Tescogen (Oct 2022)

Alzheimer’s disease

Every 3 seconds someone in the world is diagnosed with Alzheimer’s disease, the most common form of dementia. More than 50 million people live with dementia today. That number is expected to keep increasing dramatically as long as there are no ways to prevent, halt or cure the disease.

Dementia is a major cause of disability in the elderly, leading to high costs to society. As the majority of

people with dementia live at home, the disease also has a severe impact on the lives of their caregivers, which are usually close relatives.

Today, the global annual socio-economic costs for dementia care are estimated at US$ 1 trillion (Alzheimer’s Disease International). These staggering costs are predicted to bankrupt healthcare systems –unless we act now to halt the dementia pandemic.

The challenge

For various reasons, drug development for Alzheimer’s disease has had a notoriously high failure rate. One of the major contributions is the current lack of techniques to screen people at risk, diagnose the early stages of the disease and start treatments before irreversible damage has occurred.

Increasing scientific evidence suggests that modulating the activity of nerve cells (neuromodulation) by brain stimulation can offer an alternative therapeutic approach. We know that the electrical activity of several important brain networks, including the hippocampus, is disturbed in Alzheimer’s disease. This is what causes the typical cognitive problems like memory loss, as well as behavioral symptoms.

From preclinical studies in animal models, we know that electrical stimulation can preserve nerve cells (neurons), boost the renewal of neurons from stem cells, and enhance the formation of new connections (synapses) between cells in brain regions involved in cognition. Altogether, these effects have the potential to counteract or at least slow down neurodegeneration.

Yet a major hurdle remains to be overcome: today we have no appropriate, minimally invasive method available to specifically stimulate those cognitive brain regions that are affected in Alzheimer’s disease. Existing deep brain stimulation (DBS) methods are invasive: they require a surgery whereby a hole is drilled in the skull so that electrodes can be implanted deeply into the brain. Because the surgery carries a significant risk of complications, it is usually only used as a last-resort intervention for patients who do not (or no longer) respond to other treatments like behavioral therapy or medicines. Some less invasive alternatives exist, such as transcranial electrical or magnetic stimulation (TES or TMS) through the skull, but they cannot specificially target deep brain regions and are not suitable for chronic stimulation.

For brain stimulation to become widely available and make an impact for many patients, we need a better tool that is less invasive, user-friendly, cost-efficient and optimized to target deeper brain regions over longer times to protect cognition.

Our solution: transcranial electrical brain stimulation to preserve cognitive function

In this project, we are developing a novel method to stimulate deep brain regions in a minimally invasive way. Our method is based on electrical stimulation via electrodes that are placed above the skull, known as epicranial current stimulation (ECS). It is much less invasive than deep brain stimulation and similar to transcranial stimulation, but does allow chronic stimulation, as the electrodes are fixed and implanted under the skin. Driving pulses of electricity through the electrodes causes the generation of small electric fields close to the brain. Thus far, it has been difficult to target deeper regions with transcranial stimulation. The stimulation had to be very strong to be able to reach the deep brain, causing side effects because of the activation of more superficial cortical layers.

Yet a few years ago, our British collaborator Dr. Nir Grossman and colleagues developed a radically new method that they called temporally interfering (TI) fields stimulation (Grossman et al. 2017).

How does it work?

• Small electrical currents are applied to two sets of electrodes that are attached to the scalp. Each electrode has an electric field that on its own cannot modulate neuronal activity, because the frequency of the electric waves is too high. But at the location where both electric fields meet, they interfere with each other, generating a field with waves of a lower frequency that is successful in neuromodulation.

set of electrodes above the skull

resulting TI-field that can reach deeper layers

(Figure: Grossman et al. 2017)

• What’s more: the location of this TI-field can be precisely chosen by tweaking the position of the electrodes and the stimulation intensities, meaning that the effect can be targeted to a specific brain region of interest, such as the hippocampus, a brain structure that is crucial for memory and cognition.

Both methods combined form temporally interfering epicranial current stimulation, or TI-ECS.

Our goal is to explore the potential of this new technique for neuromodulation in humans. The ultimate aim is to create a minimally invasive stimulator device that can be widely used to delay cognitive decline and improve the quality of life for many patients with neurodegenerative diseases. It will be a stand-alone device with implanted electrodes and an electrical stimulator fixed behind the ear, much like a cochlear implant, to be used continuously in the patient’s home environment.

In first instance, our target population are elderly people with mild cognitive impairment, for whom we hope to be able to stop further progression into dementia. Brain stimulation with TI-ECS could allow these patients to live independently for longer, reducing the burden on their caregivers and lowering societal healthcare costs.

The stimulator will be small, wireless and implanted behind the ear, much like a cochlear implant.

(Figure: Shutterstock)

Current status of the project and outlook

In a first phase of the project, our team has been using computer models and simulations to define the optimal TI-ECS stimulation parameters.

Guided by these simulations, we recently completed a pilot study. In a first set of experiments, two macaque monkeys received standard ECS. We found that this form of stimulation can effectively modulate neuronal activity, albeit only in the upper cortical layers of the brain, as expected because standard ECS cannot reach deeper layers. Importantly, we confirmed that the electrodes placed above the skull are compatible with functional MRI brain imaging. This is invaluable for mapping the functional effects of brain stimulation, and will also be very useful later when applied in humans.

In a next experiment of this pilot study, another macaque monkey received a set of electrodes on the skull, now for stimulation with the novel TI-ECS technique. The monkey was trained on several spatial tasks. We found that the monkey had a better memory for tasks performed during TI-ECS compared to tasks learned without any brain stimulation – strongly suggesting that TI-ECS can induce memory improvements.

Several steps still need to be taken before we can start the first tests in humans.

