To keep it simple, let's say that neurons exhibit notable plasticity when still viable whereas axons and axon tracts, to much lesser extent when damaged.  Depending on the cortical areas and activities involved, there are vastly different levels of redundancy and neuroplasticity.  Often, cortical neuronal damage may be treated by activating parallel pathways (neural network approach as evidenced by Carrick, recently on a study of 200 soldiers, victims of blast injuries).  And that, dear sir, brings us to pathways....  Axonal damage means that the corridors of communication are disrupted and therefore cannot pass information from one area of the brain to another...depending on function and redundancy, naturally.  Neuroplasticity is compromised more by axonal damage, and the risk of diaschisis is superior in axonal damage due to a domino effect that direct cortical damage, especially in the higher centers, manifests less.  However, if the axonal damage is significant in the more medial and caudal pathways (cord to brainstem/cerebellum, brainstem/cerebellum to mesencephalon, mesencephalon to thalamus) the manifestations will be much more pronounced than in supratentorial axonal lesions.  That make sense, right?  There are more connections from the more primitive areas of the brain when compared to the more recently developed cortical areas.  We can liken this to damage to a tree trunk that has larger implications to the tree's functions than damage to an area of tiny branches and leaves.  Unfortunately, in mTBI, the major damage is to central structures where axonal damage has more pronounced domino-effects that dramatically effect the basal ganglia, with it's consequent motor, cognitive, and limbic manifestations.

Hello Vigneswaran ,

Such observations may also be related to the vascular injury, expected to more often co-occur in diffuse axonal injury (due to shearing forces) compared to cortical injury. Disruption of the regional blood flow due to the mechanical displacement of the blood vessels and/or the neurogenic response to diffuse axonal injury, can result in cerebral ischemia, which by itself is sufficient enough to cause or contribute to the observed neuropsychological sequelae.

Kind regards,

Tatyana

Dear Dr  Ploger and Dr Tatyana,

Thank you for sharing your thoughts on the issue at hand. Your  thoughts on the connectivity disruptions, diaschisis, increased vascular permeability in axonal injury surely adds value to issue at hand. Having said that, it is also worth noting that other factors such as the biomechanics and the forces involved may have significant influence on the outcome of TBI in general. The cortical injury is usually focal and not widespread, involving mainly the cortices, due to the nature of angular loads or linearity, as commonly seen in TBI, hence limiting the ability to affect the outcomes significantly .  Where as in diffuse axonal injury, the injury can be widespread affecting the connectivity as you aforementioned and this in return influences more pronounced adverse outcome or manifestation over time. What do you think?

Dear Wigneswaran ,

Everything is possible. However, if this is the case in the diffuse axonal injury, wouldn’t you expect to observe poor performance during the acute phase given the connectivity has been already impaired? It seems like the deficits develop with time, and therefore impaired neuronal metabolism as a result of inadequate sources of oxygen/nutrient delivery to the brain tissue (impaired blood/brain barrier,  leakage, etc. ) may be reasonable  to consider.  Good discussion.

Best wishes,Tatyana

A very valid pointer raised, Dr Tatyana. Everything is possible. From one of our recent work that has been accepted for publication,  we noted that  there were already statistically significant changes of DTI metrics in a few white matter tracts  acutely (within an average of 10 hours post trauma) that includes the genu and splenium of the corpus callosum, cingulum, posterior limb of internal capsule and optic radiation; and they were associated with domain specific neurocognitive impairments, mostly in the domains of attention, language  acutely.

However at 6 months follow up what we realised was that these patients remained impaired neurocognitively / worsen over time and the integrity of their WM were also more significantly altered  involving at least 7 out of 9 tracts which included the corona radiate, superior longitudinal  fasciculus, and middle cerebral peduncle and also the other tracts aforementioned in exception of the splenium. Additional neurocog impairment  unseen during the acute stage were also noted during the follow up and they were statistically significant as well.

We found evidence of oedematous (vasogenic/cytotoxic) process as well as inflammatory events (reactive astrogliosis/ and or microgliosis) in influencing the neurocognitive outcome.  These pathogenic process evinced acutely is also reflective of possible breach of the BBB/ mechanoporation/ microporation leading to ion/protein leakage and etc which could in return further complicate the delivery of the nutrients and  oxygen to the cells, again affecting recovery both functionally and neurocognitively.

So where does this leave us? Probably a few step closer to a lifetime journey of discovering how our brain works, and how much we know about it.

Hello Vigneswaran, your findings are very interesting. 10 hours to observe changes of DTI may in fact suggest that in diffuse axonal injury damage happens first to the astroglia, whose main function is to support and nurture neurons. They also end-feet line the blood vessels in the brain.  Best wishes with your research, Tatyana 

Thanks Tatyana for your kind words.

A fascinating discussion. I frequently find that trauma that impacts hubs in the brain is much more devastating than injuries outside the hub domain, i.e., mid-posterior parietal, mid-anterior frontal and bilateral lateral temporal parietal.

