Discussion
The main aim of this study was to assess the neural activation in
patients with olfactory dysfunction after pituitary surgery, before and
after olfactory training. We showed that compared to healthy controls,
the patient group had fewer activation areas. After 12 weeks of
olfactory training in the treatment group, we not only achieved a
significant improvement in the olfactory identification test, but also
showed an increase in activation areas compared to the no-treatment
group.
Plasticity for visual and auditory senses has been widely studied over
the past years, with reports of neural reorganization processes after
functional loss(11). For the olfactory sense, recent studies have shown
a similar phenomenon, which translates into structural and functional
alterations of brain structures(11,19). Although the mechanism that
explains plasticity and neurogenesis of the olfactory sense is still
unclear, both clinical and basic research has shown that it is a highly
plastic system that could be influenced by both bottom-up and top-down
processes that could induce continuous neurogenesis(20).
Previous studies have demonstrated that olfactory training can partially
restore olfactory function due to multiple etiologies(6,7,20). Our
results also show olfactory improvement in smell identification and an
increase in activation areas, but specifically in post-surgical etiology
patients. The treatment group presented new activation areas after
olfactory training, recovering some connections that are also present in
healthy subjects, like the orbitofrontal cortex and some areas in the
cerebellum. Even though these are not classical olfactory areas, both of
them have been reported to be involved in smell perception, especially
the cerebellum. Several neuroimaging studies have found odorant-induced
activation of the cerebellum, being a significant player in odor
recognition and discrimination(19). It is possible to infer that
surgical trauma damages olfactory epithelium, causing sensory afferent
information loss, which subsequently induces a central olfactory network
reorganization. This could be associated with the decreased number of
activation areas described by Kollndorfer et al(8,11). The therapeutic
effects of olfactory training could be attributed to several factors.
One of them could be a bottom-up modulation that consists of a repeated
exposure of the patient´s olfactory epithelium to different essential
oils, hence producing an increase in afferent olfactory inputs.
Additionally, when we combine this with a top-down modulation task, like
asking the patient to associate the smell with a memory or feeling, we
can evoke and activate other brain areas linked to the sense of
smell(21,22). Another factor to have in consideration is the indemnity
of the trigeminal pathway. Trigeminal perception is independent from
olfactory processing, given that it is due to a specific interaction
between chemicals and trigeminal chemoreceptors(23). However, almost all
odorants also stimulate the trigeminal system in addition to the
olfactory system, at least in higher concentrations(23). Consequently,
the olfactory and trigeminal systems interact intimately and work
together in the perception of an odorant(23). Additionally, Kollndorfer
et al. also suggested the intact trigeminal pathway may trigger
olfactory function recovery after olfactory training. In our study, at
the initial evaluation, all of our patients showed trigeminal related
areas activation, such as the precentral gyrus, brainstem, insula, and
pars triangularis, which could suggest pathway indemnity(10).
A limitation of this study is the small sample size of six patients with
olfactory dysfunction who completed all measurements. Even though our
study had statistically significant findings and raised the possibility
that olfactory training could induce neuroplasticity processes and
improve olfactory identification, larger scale randomized control trials
(RCT) are needed to confirm these findings. Another limitation is the
lack of a placebo group, because in our study one of the groups did not
receive any intervention. This issue has been reported by other authors,
citing that odorless training jars are usually detected by the patients
or relatives resulting in intervention abandonment(6). Damm et al. faced
this matter by using a high-odor olfactory training group, and a
low-odor olfactory training group to better control the placebo
effect(7). Nonetheless, in our study the low-odor stimulation could have
triggered neural reorganization processes; thus, we used no stimulation.
On the other hand, the use of “Sniffing Sticks Screening Test” could
be considered a limitation, due to the fact that we are only able to
assess odor identification with this instrument. To date, this is the
only validated olfactory performance test in our country, and several
other studies have also assessed olfactory function using the same
tool(13,14,16,24). Additionally, Lawton et al. calculated and published
a conversion table between the 12 Sniffing screening test and the
extended 16 Sniffing identification test(17). After this conversion’s
application, a six-point difference in the score was observed between
the before and after olfactory assessment in the treatment group. This
result is particularly important because, according to Gudziol et al.,
TDI score changes greater than 5,5 points are considered clinically
significant(25). Since TDI scores are composed of 3 subtests
(identification, discrimination, and threshold), a change in 6 points in
one of them will result in a clinically significant change in two of our
subjects.