In a recent study, a group at the University of Florida reported that they had detected an asymmetry in smell detection in people with Alzheimer’s Disease that differentiated them from people in the control groups. Could Alzheimer’s Disease lead to subtle differences in smell sensation?
The first thing to note is that it seems like quite an unusual result. After all why would smell detection in the left nostril be affected? To those less familiar with smell research these results might trigger associations with other research looking at forced left nostril breathing. Yes that’s right – there has been a lot of research into forced unilateral nasal breathing.
Part of this line of inquiry relates to Yoga. Within Yoga there are breathing techniques known as Chandra Nadi Pranayama (left nostril breathing) and Surya Nadi Pranayama (right nostril breathing). There has been a good deal of medical research into the effects of Yogic breathing techniques (e.g. see here, here, here, here, here, here, here, here, here and here).
There has also been a lot of research into the direct relationship between unilateral nostril breathing and autonomic physiology including intraocular physiology (e.g. see here, here, here, here and here), the effects on activity in the cerebral hemispheres (see here, here and here) as well as cognition (e.g. see here, and here) and emotion (e.g see here).
An intriguing piece of research from 1978 looked at unilateral nostril breathing during sleep and reported reverse patterns in narcolepsy and the control group using thermoelements. However I couldn’t find a replication study. There has also been the suggestion of a nasal cycle whereby the efficiency of breathing through the nostrils changes periodically through the day. In the above I am not commenting on the strengths and weaknesses of the above research but rather drawing the readers attention to the fact that there is an abundance of research in this area.
The Above Research As A Distraction
All of this though is a distraction because what this study is really about is smell. In the Neurological examination the cranial nerves are tested including the first Cranial nerve – the Olfactory nerve. Typically this will involve a smell challenge with the patient identifying the smell. There are however some variations in practice as highlighted in the selection of articles here, here, here, here, here, here and here. Although standardised scratch cards are mentioned in some cases there is no explicit mention of the distance of the smell stimulus that I could find.
The Genius of Standardisation
Even forgetting about the results, what is really interesting in the study discussed here is the standardisation of a smell test. A specified mass of Peanut Butter is used and the distance from the nostril at which the smell is detected is measured. This second step is transformative. Indeed the author notes that she sat in on some clinics where the neurological examination was being undertaken. This triggered the idea for her research.
The Olfactory System
There is a good summary of Olfaction in this paper which details the anatomy of the Olfactory System beginning with the olfactory epithelium around the middle and superior turbinates in the nasal cavity. From here the smell information is transmitted through the olfactory and Trigeminal nerves to the Olfactory Bulbs.
The Olfactory Bulbs
The olfactory bulbs are visualised in the above diagram and lie underneath the frontal lobes. The olfactory bulbs are required for smell. For instance when the olfactory bulbs are calcified, people can develop hyposmia (reduced smell) as in this case series. Researchers have drawn analogies between the olfactory system and other sensory modalities. Using such an analogy one group have suggested that the Olfactory Bulbs are analogous to the Retina. In this paper, researchers suggest that the Olfactory Bulbs are where smells are initially represented whereas perception occurs in the Cortex.
The Olfactory Bulbs lie on the Cribriform Plate as shown in the diagram above. The Crista Galli partitions the Cribriform Plate and the Olfactory Bulbs lie on either side.
Projections of the Olfactory Bulbs
As per the paper reference above, the Olfactory Bulbs project to the Central Olfactory Cortex (Piriform Cortex, Olfactory Nucleus/Tubercle, Amygdala and Entorhinal Cortex) as well as the Secondary Olfactory Areas (Hippocampus, Hypothalamus, Thalamus, Orbitofrontal Cortex and Cerebellum) where olfactory perception is thought to occur.
Asymmetry of the Olfactory Apparatus
The Olfactory System appears to display asymmetry. Researchers in this study looked at the anatomy of the skull in 111 people and found that just over 8% of people showed a significant asymmetry in the Olfactory fossa which is a proxy marker for the structure of the Olfactory apparatus. Although there is a scant research in this area there is some support for the suggestion that there can be an asymmetry in the Olfactory anatomy in a minority of people.
The researchers were interested in the difference between the left and right nostril sensitivity as the null hypothesis stated that there would be an asymmetry in sensitivity.
Researchers looked at four groups of subjects
- People with Alzheimer’s Disease
- People with other forms of Dementia
- People with Mild Cognitive Impairment
- Matched Controls
The researchers administered the peanut butter test. Subjects covered one nostril and the peanut butter was moved closer to the open nostril until the smell was detected. The researchers recorded this distance.
The researchers then undertook the following analysis
- An analysis of variance (ANOVA) was used to examine the mean difference in distance for each nostrils between groups
- The mean, standard error and 95% confidence interval for the difference in distance for detection between nostrils was calculated for each group
The researchers found that
- The left nostril detection distance was significantly less in the subjects with Alzheimer’s Disease than in the other groups (F(3,90) 22.28, p<0.0001)
- The mean, standard error and 95% CI for the L-R nostril difference in the Alzheimer’s Disease group was −12.4±0.5, (−15.0,−9.8).
- Interestingly although the MCI and control groups Confidence interval crossed zero, the other Dementia group showed a reversal of the nostril asymmetry compared to the Alzheimer’s Disease group (4.8±1.0, (2.6,6.9))
The researchers have concluded that the asymmetry detected in subjects with Alzheimer’s Disease in this study may form the basis for a cheap test to aid in diagnosis. In my opinion these results are extremely interesting and like all good science raise more questions. A fundamental question is whether the routine physical examination undertaken for over 160 years should be amended to include this smell test in assessment of the cranial nerves. If these findings are replicated then it would be sensible to investigate this asymmetry in other conditions.
However there is some caution. This was a small pilot study and these new findings would benefit from replication given their potential importance. The researchers have undertaken multiple comparisons (e.g. left nostril sensitivity between groups and right v left sensitivity differences within groups). Also if validated, this test would be a diagnostic aid which could be used with other components of the clinical assessment.
In my opinion therefore these results are potentially very exciting but these findings need to be replicated.
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