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.