Dissecting loneliness in the brain

Neural ‘signature’ may reflect how we respond to feelings of social isolation

THIS holiday season will be a lonely one for many people as social distancing due to Covid-19 continues, and it is important to understand how isolation affects our health. A new study shows a sort of signature in the brains of lonely people that make them distinct in fundamental ways, based on variations in the volume of different brain regions as well as based on how those regions communicate with one another across brain networks.
A team of researchers examined the magnetic resonance imaging (MRI) data, genetics and psychological self-assessments of approximately 40,000 middle-aged and older adults who volunteered to have their information included in the UK Biobank: an open-access database available to health scientists around the world. They then compared the MRI data of participants who reported often feeling lonely with those who did not.
The researchers found several differences in the brains of lonely people. These brain manifestations were centred on what is called the default network: a set of brain regions involved in inner thoughts such as reminiscing, future planning, imagining and thinking about others. Researchers found the default networks of lonely people were more strongly wired together and surprisingly, their grey matter volume in regions of the default network was greater. Loneliness also correlated with differences in the fornix: a bundle of nerve fibres that carries signals from the hippocampus to the default network. In lonely people, the structure of this fibre tract was better preserved.
We use the default network when remembering the past, envisioning the future or thinking about a hypothetical present. The fact the structure and function of this network is positively associated with loneliness may be because lonely people are more likely to use imagination, memories of the past or hopes for the future to overcome their social isolation.
“In the absence of desired social experiences, lonely individuals may be biased towards internally-directed thoughts such as reminiscing or imagining social experiences. We know these cognitive abilities are mediated by the default network brain regions,” says Nathan Spreng from The Neuro (Montreal Neurological Institute-Hospital) of McGill University, and the study’s lead author. “So this heightened focus on self-reflection, and possibly imagined social experiences, would naturally engage the memory-based functions of the default network.”
Loneliness is increasingly being recognised as a major health problem, and previous studies have shown older people who experience loneliness have a higher risk of cognitive decline and dementia. Understanding how loneliness manifests itself in the brain could be key to preventing neurological disease and developing better treatments.
“We are just beginning to understand the impact of loneliness on the brain. Expanding our knowledge in this area will help us to better appreciate the urgency of reducing loneliness in today’s society,” says Danilo Bzdok, a researcher at The Neuro and the Quebec Artificial Intelligence Institute, and the study’s senior author.
This study was published in the journal Nature Communications on Dec 15, 2020. It was partially funded by a grant to Spreng and Bzdok from the U.S. National Institute on Aging. –Science Daily

What makes us human

WITH only 1 per cent difference, the human and chimpanzee protein-coding genomes are remarkably similar. Understanding the biological features that make us human is part of a fascinating and intensely debated line of research.
Researchers at the SIB Swiss Institute of Bioinformatics and the University of Lausanne have developed a new approach to pinpoint, for the first time, adaptive human-specific changes in the way genes are regulated in the brain.
These results open new perspectives in the study of human evolution, developmental biology and neurosciences.
The paper is published in Science Advances.
Gene expression, not gene sequence
To explain what sets human apart from their ape relatives, researchers have long hypothesized that it is not so much the DNA sequence, but rather the regulation of the genes (i.e. when, where and how strongly the gene is expressed), that plays the key role. However, precisely pinpointing the regulatory elements which act as ‘gene dimmers’ and are positively selected is a challenging task that has thus far defeated researchers (see box).
Marc Robinson-Rechavi, Group Leader at SIB and study co-author says: “To be able to answer such tantalizing questions, one has to be able identify the parts in the genome that have been under so called ‘positive’ selection [see box]. The answer is of great interest in addressing evolutionary questions, but also, ultimately, could help biomedical research as it offers a mechanistic view of how genes function.”

A high proportion of the regulatory elements in the human brain have been positively selected
Researchers at SIB and the University of Lausanne have developed a new method which has enabled them to identify a large set of gene regulatory regions in the brain, selected throughout human evolution. Jialin Liu, Postdoctoral researcher and lead author of the study explains: “We show for the first time that the human brain has experienced a particularly high level of positive selection, as compared to the stomach or heart for instance. This is exciting, because we now have a way to identify genomic regions that might have contributed to the evolution of our cognitive abilities!”
To reach their conclusions, the two researchers combined machine learning models with experimental data on how strongly proteins involved in gene regulation bind to their regulatory sequences in different tissues, and then performed evolutionary comparisons between human, chimpanzee and gorilla. “We now know which are the positively selected regions controlling gene expression in the human brain. And the more we learn about the genes they are controlling, the more complete our understanding of cognition and evolution, and the more scope there will be to act on that understanding,” concludes Marc Robinson-Rechavi.
Positive selection: a hint of the functional relevance of a mutation
Most random genetic mutations neither benefit nor harm an organism: they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common ancestor. In contrast, an acceleration in that rate in a particular part of the genome can reflect a positive selection for a mutation that helps an organism to survive and reproduce, which makes the mutation more likely to be passed on to future generations. Gene regulatory elements are often only a few nucleotides long, which makes estimating their acceleration rate particularly difficult from a statistical point of view. – Science Daily

