To smell or not to smell: does the newborn habituate to sustained odorant stimulation?
Frédéric Grouiller1, Alexandra Adam-Darqué2, Russia Ha-Vinh Leuchter2, Petra S Hüppi2, and François Lazeyras1

1Department of Radiology and Medical Informatics, University of Geneva, Geneva, Switzerland, 2Division of Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland

Synopsis

The aim of this study is to better characterize the habituation effect of sustained odorant stimulation and to investigate if this effect is already present in newborns. Olfactory fMRI was acquired in adults and newborns using a 20s block design. After modelling habituation, activations in the primary and secondary olfactory cortices were observed in adults and newborns. Habituation effect to sustained odorant stimulation was strong in adults but unseen in the newborns. This study shows that the olfactory cortex of newborns is highly functional soon after birth and that the habituation effect is not observed in newborns compared to adults.

Purpose

Fast habituation effect following prolonged presentation of odorants is observed in adults. However, this habituation phenomenon of the olfactory system is not fully understood. The olfactory system is one of the first sensory systems to be functional during fetal life and has a high behavioral importance following birth1. Olfactory fMRI is considered to be challenging due to (i) strong orbito-frontal signal loss, (ii) fast habituation of the olfactory system to prolonged activation2,3 and (iii) complex spatio-temporal dynamics of the olfactory system4. The aim of this study is to better characterize habituation effect of sustained odorant stimulation and to investigate if this effect is already present in newborns.

Methods

Acquisition. fMRI was acquired at 3T (Siemens Trio, Erlangen, Germany) during olfactory stimulation in 11 healthy volunteers (6 women; median age: 29.6 years, range: 25-43 years) and in 28 full-term newborns (mean gestational age=39.5 weeks) using respectively a 12-channel head-receive coil and an 8-channel neohead coil (LMT medical systems, Lübeck, Germany). Neonates were tested in their first week of life, during natural sleep or while resting quietly, without any sedation. Functional images were obtained using a single-shot T2*-weighted GE-EPI sequence (TR=1800ms, TE=25ms, 30 slices, voxel size=2.2x2.2x3.5mm3). In adults, a B0 field-map was acquired to correct geometric distortions induced by local magnetic field inhomogeneities. A high-resolution 3D-T1 (MPRAGE, voxel size=1x1x1mm3) or a T2-weighted (113 coronal slices, voxel size=0.78x0.78x1.2mm3) images were also acquired respectively in adults and infants for anatomical reference.

Stimulations. Three different odorants (banana, cabbage and eucalyptol) were delivered using a home-made four-way odorant delivery system. Each odorant was presented in a pseudo-randomized order during 20 seconds and separated with a neutral odor (water). Two runs of 10’30 minutes including five repetitions of each odorant were acquired for each participant.

fMRI preprocessing. Functional images were pre-processed with SPM8 and included: realignment and unwarping, slice-timing correction, coregistration on the structural image, normalization to MNI space or to a T2 neonatal template (voxel size=2x2x2 mm3) and spatial smoothing using an isotropic Gaussian kernel of 8mm (adults) or 6mm (infants).

Habituation modelling. Habituation h(t) was modelled as a decreasing exponential $$$h(t)=e^{-\frac{t}{\tau}}$$$ where the time constant $$$\tau$$$ varies from 0.05s to 1000s with 21 different values sampled exponentially. We also modelled the cases of no habituation ($$$\tau\rightarrow+\infty, h(t)=1$$$) or immediate habituation ($$$\tau\rightarrow0, h(t)=\delta$$$ where $$$\delta$$$ stands for the Dirac function). The 20-second bloc stimulation is then weighted by these habituation functions and convolved by the canonical hemodynamic response function (Figure 1).

First-level analyses. For each subject and each $$$\tau$$$, a General Linear Model (GLM) was built including a regressor for each odorant. To accommodate the high level of motion in infants, images with framewise displacement superior to 1mm as well as the previous image and the two following images were excluded5 and sessions including at least one stimulation block of each odorant were built with the remaining images. Motion parameters were included into the model as covariates and low-frequencies were removed using a discrete cosine transform basis set with a filter cut-off period of 256s.

