Why can smells bring memories rushing back?

A sense of rhythm is, it turns out, critical in the brain. And oscillations provide the beat for brain cells to coordinate their activity around, so they are activated at the right time and in the right sequence. And the paper cognitive neuroscientist Duncan Astle's looked at this month is about how our genes control the rhythms with which brain cells communicate with each other...

Duncan - So let's imagine that you've got multiple different rhythms going on at once in an orchestra. And it's really, really crucial that there's some sort of common temporal code that organises all of the activity. And your brain is kind of similar. So imagine you've got different bits of brain, different brain cells in different locations that are communicating with each other and they're going at different rhythms. So if you, if you were to recall from any single cell, you get what's called spiking activity. That's the action potentials, the firing of the neuron. But if you record from little groups of neurons together, you soon find that their activity patterns rise and fall together like waves. And they produce these kinds of oscillations. And the oscillations are an important way of different groups of neurons, different groups of brain cells, communicating with each other.

Katie - That's beautiful. It kind of sounds like we're all innately musical, whether we've got rhythm or not! We're biologically rhythmic!

Duncan - Yeah. The brain is musical inherently in the way it works, I think.

Katie - What kind of science did they do to try and look into this idea of oscillations?

Duncan - It's really hard to measure oscillations in the human brain. Usually we have to measure them from outside the skull and then infer from where they're coming from. But in this study, they identified 16 humans who were about to undergo surgery to remove a part of their brain that's producing epileptic seizure activity. And in the days leading up to the surgery, what they do is they remove the skull and then they lay electrodes directly onto the brain surface, directly onto the cortex around the area that they think might be producing the seizures. And that's so they can monitor the activity and decide which parts of the brain that they should remove.

And in these days leading up to the surgery, the scientists are then able to record directly from the cortex. And in this case, they had the subjects perform a very simple word, learning task, a memory task. So that's how they recorded these neural oscillations.

Duncan - What they were able to do is look at oscillations at different frequencies. And then find across their 16 subjects, which oscillations and in which locations - so from which electrodes they'd placed on the brain - were significantly associated with people's memory performance. And then after the surgery, they're able to take the cortex they'd been recording from and run what's called an RNA transcriptomic analysis. Which is where you essentially find out which genes are highly expressed in that bit of the brain. So what they've got there is two types of data. They've got the electrical recordings recorded whilst the person was awake leading up to their surgery. And then fresh from the surgery, they've got the actual bits of brain themselves that have been removed that they could then identify which genes are highly expressed and where within that bit of cortex.

Duncan - What you can then do is explore which genes seem to be significantly predictive of the oscillation patterns that are predicting memories. So what is it about the gene expression that's significantly associated with the memory-related activity from the brain? And they're able to explore how those two types of data were associated with each other.

Katie - What kind of conclusions can you come to then about different gene expression and I don't know, quality of memory or kind of aspects of memory?

Duncan - So they found that there are about 300 genes that were significantly correlated with memory related oscillations in the bits of brains that they had removed in these subjects. And what they can then do is explore, "What do those genes do in the brain, what's their function?" And that's done using something called a gene enrichment analysis. And so what you're testing is whether these genes are scattered randomly through people's genomes, or whether they're grouped around particular types of biological process. And what they found is these 300 genes are not randomly scattered at all. Instead they're very tightly clustered around different aspects of synaptic function. So synapsis are the little gaps, the neurochemical gaps between brain cells.

And they found that these 300 genes controlled different things to do with people's synapses. So for example, how different types of ion or neurotransmitters are released into the synapse. What they were able to show is that actually these genes are implicated in a whole host of neurodevelopmental disorders. So autism, ADHD, schizophrenia, difficulties in mental health like major depression disorder. What they think they've uncovered isn't really something specific to memory, but a general principle about how synapses are a regulated by our genes and how those different patterns are associated with the oscillations that those brain cells produce.

Katie - 300 genes! That sounds like an awful lot of stuff to investigate. Is it a case in future of narrowing down a bit more over what particular genes do? Or is it more an overall kind of mechanism that is interesting?

Duncan - Yeah, but those 300 genes don't act in isolation. So they really group around five or six different processes. About 50 of them will be to do with how particular neurotransmitters are released into the synapse. So that's one process that variability in say 50 or 60 genes will be associated with. So even though it might sound like a lot of genes, that's actually not that many underlying biological processes.

Katie - How does this gene association fit in with what scientists already understand about -well, I was going to say the mysterious world of memory, but it sounds like there's a lot of other wider contexts that you're talking about.

Duncan - So the really, really exciting thing here is being able to link the gene expression with something to do with people's neurophysiology. So we've known for a long time that you can take people's genomes and see if that predicts whether they have ADHD or if they have schizophrenia, how well they do at school, all sorts of things. But the question is why? Genes don't code for how well you do at school. They code for proteins in your brain. And the answer here is that one possibility is that they code for different processes that control your synapses. And that is how they have their impact on brain activity and thus those longer term outcomes.

Katie - How do you think this needs to be taken forward? Because it's a relatively small group of people that they were looking at.

