BY MARIA BURKE | 16 FEBRUARY 2024
Smell is the only one of our senses with a direct connection to the brain, explaining why a particular smell has the power to evoke a memory or emotion. But could improving our sense of smell also improve memory and cognition? Maria Burke reports.
About a fifth of the general population has an impaired sense of smell, including roughly 5% with little or no ability to smell. Our sense of smell can be damaged or lost for multiple reasons – eg due to aging, upper respiratory tract infection, sinonasal disease and head trauma. Significantly, researchers have shown that losing the sense of smell is often linked to a decline in cognitive abilities[1]. If the loss of smell continues, patients can go on to develop mild cognitive impairment (MCI). Impaired smell also precedes or parallels the onset of a variety of conditions, including both Alzheimer’s and Parkinson’s diseases. Around 95% of patients with these two conditions suffer from olfactory disorders that often appear 10 to 15 years before other symptoms.
However, olfactory enrichment or training – where people are exposed daily to multiple odours – can improve the sense of smell in people with olfactory loss. This has been shown in ageing patients and in those who have experienced infections and head trauma. The effect is boosted by increasing the duration of exposure and the concentration of the odorants.
Mehmet Mahmut of Macquarie University, Sydney, Australia, and Florian Uecker of Charité-Universitätsmedizin Berlin, Germany, report that immersive exposure to a large number of odorants over a relatively short period is enough improve the sense of smell[2]. In their study, odorants were dispersed throughout a room and participants sniffed the air around them. The team tested 25 patients with various olfactory dysfunctions using 72 odorants. Each was presented for five seconds. Sessions lasted just over 20 minutes and took place for 14 consecutive days.
‘We found that six weeks after the odorant exposure sessions, 44% of participants demonstrated a clinically significant improvement in olfactory function, which dropped to 28% 25 weeks after the odorant exposure sessions,’ they write. ‘Preliminary findings suggest that odorant exposure exercises need not be restricted to smelling odorants from jars for a minimum of three months. [Short-term exposure to] both indoor and outdoor environments provide various odorants that can cocoon one’s entire body.’ They believe the improvements may be because conscious processing of odorants and memory triggers cognitive operations in the brain.
Smell and cognition
Image: CAIA Image / Science Photo Library
When we smell, odour molecules enter our nose and interact with olfactory receptors creating an electrical signal. This signal is transmitted to the brain for processing. The sense of smell – also called the olfactory system – has a direct connection to the brain, specifically to the limbic system, a complex set of structures involved in emotion, motivation, memory and behaviour.
As well as restoring the sense of smell, research is focusing on whether olfactory enrichment may provide a relatively straightforward, effective way to improve brain health and boost cognitive abilities and memory. The olfactory system’s unique access to the brain’s learning and memory systems suggests it could be used to prevent - or even reverse - cognitive decline by activating neural pathways.
In 2023, a team at the University of California, Irvine, US (UCI) [3], reported that inhaling fragrance at night improved cognitive performance in men and women aged 60 to 85. People in the study group, who were not suffering from memory impairment, were exposed to seven different smells/week, one/night, for two hours over six months. The study group’s performance in a word memory test was 226% better than the control group. What’s more, imaging revealed better structural integrity in the brain pathway called the left uncinate fasciculus. This pathway, which connects the medial temporal lobe to the decision-making prefrontal cortex, becomes less robust with age. Participants also reported sleeping more soundly.
‘The olfactory sense has the special privilege of being directly connected to the brain’s memory circuits,’ says Michael Yassa, a neurobiologist at UCI. ‘All the other senses are routed first through the thalamus. Everyone has experienced how powerful aromas are in evoking recollections, even from very long ago. However, unlike with vision changes that we treat with glasses and hearing aids for hearing impairment, there has been no intervention for the loss of smell.’