Covid-19 variant: What is known

THE rapid spread of a new variant of coronavirus has been blamed for the introduction of strict tier four mixing rules for millions of people, harsher restrictions on mixing at Christmas in England, Scotland and Wales, and other countries placing the UK on a travel ban.
The government’s advisers on new infections have “moderate” confidence that it is more able to transmit than other variants.
All the work is at an early stage, contains huge uncertainties and a long list of unanswered questions.
Why is this variant causing concern?
Three things are coming together that mean it is attracting atten tion:
• It is rapidly replacing other versions of the virus
• It has mutations that affect part of the virus likely to be important
• Some of those mutations have already been shown in the lab to increase the ability of the virus to infect cells
All of these come together to build a case for a virus that can spread more easily.
However, we do not have absolute certainty. New strains can become more common simply by being in the right place at the right time – such as London, which had only tier two restrictions until recently.
But already the justification for tier four restrictions is in part to reduce the spread of the variant.
“Laboratory experiments are required, but do you want to wait weeks or months [to see the results and take action to limit the spread]? Probably not in these circumstances,” Prof Nick Loman, from the Covid-19 Genomics UK Consortium, said.
How much faster is it spreading?
It was first detected in September. In November around a quarter of cases in London were the new variant. This reached nearly two-thirds of cases in mid-December.
You can see how the variant has come to dominate the results of testing in some centres such as the Milton Keynes Lighthouse Laboratory.
You can see how the variant has come to dominate the results of testing in some centres such as the Milton Keynes Lighthouse Laboratory.
Mathematicians have been running the numbers on the spread of different variants in an attempt to calculate how much of an edge this one might have.
But teasing apart what is due to people’s behaviour and what is due to the virus is hard.
The figure mentioned by Prime Minister Boris Johnson was that the variant may be up to 70 per cent more transmissible. He said this may be increasing the R number – which indicates if an epidemic is growing or shrinking – by 0.4.
That 70 per cent number appeared in a presentation by Dr Erik Volz, from Imperial College London, last Friday.
During the talk he said: “It is really too early to tell… but from what we see so far it is growing very quickly, it is growing faster than [a previous variant] ever grew, but it is important to keep an eye on this.”
There is no “nailed on” figure for how much more infectious the variant may be. Scientists, whose work is not yet public, have told me figures both much higher and much lower than 70 per cent.
But there remain questions about whether it is any more infectious at all.
“The amount of evidence in the public domain is woefully inadequate to draw strong or firm opinions on whether the virus has truly increased transmission,” said Prof Jonathan Ball, a virologist at the University of Nottingham.
How far has it spread?
It is thought the variant either emerged in a patient in the UK or has been imported from a country with a lower ability to monitor coronavirus mutations.
The variant can be found across the UK, except Northern Ireland, but it is heavily concentrated in London, the South East and eastern England. Cases elsewhere in the country do not seem to have taken off.
Data from Nextstrain, which has been monitoring the genetic codes of the viral samples around the world, suggest cases in Denmark and Australia have come from the UK. The Netherlands has also reported cases.
A similar variant that has emerged in South Africa shares some of the same mutations, but appears to be unrelated to this one.
Has this happened before?
The virus that was first detected in Wuhan, China, is not the same one you will find in most corners of the world.
The D614G mutation emerged in Europe in February and became the globally dominant form of the virus.
Another, called A222V, spread across Europe and was linked to people’s summer holidays in Spain.
What do we know about the new mutations?
An initial analysis of the new variant has been published and identifies 17 potentially important alterations.
There have been changes to the spike protein – this is the key the virus uses to unlock the doorway to our body’s cells.
One mutation called N501Y alters the most important part of the spike, known as the “receptor-binding domain”.
This is where the spike makes first contact with the surface of our body’s cells. Any changes that make it easier for the virus to get inside are likely to give it an edge.
“It looks and smells like an important adaptation,” said Prof Loman.
The other mutation – a H69/V70 deletion, in which a small part of the spike is removed – has emerged several times before, including famously in infected mink.
Work by Prof Ravi Gupta at the University of Cambridge has suggested this mutation increases infectivity two-fold in lab experiments.
Studies by the same group suggest the deletion makes antibodies from the blood of survivors less effective at attacking the virus.
“It is rapidly increasing, that’s what has worried government, we are worried, most scientists are worried,” Gupta said. –BBC