Second-level analyses. For each different habituation model and for each odorant, a second level analysis was performed using a random-effect GLM analyses in which the inputs are the contrast maps obtained during the first-level analysis. For each odorant, combined activation maps were built using the different habituation models.

Habituation maps. For each odorant, a habituation map was built by extracting optimal habituation parameter ($$$\tau$$$) for each voxel considered significantly activated (p<0.005).

Results

Whereas no significant activation were detected in adults without modelling habituation (p<0.001, uncorrected), we obtained activation of bilateral piriform cortex, amygdala and parahippocampal gyrus (primary olfactory cortex), bilateral fronto-orbital cortex (secondary olfactory cortex) and bilateral insula after modelling habituation (Figure 2). The corresponding habituation maps for the different odorants show a very fast habituation in adults (Figure 3). In newborns, we observed activations in piriform cortex, orbitofrontal cortex and anterior cingulate cortex. However, contrary to adults, the habituation effect during the 20-second sustained stimulation was not observed (Figure 4).

Discussion & Conclusion

Activations in the primary and secondary olfactory cortices were observed both in adults and newborns. Habituation effect of sustained odorant stimulation was strong in adults, but was not present in newborns in the tested time-period even if it was previously demonstrated after repetitive stimulations6. This absence of habituation to sustained stimulation may be explained by the immaturity of inhibitory system at this age7. This study shows that the olfactory cortex of newborns is highly functional soon after birth and that the habituation effect of sustained stimulation is negligible compared to adults.

Acknowledgements

This work was supported by the Centre for Biomedical Imaging (CIBM) of the Universities and Hospitals of Geneva and Lausanne, and the EPFL.

References

1 Winberg J. et al. Olfaction and human neonatal behaviour: clinical implications. Acta Paediatrica 87(1), 6-10 (1998).

2 Poellinger A. et al. Activation and Habituation in Olfaction – An fMRI study. NeuroImage 13(4), 547-560 (2001).

3 Sobel N. et al. Time Course of Odorant-Induced Activation in the Human Olfactory Cortex. Journal of Neurophysiology 83(1), 537-551 (2000).

4 Lascano A.M. et al. Spatio-temporal dynamics of olfactory processing in the human brain: an event-related source imaging study. Neuroscience 167(3), 700-708 (2010).

5 Power J.D. et al. Methods to detect, characterize, and remove motion artifact in resting state fMRI. NeuroImage 84, 320-341 (2014).

6 Engen T. et al. Decrement and recovery of responses to olfactory stimuli in the human neonate. Journal of Comparative and Physiological Psychology 59(2), 312–316 (1965).

7 Ben-Ari Y. Excitatory actions of gaba during development: the nature of the nurture. Nature Reviews Neuroscience 3(9), 728-739 (2002).

Figures

Deformable model of BOLD response to a 20 seconds olfactory stimulation ($$$\tau$$$=0s to 500s).

Group fMRI activation (p<0.001) for all odorants in adults for different habituation time constants: $$$\tau=0s$$$ (event-related, immediate habituation), $$$\tau=1s$$$ (moderate habituation), $$$\tau=7.5s$$$ (slow habituation) and $$$\tau\rightarrow\infty$$$ (no habituation).

Habituation maps in adults for all odorants, eucalyptol, banana and cabbage. For the activated voxel (p<0.005), color represents the optimal habituation time constant. Blue indicates fast habituation whereas red indicates slow habituation.

Habituation maps in newborns for all odorants. Activations in piriform cortex (primary olfactory), inferior frontal cortex (secondary olfactory) and anterior cingulate cortex (ACC) have been detected (p<0.005). Color represents the optimal habituation time constant $$$\tau$$$ for each activated voxel. Blue indicates fast habituation whereas red indicates slow habituation.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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