Next, the UCI team want to study the technique’s impact on people with diagnosed cognitive loss with the aim of devising a non-invasive technique for strengthening memory and potentially deterring dementia. The researchers also hope the finding will lead to more investigations into olfactory therapies for memory impairment.
Other studies have shown that olfactory training may be an effective approach for improving dementia symptoms. Hyegyeong Cha and colleagues at Soonchunhyang University School of Medicine, in Seoul, South Korea, exposed 34 people to 40 fragrances twice/day for 15 days. The patients showed significant improvements in depression, attention and memory and language functions, compared with the control group[4].
‘The reality is that over the age of 60, the olfactory sense and cognition starts to fall off a cliff,’ says Michael Leon, Professor of neurobiology and behaviour at UCI. ‘But it’s not realistic to think people with cognitive impairment could open, sniff and close 80 odorant bottles daily. This would be difficult even for those without dementia.’ That’s why he thinks the type of sensory enrichment used in the UCI study may be particularly useful, as it is low cost as well as low effort.
Other researchers are also studying smaller numbers of odorants with dementia patients. For example, Anna Oleszkiewicz of Technischen Universitäten (TU) Dresden, Germany and her colleagues at the University of Wroclaw, Poland, exposed 68 older adults with dementia either to nine odorants twice/day or to no new olfactory stimulation, for 3-6 months. The team found the enriched olfactory experience produced significant improvements in cognitive abilities, compared with the control group[5]. They also found that olfactory-enriched participants showed no increase in dementia symptoms over the course of the trial, while control participants did.
Brain changes
When a person’s sense of smell is stimulated, it seems changes in the brain can occur. In one study, Pengfei Han and colleagues at TU Dresden observed older adults for seven months who were exposed to four odorants twice/day. Patients were better at identifying odours than the control group and, significantly, had larger volumes of grey matter in the brain[6]. Grey matter plays a key role in processing information, governing muscle control, sensory perception and decision-making.
In another study, Antje Haehner and colleagues also at TU Dresden followed 37 patients with MCI over four months of olfactory training with odours introduced twice/day[7]. After the training, the patients were better at discriminating between odours, and imaging revealed an increased cortical thickness of the hippocampus, the region of the brain associated primarily with memory. The team also observed increased thickness of the entorhinal cortex (which acts like a hub for smell, memory, navigation, and the perception of time) and the medial temporal lobe (important in memory processing).
Both these changes were linked to improvements in global cognition - the set of skills involved in processing, storing and retrieving information. Specifically, thickening of the entorhinal cortex was linked to improved executive function, the cognitive processes and mental skills that help an individual plan, monitor and successfully execute goals.
The researchers conclude olfactory training could be used as an early intervention to prevent hippocampal atrophy, a shrinking of the hippocampus that is a common feature of Alzheimer’s. This structure in the brain plays a vital role in forming and retrieving memories, spatial navigation, and emotional responses, and is involved in learning, cognition, and memory formation.
During the pandemic, smell loss became a characteristic sign of Covid 19. And it could linger: one study found that 55% of long Covid sufferers reported continued loss of smell[8].
Now researchers from the University of Oxford, UK, have found changes to parts of the brain linked to smell in patients who had contracted even mild infection[9]. The study involved 785 participants aged 51–81 who underwent two brain scans. Around 400 tested positive between their two scans. Almost five months after infection, Gwenaëlle Douaud and colleagues observed a greater reduction in grey matter thickness in the regions of the brain associated with smell (the orbitofrontal cortex and parahippocampal gyrus). There was also evidence of greater tissue damage in regions connected with the primary olfactory cortex, an area linked to smell, and a reduction in whole brain size.
‘These participants also showed greater decline in their mental abilities to perform complex tasks, and this mental worsening was partly related to these brain abnormalities,’ says Douaud. ‘All these negative effects were more marked at older ages. A key question is to see if this brain tissue damage resolves over the longer term.’ These findings may be the hallmarks of the degenerative spread of Covid 19, she says, either via pathways related to the sense of smell, inflammation or immune response of the nervous system, or a lack of sensory input owing to a loss of smell.
