Featured Lendület Member: András Attila Horváth

András Attila Horváth and his research team will investigate the relationship between cortical hyperexcitability and cognitive decline. Cognitive decline essentially refers to the loss or weakening of thinking abilities, so it includes a range of mental functions from numeracy and literacy to drawing and abstraction and speech and behaviour. Cognitive abilities can be impaired by many neurological disorders. Some of these diseases have a neurological background, such as dementia-related diseases (e.g. Alzheimer’s disease), while others are psychiatric in origin, such as autism spectrum disorders or attention deficit hyperactivity disorder (ADHD), which most often appear in childhood but can persist into adulthood.

András Attila Horváth

There are many causes of cognitive decline, and the Momentum research group is focusing on one of these little-studied factors, cortical hyperexcitability. This involves the firing of cortical neurons at a higher intensity, where they mobilise more energy than is optimal to maintain the network system.

The link between Alzheimer’s disease and epilepsy

“We started investigating the association between cortical hyperexcitability and cognitive decline ten years ago, in 2013. At that time, we launched the National Brain Research Programme, in which we looked at the relationship between Alzheimer’s disease and epilepsy (epilepsy is associated with cortical hyperexcitability),” says Horváth.

“Our research at the time demonstrated a strong two-way relationship between them: on the one hand, epilepsy is more common amongst people with Alzheimer’s disease, and on the other, epilepsy of unknown origin amongst the elderly is often a sign of incipient Alzheimer’s disease.”

After this realisation, researchers began to wonder why these two phenomena might be related. One question is why nerve cells respond to damage by increasing activity (firing), and how this increased firing changes the overall structure of the brain and causes cognitive impairment. Around the turn of the millennium, it was noticed in animal models that epileptic dysfunction associated with Alzheimer’s disease also appears in the brains of experimental animals, even before cognitive symptoms. Then they began to look for this connection in humans. Horváth and his colleagues were among the first in Europe to demonstrate this link in humans using a large number of data points.

Although the correlation was confirmed, the mechanism was not known. What does the dysfunction resulting from the excessive firing of nerve cells in the cerebral cortex change? This has been the subject of much research since then, but to date we do not know exactly why the link exists. The new Momentum research will investigate this pathomechanism. Researchers are trying to understand

what changes in the brain occur when a patient’s cortical neurons are overactive.

Theories and questions

“We will be looking at three main concepts, three theories that explain the relationship, all of which are supported by experimental data,” says the team leader. “One theory is that pathological proteins well known in Alzheimer’s disease, such as amyloid and tau, are able to accumulate more when neuronal activity increases and are then released from neurons in synapses in greater quantities. This is not easy to study in humans. We will monitor patients’ brain activity at night with an EEG and look for signs of excessive nerve cell activity. We will then compare the amount and intensity of the overactivity events with the concentration of abnormal proteins that can be detected in the patients’ blood. In this way, we will investigate whether there is a link between the circadian rhythm of the abnormal proteins and the hyperactivity of the cortex.”

The second theory is based on the idea that optimal memory processes require memory consolidation during sleep, that is, information learned during the day is recorded at night, while different regions of the brain are synchronously activated and communicate with each other. According to the hypothesis, if there is a pathological malfunction in the brain, the synchronisation necessary for memory consolidation is disrupted. Horváth says this has an effect on brain function similar to that caused by an electrical impulse in a healthy heart rhythm. Here the impulse is the abnormal surge of excessive neuronal activity that sweeps through the brain and desynchronises brain activity. This makes the memory trace (engram) less able to consolidate, causing learning disabilities. Learning disabilities are a major symptom of Alzheimer’s disease, autism and ADHD. The researchers hope that the Momentum study will help them to better understand what causes this learning disorder and that the results may lead to the identification of a new therapeutic target. They will map the impact of this abnormal discharge sequence on brain networks.

But why do nerve cells fire more in old age? Epilepsy often occurs amongst the young, which may be because the disease is linked to neuronal developmental disorders, but it also often occurs amongst the elderly; it is associated with the abnormal firing patterns of nerve cells. One theory on why this happens is that once neurodegenerative processes have started, the patient often has no symptoms for decades, but the release of abnormal proteins causes functional changes in the brain. One such deviation is the appearance of an abnormal firing pattern. Because of this, this phenomenon can be a precursor of several neurological diseases, that is, it can be used in early diagnosis. Another theory is that even minimal changes in cerebral circulation can also trigger abnormalities in the metabolism of neurons, which respond by increasing firing.

Circular effect

“It seems that the whole process forms a vicious circle: if neurons fire excessively, changes are triggered in the brain that cause neurons to fire even more,” says Horváth. “As this self-excitatory process intensifies, various neurological diseases and cognitive symptoms appear.”

If we knew the mechanism of this circular effect, we might be able to use the abnormal firing pattern as a biomarker. In other words, we could use it to assess whether or not the intervention (e.g. medication) was effective. The treatment of cognitive complaints caused by neurological disorders is often difficult because it is still very difficult to link them to biological patterns, and thus objective information on efficacy is not available. One of the outcomes of the Momentum research

may be the discovery of measurable phenomena which show how drugs work in individuals. On the other hand, if the whole process of cognitive decline is explored and its steps and milestones are identified, new attack points could be found that could be treated with available drugs.