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Brain training — If you can get the brain to produce EPO by giving it less oxygen, it can help people with memory or concentration problems. This is often an extra complication in psychiatric disorders. New project could be groundbreaking, says professor.
There are no good drugs presently available for people with psychiatric disorders who suffer from memory or concentration problems.
Approximately half of all patients with bipolar disorder or depression develop lasting cognitive difficulties that can lead to difficulties solving tasks in their daily life or in the workplace.
The treatment options are currently few and far between in these cases. But a new research project at the Department of Psychology at the University of Copenhagen may be able to do something about it.
There are strong indications that artificial altitude training combined with the simultaneous performance of different cognitive training tasks can increase the brain’s ability to remember or concentrate.
»Our project can be groundbreaking in developing new treatment methods in relation to cognitive difficulties that we are not yet able to treat using medicine or cognitive training alone,« says Professor of Cognitive Neuropsychiatry Kamilla Miskowiak, Department of Psychology.
She and her team have received DKK 15 million from the European Research Council to conduct research into the effect of artificial altitude training on cognitive functions in the brain in connection with a five-year project called ‘Altitude-like hypoxia cognition training to target brain erythropoietin as a novel mechanism of long-lasting enhancement of neuroplasticity and cognitive functions’.
Depression leads to 6,700 extra deaths in Denmark every year. It also costs society DKK 10 billion in treatment and more than DKK 25 billion in lost production due to absence from the labour market and premature death. So apart from the human suffering, there are good reasons to try to find new ways to treat the side effects.
In a Danish context, and according to the Danish Psychiatry Foundation lobby, up to 100,000 people get bipolar disorder during the course of their lives, with 300,000 to 375,000 people currently being affected by depression. So there are some large patient groups out there.
Attempts have been made to help patients with memory or concentration problems in connection with bipolar disorder or depression for many years. But Kamilla Miskowiak’s project is the first in the world to expose them to oxygen-deficient air and at the same time train them cognitively over an extended period of time.
In a series of experiments, Kamilla Miskowiak hopes to be able to stimulate the brains of a group of a total of 180 test subjects, of which 120 are part of a control group of healthy people, with the remaining 60 having bipolar disorder or depression.
The mental training they have to carry out consists of solving cognitive training tasks on an iPad for a large part of their time inside an altitude chamber that has been built indoors at the Department of Psychology. The test subjects are to stay in it for 3.5 hours a day for three weeks.
Research on animal models and on people over the past 20 years has shown that EPO has a beneficial effect on the brain.
This is how it works
EPO increases the activity of, and volume of, the hippocampus in the brain, which is an area associated with memory.
When scientists, in experiments, block EPO and EPO receptors in the brains of rodents, the animals’ develop an unusual or morbid nervous system.
Experiments indicate that the brain needs EPO to prevent damage to the brain and to function, and researchers have seen the same effects in experiments with healthy people and people with depression.
The experiment’s website is here.
EPO is a hormone that can also be artificially manufactured. Manufactured EPO was approved as a medicinal product in 1989. It is probably mostly known from the world of cycling, because it was revealed that many professional cyclists injected it as blood doping to increase the number of blood cells that can absorb oxygen.
EPO, however, is produced in both the kidneys and in the brain, and in the brain it plays a key role in helping protect brain cells and strengthening their interconnections.
And the production of EPO increases in the brain when humans are at high altitude where the oxygen content in the air is lower. It is the beneficial effects of this treatment that Kamilla Miskowiak is investigating in an altitude chamber, where the oxygen percentage is down at 12 per cent — the equivalent of standing at the top of the highest mountain in Europe, Mont Blanc, at 4,400 metres. The oxygen content at sea level is 21 per cent.
Researchers have attempted to dose people artificially with EPO who have memory or concentration problems. But this has turned out to have serious side effects from the method of treatment. In practice it has therefore not turned out to be suitable as a drug for everyone. This is why Kamilla Miskowiak is trying to find a new way of stimulating the brain’s own production of EPO.
Kamilla Miskowiak has been interested in using EPO to treat neurological diseases and cognitive difficulties since she, as a psychology student in 2001, read an article in the Danish science weekly Ugeskrift for Læger about how EPO reduced the extent of physical brain damage in animal models.
»Back then, I thought it would be incredibly interesting to also investigate whether rats improved their cognitive performance. No one had ever looked at it before, but something interested me based on my background in psychology,« says Kamilla Miskowiak.
She did an experiment in which she gave EPO to rats who had sustained hippocampus injuries, an area in the brain that is crucial to memory. The experiments showed that EPO improved learning and memory in the rats.
In 2023, she has now built up a series of experiments in her, and her team’s, altitude chamber for humans. This time, the experiments are based on some experiments in mice, which have revealed that less oxygen in the air over a period of three weeks strengthened the formation of brain cells as well as the cognitive abilities of mice.
»There is, of course, some distance from mice to humans, and we cannot just conclude that our project will work. But there are some indications that there is a growth of new brain cells, and that new compounds are created in the brain – and that the brain’s own EPO production is central to these beneficial effects of a lowered oxygen level,« says Kamilla Miskowiak.
Kamilla Miskowiak compares the use of the altitude chamber to what happens in a fitness centre, and compares the brain to a muscle.
»The combination of oxygen-deficient air and cognitive training with an effect on the brain is equivalent to exposing the body to mild stress. This is just like at a fitness centre, when athletes can train under lower oxygen conditions, say via oxygen masks,« says Kamilla Miskowiak. The artificial altitude training has a significant positive effect on muscle structure compared to training without oxygen masks.
»I think that it is pretty much the same for the brain when we expose it to a mild oxygen deficiency in combination with some cognitive training assignments or mental gymnastics,« says Kamilla Miskowiak.
In the first couple of sessions, being in the altitude chamber can make people tired and give them a light headache. But according to Kamilla Miskowiak’s hypothesis, a session in the height chamber along with cognitive training on the iPads over an extended period of time leads to a strengthening of the brain cells’ interconnections and a maturation of the brain’s stem cells.
The hope is that this will produce a beneficial effect on the brains of both the 60 patients and the 120 healthy test subjects.
The first test subjects are already taking part in the study, with two teams a day in the altitude chamber. But the participants need to be physically healthy for safety reasons, so Kamilla Miskowiak spent a lot of time finding a sufficient number of suitable test subjects.
In three years time, when the data from the experiment has been processed, Kamilla Miskowiak and her colleagues will be able to say something with more confidence on whether oxygen-deficiency in combination with cognitive training supports the regeneration of the brain. They will also examine whether healthy volunteers will also improve their brain function and their cognitive skills.
The big question is therefore whether a ‘mild stressor’ such as low levels of oxygen in an altitude chamber in combination with cognitive training can strengthen the brain’s natural production of EPO and whether this leads to cognitive improvements.
If this is the case, Kamilla Miskowiak and her team can do follow-up experiments to find out how they maintain this effect. Do patients, for example, need to turn up for treatment once every fortnight, or are there other less expensive ways to achieve a lasting effect?
»Even if it works, we still have a lot of work to do before we can alleviate the frequent cognitive difficulties that people with psychiatric disorders have,« says Kamilla Miskowiak.