FMRI correlates of olfactory processing in typically-developing school-aged children

Highlights

• Olfactory fMRI activation is robust in school-aged children.

• Our respiratory-synchronized odor stimulation task is fast and clinically feasible.

• Olfactory fMRI activation reflects individual differences in ability to detect odors.

Abstract

Human olfactory processing is understudied relative to other sensory modalities, despite its links to neurodevelopmental and neurodegenerative disorders. To address this limitation, we developed a fast, robust fMRI odor paradigm that is appropriate for all ages and levels of cognitive functioning. To test this approach, thirty-four typically developing children aged 7–12 underwent fMRI during brief, repeated exposure to phenylethyl alcohol, a flower-scented odor. Prior to fMRI scanning, olfactory testing (odor detection and identification) was conducted. During fMRI stimulus presentation, odorant release was synchronized to each participant's inspiratory phase to ensure participants were inhaling during the odorant exposure. Between group differences and correlations between activation and odor detection threshold scores were tested using the FMRIB Software Library. Results demonstrated that our 2-min paradigm significantly activated primary and secondary olfactory regions. In addition, a significant relationship between odor detection threshold and higher activation in the right amygdala and lower activation in the left frontal, insular, occipital, and cerebellar regions was observed, suggesting that this approach is sensitive to individual differences in olfactory processing. These findings demonstrate the feasibility of studying olfactory function in children using brain imaging techniques.

Introduction

Relationships observed between olfactory dysfunction and both neurological and psychiatric disorders support the importance of understanding the neural correlates of olfactory function. Olfactory dysfunction has been linked to brain-based disorders that emerge across the life span, including depression (Croy et al., 2014, Pause et al., 2001), autism spectrum disorder (Hilton et al., 2010), schizophrenia (Moberg et al., 1999, Woodberry et al., 2010), Parkinson's Disease (Doty, 2007, Iannilli et al., 2017), and dementia (Atanasova et al., 2008, Murphy et al., 1990). Despite these links to neurological and psychiatric disorders both in children and adults, imaging research to elucidate the developmental patterns of olfactory processing has been limited relative to other sensory systems (Wang et al., 2014).

Functional magnetic resonance imaging (fMRI) is increasingly being leveraged in developmental research to assess how neural functioning during childhood and adolescence relates to psychiatric disorders (e.g., Daivs, 2006, Dapretto et al., 2006, Forbes et al., 2006, Levitin et al., 2003), developmental stage (Pruett et al., 2015) and to improve diagnosis (e.g., Emerson et al., 2017, Luking et al., 2011, Philipsen, 2006). FMRI research focused on brain regions involved in olfaction can potentially help to bridge gaps in our knowledge of the role abnormal olfactory processing plays in the etiology of neurodevelopmental disorders. Few studies, however, have used fMRI to study olfaction at specific developmental stages during childhood. This, in part, may reflect the combined methodological challenges of obtaining strong, and robust Blood Oxygen Level Dependent (BOLD) signal response to olfactory stimulation and the difficulties of conducting imaging studies on children. Research on olfactory perception must manage the technical challenges linked to rapid habituation or desensitization to odorants (Poellinger et al., 2001, Sobel et al., 2000), which can rapidly decrease the strength of the BOLD signal response. Further, aside from physiological differences, children exhibit greater head motion (Power et al., 2014), and may experience greater anxiety during the protocol than adults; thus, acclimation to the scanning environment and head motion training is critical to success of the study (Davidson et al., 2003). Moreover, researchers must develop tasks that are suited for the cognitive abilities and attention span of a younger sample (Davidson et al., 2003).

The current study describes an experimental design that demonstrates the feasibility of obtaining robust fMRI responses to an olfactory stimulus from a sample of typically developing school-aged children from 7 to 12 years of age. Activation targets included the primary olfactory cortex (POC), comprising of a set of integrated brain regions (piriform cortex, periamygdalaloid region, anterior and posterior nuclei, nucleus of the lateral olfactory tract, the medial nucleus and the entorhinal cortex) with direct input from the olfactory bulb that detect, identify, and evaluate odors (Gottfried and Zald, 2005, Iannilli et al., 2013, Mori and Sakano, 2011) and secondary olfactory cortex (SOC), which is comprised of brain regions that do not receive direct input from the olfactory bulb (lateral orbital frontal cortex [OFC], medial OFC, insular cortex, hippocampus, lateral nucleus of the amygdala, and the thalamus) but are involved in higher-order odor-related processing, such as behavior regulation, reward processing, memory, and emotional response (de Olmos et al., 1978, Gottfried and Zald, 2005, Martinez-Marcos, 2009). The experimental procedure employed an olfactometer that can deliver discrete and quantifiable olfactory stimuli, a short fMRI protocol that is both suitable for imaging children and limits the potential of rapid habituation to olfactory stimuli, and individualized timing of odorant release to maximize the effect of the stimulus. We additionally investigated whether there was a relationship between patterns of brain activation to the odorant stimuli and participant's olfactory detection threshold measured using the Sniffin’ Sticks task (Hummel et al., 2007, Hummel et al., 1997), which quantitatively assessed the concentration at which a person can identify the presence of an odorant. Odor detection is dependent on the intact functioning of olfactory receptors, the olfactory bulb, and POC. Thus, we predicted robust activation within the POC and SOC in response to the odorant stimuli, and that a lower odor detection threshold would be associated with increased activation within the POC.