Decompression surgery may only go so far in relieving pressure on cord

I’m a fan of translational models; one can do, and has done, a lot using rodents, but no one model is ideal. At the very least there is the concern that what works in one species doesn’t in another, so alternative models begin to give one a feel for the robustness of a therapeutic effect.  Likewise, the scale and proportion of humans and rodents is very different. This matters because distribution of the cell or drug of interest may be dependent on such things. And outcomes that we measure to demonstrate effect (positive or adverse, alike) are inevitably dictated by the species you choose.

A number of groups are now working on pig models. While they (pigs that is, not the researchers) are not perhaps the best to measure “hand” function, they do offer distinct features which I see as advantages. Perhaps the major one is the obvious size. Working on pigs allows techniques to be developed and refined which inform how these might be done on humans – surgery, intra-operative monitoring etc. Kwon and others are using the greater accessibility to cerebral spinal fluid (CSF) that pigs offer to profile changes in molecules found in this fluid after injury which offers up the possibility of using this information to aid diagnosis, prognosis and treatment strategy – standard stuff in other areas of medicine and greatly needed in SCI.

A poster by R Tabanfar [629.17] examined the consequences of decompression after SCI. Decompression – surgically realigning displaced bony structures to relieve the pressure being exerted on the cord – is a common procedure in SCI treatment. The assumption is that in doing so blood will flow more freely, stop the tissue from being starved of oxygen and reduce further damage. The group inserted pressure probes into the cord and then applied a sustained compression on the cord to simulate the conditions experienced  following injury. Pressure was maintained for a few hours to replicate the real world scenario and released to mimic decompressive surgery.

As expected, the pressure markedly dropped on release and imaging confirmed the return of gap between the cord and the surrounding dura (the membrane that surrounds the cord and retains CSF that bathes the cord). However, due to the damage sustained by the cord, it begins to swell over the next few hours and expands until it hits the dura. The dura then restricts further expansion and the pressure in the cord begins to rise once more and appears to remain high for some time. Further studies will examine just how long this elevated pressure persists and hopefully answer whether this prolonged elevation of pressure post decompressive surgery has an impact on outcome.

 

Chaperone proteins play role in neuroprotection by fatty acids

The earlier post on Omega-3 suggests a very broad applicability and therapeutic potential for polyunsaturated fatty acids in central nervous system disease and dysfunction. It does, however, skip around the issue of how this can possibly be and the mechanism by which it may give rise to these beneficial effects. The reason for this is that we really don’t know.

An observation one can make is that all therapeutic examples – in the trauma setting at least – appear to require very acute delivery (within an hour) for efficacy to be demonstrated. What this is telling us, I’m not sure, but it is an important and intriguing observation sentinel which is surely pointing to something. Anyway, JD Figueroa [presentation 341.30] presented a poster on so-called chaperone proteins that are required to bind fatty acids such as DHA (making this fatty molecule more soluble in the watery biological environment) used in the studies referred to in an earlier post.

Figueroa and colleagues are studying something called the fatty acid-binding protein 5 (FABP5). Present in neurons in the uninjured cord, after injury the level of FABP5 appears to increase significantly during the first week in Glial cells such as astrocytes and oligodendrocytes. This story is far from complete but a key experiment they performed was to look at what happened when they blocked the production of the chaperone FABP5. Normally the administration of the fatty acid DHA led to improvements in function but blocking FABP5 resulted in poorer function. While this doesn’t itself represent a therapeutic mechanism the group suggest that chaperone proteins play an important part enabling the cell to take up and make use of the therapeutic fatty acid and may itself be a potential therapeutic target.

Elsewhere, Alexander (Sasha) Rabchevsky continued his exploration of the potential beneficial effects of the licensed drug Gabapentin for autonomic dysreflexia, muscle spasticity and as presented [341.29] ameliorating the chronic inflammatory response they propose is associated with autonomic dysreflexia.

The Lu et al., paper in the high impact journal Cell last year showed that embryonic stem cell-derived neural stem cells could survive, integrate and form synapses with host tissue and regenerate to an unprecedented degree in adult spinal cord. Lu presented [342.23] on more recent work where they took fibroblast cells from a healthy adult male, and created inducible pluripotent stem cells, or IPSCs, by genetic manipulation. Again, the poster was filled with remarkable images of regenerating axons growing both up and down the cord from the graft site. If anything “the response was more robust”, said Lu. IPSCs are a potentially important source of cells that can be harnessed for therapies. Safety concerns remain with such approaches but the ability to source and expand one’s own cells for treatment is appealing.

Fish oil found all over SfN 2013

Sometimes it’s nice to visit other areas of research to catch a little of what they are doing. Traumatic brain injury (TBI) isn’t exactly a million miles from SCI – both involve traumatic insults to the central nervous system tissue and can result in similar outcomes – but it can be good to observe similarities and differences in experimental design, therapeutic concepts and progress.

