% of all CNS glial cells (Soulet & Rivest, 2008). They are located in the brain parenchyma & appear to act as sensors of the extracellular environment, by responding to & potentially communicating changes of injury to surrounding neural cells or non-CNS immune cells.
Soulet, D. & Rivest, S. Microglia. Curr Biol, 2008; 18: pp R506-508
So how might all this neurophysiological & neuroanatomical information be used to inform the sports science & medical services staff attempting to gauge the ability of our athletes to recover from concussion or acquire & refine neuromuscular patterns, as I so provocatively claimed at the beginning of this post?
A good place to start joining the dots are with activated microglia, which secrete high levels of numerous cytokines including tumour necrosis factor alpha (TNF alpha), which is pro-inflammatory & involved in demyelination. Microglial-derived TNF alpha is involved in promoting the generation of new oligodendrocytes in mouse models of demyelination (Arnett et al, 2001).
Arnett, H.A. et al. TNF alpha promotes proliferation of oligodendrocyte progenitors & remyelination. Nat Neurosci, 2001; 4: pp 1116-1122
In addition, these cytokines weaken the integrity of the blood brain barrier during brain inflammation, whilst also controlling normal function & plasticity of neural circuits (Kaneko et al, 2008).
Kaneko, M. et al. Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron, 2008; 58: pp 673-680
Work by Stevens et al (2007) suggests that microglia mediate the selective elimination of inappropriate synaptic connections during CNS development.
The process of synaptic stripping, where microglia phagocytose synaptic terminals of spinal & hypoglossal motor neurons following injury, would indicate that immune system molecules are crucial for the patterning of neural circuits (Boulanger & Shatz, 2004).
In fact, in all of the most common brain diseases, including traumatic brain injury (along with stroke, spinal cord injury, MS, epilepsy, Alzheimer’s, Parkinson’s, ALS, Down’s Syndrome, glioma, depression & autism), glial cells are central contributors.
However, once again, research has yet to demonstrate exactly how glial pathology contributes to neural dysfunction & vice versa.
As Barres (2008) nicely summarises, it appears that glial cells play “a critical role in controlling the timing, location, number, function & plasticity of synapses & perhaps in the evolution of greater synaptic plasticity in human brains”.
The next step along the road, is that we now have to relate glial cell activity back to TMJD, to establish whether or not my hypotheses are worth considering.
The critical paper I read that helped with understanding this, was by Gen Piao et al (2006), who investigated the effects of trigeminal nerve damage & hypersensitivity on glial cell activity.
After transecting components of the trigeminal nerve, the hypersensitivity was significant immediately & remained raised for 28 days. Microglial activation was initiated at day 1 post-resection, before peaking at day 3 & staying raised until day 14. Meanwhile, astrocyte activation was more marked at days 7 & 14 following transection than at day 3.
Therefore, given that the trigeminal nerve has an extremely dense concentration of C fibres (pain fibres), it is not unreasonable to assume that TMJD, which has been shown to increase trigeminal nerve sensitivity, could influence glial cell activity, namely microglia & astrocyte activity, by causing a subsequent increase.
Back to the athletes & is it then feasible to suspect that the effect of trigeminal nerve-induced microglial disturbance on myelination, axonal development & synaptic function might have a knock-on effect? In a non-injured state, could this then have an impact on neural pathway patterning & synaptic plasticity, which would have a potential influence in skill acquisition & refinement of neural pathways & synaptic control during practice/skill repetition.
Meanwhile, the neurotoxic effects of increased microglial activation on synaptic function, neuronal survival & blood vessel flow should also be considered. Is it a plausible consideration that existing raised glial cell activation might be exacerbated due to brain trauma in a post-concussive state? If this were the case, would it not be unreasonable to suggest that recovery from concussion might take longer in an athlete with TMJD, as pre-injury astrocyte scarring might have a greater impact on inhibiting axonal & blood vessel regeneration.
Furthermore, given that existing research has already established that glial cells are central contributors in common brain diseases, including traumatic brain injury (along with stroke, spinal cord injury, MS, epilepsy, Alzheimer’s, Parkinson’s, ALS & depression), does this information raise a number of questions if you think about our athletes that engage in sports where blows to the head might contribute to TMJD? This is especially pertinent when you look at some of the concerns being raised in relation to the effects of repeated concussive, or sub-concussive events.
So there it is. Whilst, I have admittedly demanded some giant leaps of faith & asserted some blatant assumptions based on the research that is out there, I want to promote debate in the area. These are areas in which the research is just starting to uncover more questions & I certainly think there is a strong argument to encourage more research to be conducted, so why not encourage a collaboration of dental experts, neurologists, movement specialists & coaches?
