Dr. Sylvain Williams and Dr. Guillaume Etter

By Nicola Di-Narzo

A new study led by Dr. Sylvain Williams, Professor in the Department of Psychiatry and his postdoc Dr. Guillaume Etter suggests that even at advanced stages of Alzheimer’s disease, there are possibilities for therapeutic treatments. Deep brain stimulation, a method that uses electrical stimulations of neurons and brain circuits to treat some of the symptoms of Parkinson’s disease, is now being tested to treat memory loss in patients with Alzheimer’s.

Dr. Williams, who is also a researcher at the Douglas Research Centre, took some time to answer a few questions about this study, the results of which are published in Nature Communications.

What is new in your study?

We found that we could rescue memory in mouse models with Alzheimer’s disease. Deep brain stimulation (DBS), is a method that uses electrical stimulations of neurons and brain circuits to treat some of the symptoms of Parkinson’s disease and there is now a lot of interest to use this to treat memory loss in patients with AD. However, two important concerns remain, namely which areas of the brain to stimulate, and the nature of the stimulation we wish to use for AD. We therefore used mice models with AD to determine this. In our particular study, instead of using DBS to stimulate all neurons, we used a more advanced technique called optogenetics, with which we genetically engineered specific neurons so that they can be activated with light. This way, we could perform stimulations that precisely targets a specific set of neurons in one region of the brain known to be important in memory, and thus minimizing side effects. Interestingly, these stimulations rescued memory at ages where mice displayed significant beta Amyloid plaque deposition, one of the hallmarks of AD. This suggests that even at advanced stages of the disease, there are possibilities for therapeutic treatments.

 How do these findings add to what was already known and how did you make the discovery?

DBS is already used successfully in the treatment of Parkinson’s disease. Here we have found the right parameters for optimal neural circuit activation with which brain areas can be stimulated to rescue memory. Another important finding was that we knew that the hippocampus, a brain region involved in memory functions, is known to display altered brain oscillations in Alzheimer conditions. We asked whether reinstating these brain oscillations in the hippocampus can improve memory and showed that it did.

We spent significant amounts of time testing various stimulation frequencies, and first recorded brain activity during the stimulations to see whether we could enhance them in Alzheimer’s conditions. Then, when we found the ideal stimulation frequency, we applied it to mice exactly when they were performing a memory task and observed significant improvements when stimulated at 40 Hz, which is in the so-called ‘gamma’ frequency band. Interestingly, we wanted to use a memory task that had some similarities to a human situation. We used a task named the object-place recognition task which bears some resemblance to an event where you’re trying to recognize your car key. For example, one difficulty in some AD patients would be to recognize if a car key is really theirs if it has been placed in another room. If you know its yours and recognize it right away, you can grab it quickly and use it. However, if you don’t remember that this is yours, you will take more time exploring it and trying to remember its features to see if its yours. We found that when gamma oscillations were introduced when trying to remember, memory was rescued.

 What led you to ask this question and explore it in this way?

Gamma oscillations have long been associated with cognitive processing such as learning and memory. For instance, in humans, higher levels of gamma oscillations can be observed when remembering past events, so we suspected that one possible explanation for impaired memory retrieval in AD is the lack of ‘normal’ gamma oscillations. However, and to this day, there is still no definitive demonstration that gamma oscillations are doing anything useful at all. Consequently, in addition to exploring therapeutic tools for AD, we also wanted to know whether enhancing these oscillations could be beneficial in pathological conditions.

 Any anecdotes about colourful fieldwork, or major hurdles along the way?

It took quite some time to find the right parameters to test our ideas. In addition to finding the right stimulation frequency, we also spent significant amounts of time finding the right memory test for mice. Sometimes the tasks were too easy, and our Alzheimer mice could find the solution just as well as wild-type mice. This was the case when the memory tests did not rely as much on short-term or spatial memory, which is interesting because Alzheimer’s patients can also perform very well in situations where they can rely on habits in familiar environments but become very impaired in novel environments that involve spatial learning. In some of the tasks we used, the Alzheimer model mice lacked complete short-term memory and could not even learn the rules behind the task. Finding the right task to be able to observe memory improvements was challenging.

 Why is this paper important? What are the practical implications?

There are still no treatments for AD. More importantly, we do not fully understand the disease itself and there is still so little we know about the basic mechanisms underlying memory function. In AD patients, a protein called beta amyloid can be found in large quantities, forming plaques that are known to prevent normal neuronal functions. Most treatments have focused on removing this protein, but the results are quite underwhelming. We hypothesize that cognitive functions are impoverished in AD mostly because of impaired brain oscillations, which can be observed before amyloid plaques and predict the first symptoms of the disease. Our study strongly suggests that we could focus our research efforts in earlier stages of the disease, and that improving oscillation physiology could be more efficient than reducing amyloid beta load.

 In our study, we have genetically engineered neurons to respond to light stimulation (instead of electrical stimulation that are used for DBS). Although this technique is more advanced and provides unprecedented precision, we are many years away from its use in humans. However, clinical trials using electrical stimulations have started in AD patients and offers hope. Our study provides evidence that stimulation at specific frequencies given at a particular brain region and at a moment during retrieval could provide some memory rescue. Other studies suggest that simple visual, high frequency stimulation could also lead to increased cortical oscillations and memory improvements. In both cases, we will need more clinical trials to know if this could work in humans.
 Were any findings particularly surprising?

It was very surprising that we could improve memory in these mice that already displayed plaque deposition. Moreover, not every stimulation led to memory improvements. We observed the most positive effects in the gamma range, at 40 Hz. However, high gamma frequencies, such as 80 Hz did not produce such beneficial effects. This suggests that the brain might use different frequency bands to communicate information: just like a radio, some channels are more relevant for some information than others. In our case, enhancement of 40 Hz oscillations led to improved memory retrieval in our mice with AD.

 What questions might other scientists raise about this study?

The exact role of gamma oscillations remains to be explored. We found that enhancing 40 Hz but not 80 Hz led to memory improvements. This really supports the idea that different oscillations are involved in different cognitive processes. However, there are still many experiments that remain to be done to understand the role of these oscillations. What happens if we impair these specific oscillations in healthy mice? The experiments to definitively prove this will be very difficult, but this would further help us understand the specific role of brain oscillations.

 What are the next steps for this research?

In our daily life, memory does not only happen during wake when we go around our business. Processes related to memory, such as the conversion of short to long-term forms of memory also occurs during sleep. In our Alzheimer mice, we found that brain activity is abnormal during sleep, and we are now trying to see if applying our stimulation treatments could have further beneficial effects on memory.

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