Absolutely, Vigneswaran, but we need to dig deeper.....Tatyana, vascular issues are obviously present if the TBI provokes vascular lesions.  The ugly truth is that mTBI USUALLY does not provoke direct vascular lesions....but "fuel supply" may be extremely significant, anyway!  Let's get into this for a moment.  We are all in agreement that cortical "bruising" is local and deals with specific "higher" function neurons, depending on where the insult occurs.  But you experts know that the twisting nature of the vast majority of TBI creates lesions that affect the central structures (brainstem and mesencephalon) that govern all of the majesty of higher functions (ability to fixate, ability to execute accurate saccades and pursuits, the ability to suppress the VOR with fixation, etc. etc.).  I don't think I need to elaborate on how altered nigral output can result in significant changes to executive, limbic, hippocampal, or motor/oculomotor programs through the basal ganglionic circuits or simply through modified inhibition of collicular activation of omnipause neurons and activation of the burst generators in the PPRF.  When vestibular integrity, VOR integrity, and integrity of the neural integrators (NPH, MVN; INC and riMLF) are compromised, dysautonomia is inevitable (Tatyana, this is a FUNCTIONAL vascular phenomenon (without ablative vascular lesions) that are almost ALWAYS present in TBI) and can be observed  by autonomic parameters in the mesencephalon through the EW nucleus (anisocoria, Horner's, hippus, etc. etc), or by evaluating changes in the IML from right to left (heart rate, splits, peripheral autonomic signs, SpO2, perfusion indices, ejection coefficients, etc.).  The bottom line is that functional changes to the central pathways create dramatic "cortical" changes.  That is why it is so very very important to evaluate integrity and R/L functional symmetry of the neuraxis; it is paramount to developing appropriate and effective treatment protocols....vestibular integrity, gait parameters, ocular movement integrity (the visual system is attached to the entire neuraxis and is therefore an excellent window into dysfunction in the pathways), somatosensory integrity (redundant with gait parameters but extremely useful in activating cerebellar-related pathways that can be used to activate neurons of the neuronal pools post-synaptic to the lesioned area), and of course, cognitive and behavioral parameters......the latter I tend to consider more as symptoms and confirmations of greater central evils, rather than points to direct therapy.  (If the oil light turns on while your on the highway, you don't waste much time worrying about the integrity of the oil light....you think about the danged motor!)  Sure if the oil light is fried, you have to find another way of monitoring and signaling problems with the motor.  Are my metaphors bothersome? ;-)

Dear All,

I do not think it is possible to damage the axon with the shearing forces without damaging first its protective layer, made of oligodendrocytes (i.e., the myelin sheath around axons).  Once the myelin sheath around axons is damaged, the disruption to the neurovascular bridge (i.e., mage of the astrocytes with one arm at the blood vessel, with other at the neuronal membrane, synapse, or axon) expects to be disrupted as well.  Also, given that the glial cells have shorter processes than neurons, it is anticipated that when external forces are applied, damage first will happen to them.  I do not think that microbleed is absolutely necessary in order the neuronal function to be impacted; even the displacement of the neurovascular bridge may be sufficient to disturb homeostasis and initiate the cascade of the adverse events. These thoughts  are hypothetical.  

Best wishes,Tatyana

Excellent discussion.  I am so proud of you and to be a part of this discussion, even though I'm more a clinician than a researcher.  I think we're all pretty much together here, but we're coming from 3 different directions.  When the trauma is mild and there is not significant structural damage, inflammatory processes are activated in any event, with consequent cytokine mediated damage, modified NMDA activation, modified sodium potential, glial activation, modified BBB integrity, etc. etc.  What are the most metabolically active areas of the brain?  That is to say, which structures will suffer FIRST from metabolic alterations?  The basal ganglia and the cerebellum....big-time hubs.  Their metabolic requirements are superior and therefore, they are more subject to relative hypoxia, local alterations to Ca++ and Na+ gradients, and neurotransmitter metabolism.  Interestingly, changes in these structures, especially when asymmetric, generate autonomic changes which may manifest as local cerebral vasoconstriction (evaluate the VA ratio in both eyes, the EW nuclear parameters on pupillary exam, response to the red test, pupillary hippus, etc.) or in a more systemic fashion due to the decreased cortical inhibition of the PPRF which in turn should inhibit the ipsilateral IML.  Inhibition of inhibition means increased sympathetic tone on the side of cortical damage....functional or structural.  What's more, the PPRF is critical in the generation of saccades!  We can use them to monitor integrity of the brainstem.  These autonomic concomitants can further compromise an inflammatory-compromised neuronal pool with consequent failure or hyper-activation of its post-neuronal pools. (diaschesis or plastic effects due to loss of inhibitory checks).  Just for kicks.....hoping my humble contribution which is less lofty than yours' and more therapeutic can nourish a common, more balanced understanding of what's going on. No doubt about the glial activation early on, Tatyana....there's stuff to clean up!  Problem is that it is a local, not global activation and therefore pharmacological intervention would likely not be specific to the local inflammation, possibly creating other compromise, elsewhere, in the healthy regions.  How do you deal with it?  But that's another issue for another question.

The Gregory answer is very complex. I, personally, have a very simple explanation: the diffuse impairment of many connections (probably irreparable) produces a larger functional impairment that the “focal” post-traumatic injuries (partially reversible). The more recent observations on cerebral connectivity sustain, in my view, this anatomic-functional hypothesis.

Anna, want to keep it simple?  Connections broken or inflamed?  New connections made (if post-neuronal pools are sustained and permitted to go plastic), local blood flow improved, integrity re-established, at least partially.  That's it.  With local network damage, it's easier.  With more extensive damage, the parallel neural networks are more complicated.....but it helps almost always!  Please read my mentor's recent paper on TBI soldiers that using vestibular, ocular and somatosensory stimulation got better results in 2 weeks than the VetAdmin in 6 months to 2 years on SSRI's and counseling....for neuroPSYCHIATRIC issues (PTSD).  The statistics are very, very impressive.

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Thank you all for your kind feedbacks and views. It has definitely helped me to form a better theoretical basis in explaining the paradoxical results that I have in my study. Next, I am looking at imaging evidence of microstructual injury or architectural alteration in patients mTBI. Looking forward share our results with you all soon.