Meanwhile, Johannes Frasnelli of the Université du Québec à Trois-Rivières, Canada, has looked at how the brains of sommelier students change over the course of their training as they are exposed to dozens of novel odorants each day. His team used MRI to image their brains at the start and end of their 18-month training and compared them with a control group. In the 17 sommelier students, they found increased volume in the olfactory bulb, a structure located under the frontal lobe of the brain which receives input directly from olfactory cells and plays a critical role in processing smell[10]. They also observed the thickness of the right entorhinal cortex increased. There were no significant changes in control group brains.
‘The regions of the brain affected are not just associated with the sense of smell; they are also responsible for emotion, memory, reward and learning,’ Frasnelli says. ‘We don’t know yet if this means that smell training will have consequences on these functions. If so, it might be possible to protect the brain with smell training, for example, to protect against depression or memory loss.’
Early detection
Frasnelli has also been studying the link between smell disorder and Parkinson’s, and believes, in the long term, it could help detect the disease several years before the onset of motor symptoms[11]. ‘We’ve known for a while now that the vast majority of people (90-95%) with Parkinson’s and Alzheimer’s also have a strongly impaired sense of smell. Usually, this happens ten to 15 years before other symptoms develop and diagnosis. However, not everyone who loses their sense of smell will go on to develop the diseases. We have confirmed there is a specific profile of chemosensory impairment specific to Parkinson’s that could potentially be used as a screening tool.’
Unlike the other senses – sight, hearing, touch – which respond to physical stimuli, the chemical senses are stimulated by molecules present, for example, in food and perfume. These are the senses of smell, taste and the ‘trigeminal system’, a complex nerve system connecting the face and head to the brain using the oral and nasal passages.
‘The trigeminal system conveys, for example, the spiciness of peppers or the freshness of peppermint, and its signals are processed differently in the brain,’ Frasnelli explains. ‘It is independent but closely connected to the sense of smell. Normally, when there is a reduction in the sense of smell, there is also a reduction in the trigeminal system. However, we have confirmed that in Parkinson’s, while the sense of smell is reduced, the trigeminal system is not, and we are looking into why this happens.’
It’s not known yet whether this profile is also common to dementia patients, but Frasnelli says that patients do show a distinct pattern when it comes to olfactory tasks such as perceiving, distinguishing and identifying smells. ‘In Parkinson’s patients, all tasks are impaired to the same level but, in Alzheimer’s patients, recognition and identification of smells are much more strongly impaired, which is not surprising as they are linked to memory. These effects occur ten years before other symptoms. We are currently studying people with a high risk of developing dementia and with MCI to see if there is a pattern in the subclinical stages that could be used to indicate which people go on to develop dementia.’
References
1. J. S. Choi et al, Int. Forum Allergy & Rhinology, 2018, 8, 648.
2. M. K. Mahmut et al, J. Sensory Studies, 2020, 35, e12559.
3. C. C. Woo et al, Front. Neurosci., doi: 10.3389/fnins.2023.1200448.
4. H. Cha et al, Geriatrics & Gerontology Int., 2022, 22, 5.
5. A. Oleszkiewicz et al, Eur. Arch. Oto-Rhino-Laryngology, 2022, 279, 225.
6. P. Han et al, I-perception, 2021, doi:10.1177/20416695211005811
7. A. Haehner et al, J. Alzheimers Dis., 2022, 88, 743.
8. E. L. Graham et al, Annals Clin. Transl. Neurology, 2021, 8, 1073.
9. G. Douaud et al, Nature, 2022, 604, 697.
10. G. Filiz et al, Human Brain Mapping, 2022, 43, 2621.
11. C. Tremblay, J. Frasnelli, Chem. Senses., 2021, 46, bjab018.
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