Biology Reference
In-Depth Information
limited distance needs to be demonstrated but also the reinnervation of ap-
propriate target neurons. Recently, published studies provide excellent ex-
amples for specific treatment strategies to promote reinnervation of target
neurons (
Alto, Havton, Conner, et al., 2009; Bonner, Connors,
Silverman, et al., 2011
). Moreover, suitable neurophysiologic assessment
tools allow for a specific correlation of observed structural changes with
function (
Bonner et al., 2011
), which is often completely lacking in
rough locomotor assessment measures such as the BBB scale.
Besides vague structural mechanisms, the demonstration of a robust
structural and functional effect is almost always missing. Typically, effect
sizes in terms of functional recovery range in the magnitude of 2-4 BBB
points, which obviously is not sufficient for clinical translation. For example,
a BBB score of 3 is defined as “extensive movements of two joints,” whereas
a BBB score of 7 represents “extensive movements of all three joints of the
hindlimb” (
Basso et al., 1995
). This magnitude of BBB improvement cannot
be considered as being clinically meaningful, leaving aside the fact that an
untrained observer is unable to detect such subtle differences. Therefore,
it is suggested to define a threshold to be reached of at least nine on the
BBB locomotor rating scale (“
...
weight support in stance only
...
or occa-
sional, frequent, consistent weight supported dorsal stepping
...
”). Further,
average improvements of at least 6 BBB points compared to an appropriate
control should be achieved to increase probabilities that the observed im-
provements predict a clinically meaningful difference.
The “robustness” factor also applies to the extent of structural repair.
Looking at the lesioned CST, the smaller subcomponents (ventral and dor-
solateral and lateral), which account for 2.5% (roughly 400 axons) of the
complete CST in rats, allow to compensate for the transected main dorsal
component (roughly 17,000 axons) to restore forelimb reaching function
(
Weidner, Ner, Salimi, et al., 2001
). Therefore, at least 2.5% of a transected
tract system should regenerate to predict meaningful functional improve-
ment in a planned clinical trial. A recent study, which is one of very few
studies fulfilling the “robustness” criterion, demonstrated massive axon out-
growth into the completely transected adult rat spinal cord originating from
embryonic day 14 rat spinal cord (
Lu, Wang, Graham, et al., 2012
). Ideally,
the observed axon regeneration should lead to substantial target rein-
nervation. In a case where axon regeneration is determined as the relevant
mechanism, proper myelination of these axons represents another hurdle to-
ward restored nerve conduction and ultimately functional recovery. As an
example, the unmyelinated state of regenerated axons prohibited restoration