Duncan - Yeah I agree it's really interesting. Also lots of caveats, as you say it's just 16 people, they all have temporal lobe epilepsy. But one really interesting thing to do is you can take brain cells and grow them in a dish. One thing you could do is by growing brain cells in a dish in what's called a multi-electrode array, you could actually explore the formations of synapses themselves. And of course you can alter the genes in a causal way in that context. And so you'd be able to then take these 300 and start testing, experimentally, the impact that they have on oscillating activity or spiking activity of the neurons in the dish. So there are all sorts of ways that you can take this forward, now we've got some hypotheses about what these 300 genes are doing and why they're important.

Do you ever come across a smell that - when you encounter it - you’re transported back in time to a particular event, or place, or experience? Perceptual psychologist Helen Keyes explained that it’s long been wondered whether the particularly strong link between smell and memory is down to a stronger connection between the part of the brain that processes smell called the olfactory cortex and the hippocampus - the so-called seat of memory in the brain. But the paper Helen’s been looking at is - she says - the first study that’s actually directly looked at the strength of this connection, in comparison to the other senses’ connection to the hippocampus. Here’s Helen...

Helen - This paper used fMRI to look at 25 healthy participants and it did a whole brain analysis. And it looked at the olfactory (so your smell), the somatosensory (your touch), your visual and your auditory systems in the brain. And for each of those systems, the fMRIs looked at the functional connectivity between the hippocampus and those areas. So in other words, when one of those sensory areas of the brain is activated, is the hippocampus also activated at the same time? And they found that the connectivity, so that activation at the same time between the hippocampus and the olfactory cortex, was much stronger and significantly stronger than any other connection with the hippocampus.

The authors followed this up using intracranial EEG. And this is really interesting. This is where there's some surgically implanted electrodes in people's brains. So they just looked at eight participants here who had surgically implanted electrodes, because they also had epilepsy. But the authors took advantage of this. And they looked specifically at what's happening in terms of timing. So they looked at the auditory cortex and the hippocampus, and they also looked at the olfactory cortex and the hippocampus. And they found this significant phase locking. So in other words, and if you're looking at the timing of when something is happening, when an area is activated, that's the phase locking if these two areas are activated at the same time together. And again, they found significant phase locking between the olfactory cortex and hippocampus, but not so significant locking between the auditory cortex and the hippocampus. Again, suggesting that really strong, direct link between the olfactory cortex and the hippocampus where we form our memories.

Katie - In these experiments, was there any stimulus being applied?

Helen - So in each of these experiments, it was resting state. So participants were just breathing normally, not particularly having any one of their senses stimulated. And it's interesting to us that we can observe, even in resting state, this really strong connection or activation at the same time between these brain areas.

In our evolutionary past, at some stage at some mammals, including humans, developed a neocortex or cortex. So this part of our brain that was distinct from this base primal animal brain. So our hippocampus sits in our real base primal part of our brain, but the rest of our brain, our cortex, when that evolved many of our other senses, so sight and hearing and touch rerouted to those newer parts of the brain, the cortex, that allowed us a species to engage in real cognitive flexibility and abstract representation. So this was a real leap forward for us, for humans. But smell didn't follow the other senses. It stayed deeply rooted in this primal animal brain, right beside the hippocampus.

Katie - That's so interesting. Is this a well-recognised evolutionary path, or is this something that the scientists of this, the authors of this paper are kind of theorising about? Do we know if this is the case?

Helen - We know that the olfactory cortex is located right beside the hippocampus. So we've known there's this integration, this almost physical integration, they're very close to each other. But what this paper has shown is that the other areas, the other senses, haven't got this real direct connection or this activity that's as in sync with the hippocampus as the olfactory cortex. So it could be a possibility - before this study we didn't know if these are the senses, so for example, sight. That could have had a really strong connection with the hippocampus, just via an association cortex via another part of the brain. But this really shows that actually, no, we can directly see that there's a much stronger functional link between the olfactory cortex and the hippocampus compared to any other sense.

Katie - This strong functional link - do you think there's any potential of things working in the other direction? If someone loses their sense of smell, would that have any impact on the way they remember things?

Helen - I think this is a really interesting question and it's going to become more and more important. So there's lots of research done on people who lose their sense of smell. And that research nearly always shows that a loss of a sense of smell can be linked with depression and in general, a poorer quality of life. So we already know that losing your sense of smell gives you, you know, less pleasurable experiences. You don't experience food in the same way, for example. But there is a suggestion perhaps that if your sense of smell is so linked with formation of memories, you're also going to be losing out on that lovely connection on that reminiscence or that ease that you feel often when you get that flood of memory that you associate with a smell. So it's very much understudied at the moment, but will potentially become more and more studied as we're looking at the effects of long COVID for example, with people losing their sense of smell. And what this might mean for them to lose that connection between smell and memory.

Katie - But what you're not saying is that if one loses one's sense of smell, one isn't going to be able to make memories in the same way.

Helen - Oh, absolutely not. It wouldn't be necessary to have a sense of smell to make memories in any way. It's just that they're so connected that those memories and those smells tend to be more integrated. That's all it is.