Covid-19 and the brain: what researchers already know, what they still don't know

Patients who can no longer follow the thread of a conversation, for whom watching an entire film proves impossible, or who get lost on the way to their work… Many patients suffering from Covid long report symptoms cognitive impairments on a daily basis, primarily with difficulty concentrating and loss of memory. According to a study published in January 2022, infected people are also more at risk of developing anxiety or depression in the months following their infection. So many disorders for which the link with the virus still remains mysterious.

While some scientists attribute these manifestations at least in part to psychosomatic causes, others are continuing investigations to better understand the possible effects of Sars-CoV-2 infection on the brain. In the absence of certainties, all hypotheses remain open. Moreover, they do not turn out to be incompatible, as the ailments described vary from one person to another. “The mechanisms are probably not the same. We should speak of ‘long Covid’ in the plural”, confirms Dr Olivier Robineau, infectious disease specialist at Tourcoing hospital.

In France, teams from the Institut Pasteur were the first, in 2021, to show that the virus could have a tropism for the central nervous system. A possible gateway: the nose, where sit sensory neurons that send information to the brain about the smells that surround us.

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“Initially, this was not a very orthodox view, because the first publications had shown that the cellular receptor used by the virus to infect us was not present in the olfactory neurons. In reality, as we showed , the coronavirus first passes through other cells to infect the sensory neurons of the nasal cavity, the extensions of which go into our brain”, recalls Professor Pierre-Marie Lledo, head of the “perception and memory” unit. from the Pasteur Institute. But will the virus actually then travel inside the brain? Pasteur’s teams have shown, with experiments carried out on hamsters, that, in these animals at least, this would indeed be the case.

Increase the risk of developing dementia

Is it the same with humans? In the most serious forms of Covid-19, it seems so, but by another route: blood circulation. Another French team, led by Vincent Prévot (Inserm, University and University Hospital of Lille) provided proof of this in a study published in October in the journal nature neuroscience.

“We were able to study the brains of several people who died from Covid and we discovered that, in these patients, the virus had attacked the endothelial cells which form the blood-brain barrier [NDLR : qui isole, entre autre, le système nerveux central de la circulation sanguine]”, explains the researcher. With two major consequences: a temporary rupture of this barrier, causing microhemorrhages, then a decrease in blood flow where the vessels are no longer functional.

But these people with very severe forms do not say anything about what is happening – or not – in subjects who have presented a less serious form of the disease. To find out more, Vincent Prévot’s team therefore also relied on studies on hamsters, which only show minor forms of the disease. “At the peak of the infection, we see that cerebral vessels are attacked. But this situation seems reversible, because a month after the infection, we no longer find any lesions”, he explains. Good news ? Not so sure, according to this scientist: “If the same phenomena take place in humans, they could create fragilities, cause cognitive problems, or even increase the risk of developing dementia in the future.”

However, these first works on animals are not enough to demonstrate with certainty a biological link between a mild infection and cognitive disorders or psychiatric illnesses such as depression or anxiety. Scientists will therefore continue their research. At the Institut Pasteur, Prof. Lledo’s team will work with anosmic patients – who have lost their sense of smell – followed in the ENT department of the Lariboisière hospital in Paris.

“We will look for the presence of the virus in their olfactory epithelium [NDLR : une muqueuse de la cavité nasale] and, in parallel, we will look by electroencephalogram if we find particular electrical signatures in the brain which could be the consequence of the presence of the virus or of inflammatory responses. And, of course, we will also see if there can be any correlations with possible memory loss or mood disorders.

Resolving the debate on the origin of the symptoms

Still at the Institut Pasteur, another team will explore “the causal and mechanistic links between infection, loss of smell and anxiety-depression syndrome”, explains Hervé Bourhy, who heads the unit. “Lyssavirus, epidemiology and neuropathology”. To do this, these scientists will look, on “mini-brains” – cell cultures of neurons, astrocytes and microglia, here in two dimensions – if the virus can infect neurons and trigger immunological and inflammatory disorders.

“At the same time, we will continue animal tests, with behavioral experiments to see if exposure to the virus alone is enough to cause anxiety and depression symptoms”, specifies Guilherme Dias de Melo, researcher in the same unit. Work that could even make it possible to settle the debate on the origin of the symptoms of the patients: “These animals do not present psychosomatic disorders and do not go to intensive care, which is a known risk factor for anxiety and depression. direct link with the virus will, if necessary, be easier to establish”, indicates Hervé Bourhy.

Other scientists have taken a different course: observing the brains of patients suffering from long Covid. Eric Guedj, head of the nuclear medicine department at the Timone hospital in Marseille (Assistance publique- Hôpitaux de Marseille), is one of the French experts in molecular imaging in neurological and psychiatric diseases. “From April 2020, we started to see rather young patients arriving who presented the same symptoms – cognitive disorders, exhaustion, residual shortness of breath -, we thought that these symptoms could be explained by brain damage”, is he remembers.

The first examinations, MRI and scanner, do not show any abnormalities. On the other hand, another device, the PET-scan, which measures the metabolism of glucose brings to light “hypometabolism”. “This reflects a decrease in brain activity, particularly in the olfactory bulb and in regions connected to it, such as limbic regions related to memory, the brainstem, which controls the autonomous functioning of breathing or sleep. , and, finally, the cerebellum, which plays a role in motor skills and balance”, explains the doctor, who also observes that the more patients have severe symptoms, the more this network appears to be altered.

His observations so far relate to a small number of patients. They seem to be confirmed by a British study in pre-publication: “MRIs carried out before and after infection in individuals suffering from ‘Covid long’ show that the same areas show atrophy”, specifies Professor Guedj.

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Unfortunately, this work does not reveal any explanations for the damage identified. “These lead us to believe that these are indeed organic lesions, but we do not know the viral, inflammatory or vascular mechanism”, recognizes Eric Guedj. Research is continuing to better understand the origin of the ailments from which patients suffer. An emergency, even if the current care, based on physical rehabilitation and behavioral therapy, already allows some of them to see their condition improve.