Brain signals for drug screening

There are still comparatively few therapies for brain diseases. This is partly due to the difficulty in developing new drugs, because the effects and side effects of a substance on the Brain are not so easy to detect. Standard in drug research are behavioral studies on rodents. In these studies, researchers give the animals a new active ingredient and document their behavioral patterns. These studies are important, but they are unsuitable for the search for new active ingredients in high-throughput screening. In this procedure, which is used in the pharmaceutical industry among others, tens of thousands of substances are tested in parallel. This is not possible with behavioral observations on rodents.

Mehmet Fatih Yanik, professor at the Laboratory of Neurotechnology, has therefore developed a new test model with an international working group. This allows the effects and side effects of several substances to be studied simultaneously and in large numbers. The researchers report on this in the scientific journal Nature Communications.

Looked into the brain

"The brain is made up of highly complex, interconnected structures that communicate with each other in multilayered ways," explains Yanik, a physicist and engineer. In humans, these signals can be derived from the surface of the skull. Information from many nerve cells is combined to form a brain waveform, the electroencephalogram (EEG). Doctors use these wave patterns to analyze sleep, detect diseases such as epilepsy, or test the effectiveness of drugs. In the early development of new active substances against brain diseases, a comparable tool has been lacking until now.

Yanik and his team therefore looked for a way to read out and analyze brain activity using electrophysiological signals. Using zebrafish larvae as a model organism, they found what they were looking for. The almost transparent larvae are tiny with a body length of two millimeters. This makes it possible to study many of them in parallel. The researchers placed the larvae in a gel in thin glass tubes so that they did not move for the duration of the experiment. Using this trick, the researchers were able to attach the electrodes for deriving the electrical brain signals directly to the larvae's brains: This enables them to read out the information directly where it is generated.

Epilepsy triggers recreated

In their experiments, the scientists used larvae that have a mutation at the SCN1A gene. In humans, this mutation is coupled with various forms of childhood epilepsy such as Dravet syndrome. Children with Dravet syndrome experience severe epileptic seizures as early as the first year of life and often have delayed mental development. The seizures are difficult to treat with medication and can be triggered by light, among other things.

Yanik and his team have now demonstrated the same sensitivity to light in larvae with the SCN1A gene mutation. In the experiment, the researchers exposed the larvae to flashes of light and recorded the electrical signals originating from the intercellular spaces of nearby neurons. In principle, this is like sitting in a telephone exchange and eavesdropping on the communications of the surrounding phones. The researchers used a newly developed algorithm to evaluate the signals from the brain. "In our experiments on the larvae with genetic defects, we found the typical signals that occur during seizures. This was not the case in the healthy larvae," Yanik reports.

Healthy diversity in the brain

While multilayered local brain activity patterns were recorded in the healthy zebrafish larvae, these were much simpler in nature in the larvae with genetic defects. This corresponds to observations in humans, according to which brain waves in patients with Parkinson's or schizophrenia are less complex. The more multilayered nerve cells communicate with each other, the healthier the brain seems to be.

If it were now possible to increase the complexity of brain signals with active substances and define this as a therapeutic goal, we would finally have a measurement parameter directly from the brain to evaluate the effects and side effects of chemical substances, Yanik is convinced. That would be a major advance in drug research.

Text: ETH