First of all, we need to further optimize the stimulation parameters for TI-ECS using computer models and simulations. Different stimulation protocols and frequencies will be first tested in laboratory rats to study which cellular changes they cause in the hippocampus, and how TI-ECS can improve cognitive processes.

We will also implant more macaque monkeys, including aged animals, and combine electrophysiological readouts with memory tests and functional MRI imaging to bridge the current knowledge gap of neuromodulation effects at different levels and confirm the efficacy and safety of TI-ECS.

A unique opportunity to do this is presented by patients with epilepsy, some of which have electrodes implanted deep in the brain to measure activity during epileptic episodes. Epileptic activity often originates from the same regions affected in neurodegenerative diseases, including the hippocampus.

The neurosurgeons in our team will specifically select suitable epilepsy patients and ask them if they want to participate in some tests with ECS and/or TI-ECS. Thanks to the electrodes they already have implanted in deep brain regions, we will be able to measure the local effects of the new type of brain stimulation on neuronal activity and plasticity. By asking these patients to additionally take some memory tests, we can also start investigating the potential of TI-ECS for cognitive improvement in humans.

Once all parameters are optimized and the new brain stimulation method is validated in monkeys, we will be able to start testing it in humans.

In parallel, we have started developing a first prototype for the wireless stimulator device that will be capable of delivering constant, chronic TI-ECS.

In a later phase, ECS and/or TI-ECS will be applied to patients with mild cognitive impairment and Alzheimer’s disease. The effect of the stimulation on markers of neurodegeneration and neuroplasticity will be assessed using brain scans and other diagnostic tools, and the potential cognitive enhancement will be measured by memory tests.

Brain stimulation alone may not be sufficient to cure neurodegenerative diseases, but it could help to delay the progression of cognitive decline by several years

– which would already make a huge difference to millions of people.

While our initial focus is on Alzheimer’s disease, our new tool for minimally invasive brain stimulation may later be applied to other diseases. Our approach could be useful to a large number of conditions where pharmacological treatments fail or deep brain stimulation is considered too invasive, such as Parkinson’s disease, chronic pain, depression and obsessive-compulsive disorder.

The electrodes used for ECS are compatible with MRI brain scans. This is very valuable to assess functional effects, especially for the first tests in epilepsy patients.

References and further reading

https://www.kuleuven.be/english/research-stories/2020/a-memory-aid-with-electric-current

Grossman et al. 2017 (Cell)

first description of temporally

Brain Stimulation

field

• Grossman 2018 (Science) Modulation without surgical intervention

Temporally Interfering Electric Fields

• Khatoun et al. 2019 (Front Neurosci) Investigating the Feasibility of Epicranial Cortical Stimulation Using Concentric-Ring Electrodes: A Novel Minimally Invasive Neuromodulation Method

• Romero et al. 2019 (Nature Communications) Neural effects of transcranial magnetic stimulation at the single-cell level

For the latest overview of our publications, go

team of experts

Peter

Dr. Tom Theys

Van Helleputte

Mission Lucidity embraces interdisciplinary collaboration across borders. One of our major aims is to connect fundamental scientists, engineers and clinicians and stimulate them to work on innovative projects. However, every now and then, as a bonus, you find all of those specialties in one person. Meet Dr. Hannes Heylen, psychiatrist in training and biomedical engineer, who recently joined the TESCOGEN project as a PhD student.

What inspired you to work at the crossroads between medicine and technology?

I graduated as a medical doctor in 2015 and started my residency in psychiatry right after, but technology and engineering had also been fascinating me for a long while. So I decided to pause my residency and pursue an additional master’s degree in biomedical engineering, which I completed in 2018.

During the engineering master’s, I was fortunate to be selected for an internship at Johns Hopkins University in the US. Over the summer, I worked in the research group of Prof. Jiande Chen on a very exciting neurostimulation project. This enriching experience connected two of my passions; medicine and electrical engineering, and really spurred me to continue in interdisciplinary research.

How do you experience the interdisciplinary collaboration in Leuven?

We truly have top-notch expertise in electrical engineering, fundamental neuroscience and clinical care in Leuven. Bringing together all of our respective visions and backgrounds to create one device for the clinic: I find that utterly fascinating.

Our project is very technical, but also very human. It’s about diseases affecting cognition, which have a huge impact on society and about which we are rightly very concerned. We’re all getting older, so the prevalence of cognitive disorders keeps increasing, and we all want to be in good health for as long as possible. It’s great to live in this 21st century where interdisciplinary research is central. We are on the verge of some fascinating innovations that will have a significant impact on the quality of life of our patients.

Vascularized chip-based brain organoids

Towards improved and humanized disease models

Personalized genetic risk profile

Translating individual risk to disease phenotypes and prevention

A human brain on a chip

Re-creating neural circuits to stratify patients and identify new drug targets

Non-invasive transcranial electrical stimulation

Stimulating the brain to preserve cognitive function

Detecting disease by retinal imaging

The eye as a window to the brain: early biomarkers in the retina

About Mission Lucidity

Founded in 2018, Mission Lucidity is a partnership between four research institutes in Leuven, Belgium: imec, KU Leuven, University Hospitals Leuven and VIB.

By leveraging the expertise of engineers, clinicians and scientists, combined with the backing of visionary donors, we aim to develop game-changing, scalable technology platforms and tools for neurodegeneration research. This will give the scientific community at large a unique opportunity to deliver scientific and medical breakthroughs.

Our projects adopt a multi-angle approach: from zooming in on the cellular and intracellular level via technology development at nanoscale, to studying biomarkers and disease mechanisms in humans.

Ultimately, our transformative technologies will allow us to answer longstanding questions and better understand, predict, diagnose and treat neurodegenerative diseases.

Visit www.missionlucidity.com/research to learn more about our projects.