I’ve talked about fish oils before, specifically Omega-3 polyunsaturated fatty acids (PUFAs) and Spinal Research has funded in the area too. The story of PUFAs actually began in major trauma and I came across a poster [presentation 147.18] today from a London-based group that examined the effect of an Omega-3 called docosahexaenoic acid (DHA) in mouse TBI model. They found that if DHA is administered very early after injury the cognitive outcomes are better – the mice showed a marked improvement in memory tests. Omega-3 fatty acids are thought to act as neuroprotectants – that is their presence in high levels protect neurons from cell death after injury.

What they found was that DHA also changed the response of astrocytes which are cells that react angrily to injury and lay down scar tissue amongst other things. This astrocytic response was not expected as they had not observed this in their studies of SCI.

A quick check for other mentions of fish oils and Omega-3 in the meeting abstracts found 25 papers dealing various aspects of Omega-3 action in fields such as Alzheimer’s, Autism, visual development, stroke, pain and drug abuse (including nicotine-craving).

Tapping in to the intelligent cord

The intelligent cord has circuits that independently coordinate and monitor information coming in from the body and generate appropriate outgoing signals to muscles, particularly during actions such as walking. The concept of a so-called “central pattern generator”, or CPGs, has been around for a long time and was demonstrated in animals very convincingly many years ago. It is now accepted that humans have CPGs in regions of the cord involved in walking and rhythmic generators are proposed for other functions as well (see presentation 74.18, for example].

The brain obviously has executive control but this is often lost after SCI resulting in paralysis. But more recent evidence in the lab and clinic suggests with a little local priming these rhythmic functions can be restored to some extent.

One demonstrated way of priming CPGs is with electrical stimulation. This can be achieved in a number of ways but each has its own benefits and drawbacks. Inserting fine electrodes into the cord tissue itself (intraspinal microstimulation – ISMS) offers the potential to more precisely stimulate groups of neurons controlling muscles, the drawback being it is invasive to do so and often requires more accurate placement of multiple stimulating electrodes.  Epidural stimulation, where the surface of the cord is stimulated, is less invasive and entirely feasible due to the fact that epidural stimulation is used routinely for example in pain management. The stimulation is less precise and one might suspect that this would cause uncoordinated stimulation of all muscles but it doesn’t if done at a level just enough to prime but not activate. And an increasing number of labs are looking at stimulation with electrodes placed on the skin – transcutaneous stim – which is obviously the least invasive option but has the real potential to stimulate both incoming (sensory) and out-going (motor) signals.

As you move from ISMS to epidural to transcutaneous stimulation the stimulating energy needed greatly increases. A number of posters I saw today examined these techniques and a couple are worth a mention. PJ Grahn [presentation 74.02] compared results from ISMS and epidural stimulation in a pig model. M Krenn [presentation 74.03] looked at how selective one can be using transcutaneous stimulation as they tried to stimulate the sensory fibres coming up from muscles in the leg to enhance reflexes in humans.

It's not what you do, it's how hard you do it

The poster session today was dominated by all things motor. A paper that caught my eye was presented by K Leech [presentation #74.05]. We accept that rehabilitation has an important part to play in recovery from SCI but how much is optimal and for how long should it be given?

Animal studies have shown that high intensity rehab increases the amount of a neurotrophic factor called brain derived neurotrophic factor, or BDNF, which is associated with improved recovery of stepping. BDNF is a potent promoter of neurite growth, has neuroprotective activity, can enhance plasticity and even give rise to re-myelination (see Weishaupt et al, Exp Neurol, 2012). It is actively being researched as a possible candidate treatment for SCI. Exercise is known to cause changes in BDNF levels in the periphery and in the central nervous system.

Leech’s findings are important because they shed a little light on the possible mechanisms by which BDNF might be beneficially modulated in patients with SCI. Leech and colleagues monitored the level of BDNF in the blood and compared levels after various regimes of rehabilitation exercise. They found that only high-intensity exercise elevated BDNF levels whilst low to moderate levels had no effect. Increasing the duration of moderate exercise didn’t change matters either suggesting that a threshold of intensity is needed for that all important hit of the neurotrophin.

Future studies will look at whether the increase in BDNF is related positively to better outcomes in patients. Interestingly, some patients studied had a common genetic variation which means for them it is harder to achieve elevated BDNF levels and their BDNF response to high-intensity exercise was “blunted”. Such understanding might lead to better rehab regimes tailored to the individual for optimal neurological effect.

It's time for SfN 2013

Welcome to what is the first post from this year's Society for Neuroscience annual meeting, San Diego. It is traditional for me to upload the SfN newest logo so here it is:

Inspired by the work of neuroanatomist and SfN President, Larry Swanson.

The weather is good so let's put that out of my mind and delve into the convention centre for the first main session.


Before I do you might like to check out other bloggers (these ones are "official") or visit the SfN site itself.