Brain waves and what they mean for people with Angelman Syndrome (AS)

With ongoing and upcoming trials, there is a palpable excitement with the potential that our loved ones with AS might receive a treatment that dramatically improves their symptoms. Incorporated into the language used to describe the trials and the corresponding advances in therapeutic science are terms like, “disease-modifying” and “profound change”. Hearing these only increases the hope that we might see quick advancements and progressions for those with AS and that they will be receiving their long-awaited chance. Our hopes are high.

This exuberance should be tempered with a recognition that change takes time. Different studies in AS mice and rats have revealed that changes obtained from therapeutics can be seen very quickly. However, we should recognize that, aside from the obvious, mice and rats develop much more quickly than humans; a 3-to-6 month old mouse is equivalent to a 20-to-30 year old human^[1], so when we test a rodent for symptom improvement (also known as behavior rescue) 8 weeks after a therapeutic is given, that would be equivalent to tests being done decades after the treatment in a human. We need to think about this as we set our expectations.

What does this mean for those with AS? How quickly can we expect to see significant results from the potential treatments that are being developed for humans? The answer is probably quite a bit longer than we all want, and we might need to be patient while maintaining the hope and optimism that a difference can occur. 

Let’s frame the reasoning behind this. Neurotypical children take years to go through the sequence of their developmental stages. While much of these changes can be visibly observed, other methods, like electroencephalograms (EEGs) can quantify and confirm these changes. This is why EEGs are great biomarkers for AS and, arguably, they are one of the most objective biomarkers that we currently have. This is supported by clinicians and industry partners working together through the Angelman syndrome Biomarker and Outcome Measure Consortium (ABOM).

What is an EEG? When neurons in the brain send signals to each other, they create electric waves. These waves move in speed cycles per second and are measured as Hertz (Hz), which can be measured on an EEG. Most of us know EEGs as the tool we use to identify and understand seizures, but they also hold the potential to help AS researchers identify changes brought on by therapeutics as the different power of brain waves can be measured, and they each represent different things.

To understand the science of EEGs, let’s delve into the science of brain waves. Brain waves are divided into 5 main bands:

• Delta 1-4Hz: Delta waves are the slowest type and are mainly seen while sleeping in neurotypical brains.
• Theta 4-10Hz: Theta waves are necessary for REM sleep and infants spend most of their time in this frequency. Theta is important for imagination and creativity.
• Alpha 8-12Hz: Alpha waves are important for working memory and cognitive performance.
• Beta 12-30Hz: Neurotypical adults that are engaged in mental activity show beta waves starting at 14Hz.
• Gamma >30Hz: Gamma waves can be seen during focused attention and motor task execution. They facilitate neuronal communication and efficient cognitive processing.

Looking in more detail we find that at different developmental stages, different brain waves dominate the background.^[2]

• Neurotypical newborn babies: 3-4Hz  frequency (delta)
• 6 months: 4-5Hz (theta)
• 12 months: 5-7Hz (theta)
• 3 years: 8Hz (alpha)

People with AS usually show distinct delta activity on their EEG with a higher delta power compared to their neurotypical peers. This is measurable and consistent in AS. A 2021 study associated EEG abnormality with symptom severity in AS.^[3] Another 2021 study showed that delta power robustly predicts cognitive function in AS.^[4] With age, those with AS may progress to the theta range but it is rare for them to reach alpha. Yet this is where we need to be in order to maximize learning. Moreover, 2-4Hz delta power is seen at almost double the amount in people with AS compared to neurotypical 4-8 year old children.^[5]

Younger neurotypical children have more pronounced theta. Neurotypical children at the age of 6-7 years usually show an EEG frequency range of 8-9Hz. 9-11 year-old children that speak clear complex sentences are characterized by alpha rhythm expression in the EEG patterns. The age at which children learn to read is closely linked to their level of speech development.

Beyond just reaching optimal EEG frequencies, scientists have shown that the patterns behind these waveforms matter. One study managed to link the asymmetry pattern of alpha and beta waves between the left and right side of the brain to intelligence levels in neurotypical adults.^[6] Low IQ levels were shown among those with brain activity that was left dominant, whereas medium IQ levels were right balanced. Those with measured high IQ showed right dominant alpha activity and left dominant beta activity. Another study shows that neurotypical infants show a right hemisphere dominance of synaptogenesis (the formation of synapses) in the first year.^[7] The hope could be that successful therapeutics should be able to show changes in EEG that reflect less asymmetry over time.

A recent study confirms that the EEG frequencies increasing over time in neurotypical children mirrors synaptogenesis and myelination (a neuronal cellular process that improves the transmission speed of neural information along neural fibers).^[8] Myelination is key for normal motor function, sensory function, and cognition. Studies have also shown that both synaptogenesis and myelination are negatively affected by AS, both of which we would like to see change with a meaningful and effective therapeutic. Yet, synaptogenesis and myelination take time. These are physical processes that do not happen overnight. In neurotypical children synaptogenesis takes years. 

To be more specific, synaptogenesis does not happen in all the different areas of the brain at the same time. Studies have confirmed that synaptogenesis in areas of speech production does not happen before 7-8 months and continues until 4 years of age in neurotypical children.^[9] 

For therapeutics that claim to improve brain function, we need to have objective measures, or biomarkers, that can capture this change, which we expect could happen well before we see symptomatic improvement. EEG could be this biomarker with improvements to brain waves progressing closer and closer to normal. There, we can observe how the Hz frequency increases over time and moves towards these neurotypical ranges. A 2022 study developed an EEG model based on human natural history data and looked at ube3a levels of mice treated with ASO to develop a model that would allow for delta power to function as a mechanistic biomarker for potential treatments.^[10] We also need to consider trials for clinical improvement to be longer than 12 weeks if we want to give any potential therapeutic a chance to show major clinical change. This could come far after the biomarker change.

More and more, a consensus is building - AS is a disease for which meaningful therapeutics are possible. We remain resolute in our quest for these treatments and recognize that when they come, the changes in our loved ones can and will happen. But we observe this process is complex and we should expect it could be lengthy. Rome was not built in a day and the neuronal changes will take time as well. We are ready.

Authors: Isabel Orellana, Evelin Dietrich, David Gurzick, Ph.D., April 2022

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