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Effective research requires teamwork.

Research into the biological basis of MdDS has advanced rapidly in the last 10 years through the collaborative efforts of scientists, engineers, clinicians, funding organizations, and not least of all, people affected by MdDS. It would be difficult to find any other disorder in the same time period that has been investigated with such a variety of modern research tools. These include multimodal brain imaging studies with PET, fMRI, and EEG, web-based applications for tracking symptoms, and new treatments using brain stimulation and vestibulo-ocular modulation.research recruiting

Brain stimulation studies have very much evolved through this time. These studies have given us an understanding of the neural basis of MdDS, guiding the development of different forms of non-invasive brain stimulation therapies, and working towards the creation of portable therapy options.

From the patient’s standpoint, research studies advance at a glacial pace. In real life patient terms, two years can mean the difference between a forced early retirement and continuing in a job that one loves. Two years in clinical trial terms is, however, a ‘drop in the bucket’.research recruiting

From the investigator’s standpoint, the choice of stimulation paradigm, duration, and site of stimulation need to be considered very carefully in order to yield the maximum degree of reliability and interpretability. Clinical trials are extremely expensive in terms of time, effort, and money. Research participants have pushed these efforts forward, however by contributing their unique histories, brain signatures, and clinical responses to experimental treatment.

Our unsung heroes in this regard were whom I think of as “the selfless 20.”

Hopefully some of them are reading this now. These were individuals with MdDS who had participated in the first PET and fMRI studies dating back to 2009 at UCLA. These individuals gave of their time, effort, and finances to travel to our center (often flying across the country) in order to advance our understanding of MdDS as a brain-based disorder. They had nothing to gain personally from a therapeutic standpoint. They knew this, and they participated anyway.

It took over two years to image those 20 individuals and their age/sex matched healthy comparison group. The patience paid off. The data that was generated by that study became a critical foundation for designing future brain stimulation studies. Most importantly, this data provided the first indication that MdDS has a brain signature. This study was published in 2012 (www.ncbi.nlm.nih.gov/pubmed/23209584).

The next set of heroes in MdDS studies was “the pioneering 10.”

These were individuals who traveled to UCLA, starting in 2011, to become the first participants subjected to repetitive transcranial magnetic stimulation (rTMS). rTMS had never been used to treat a motion perception disorder before and MdDS became the first because of these individuals. These individuals each received four different stimulation paradigms over the prefrontal cortex. Some got temporarily better, some got temporarily worse. That pattern helped us to figure out the specificity of the stimulation effects and how they relate to aspects like side of stimulation and handedness. It was through this study that we determined that rTMS could in fact change motion perception and lead to symptom relief beyond the stimulation period. This study was published in 2013 (www.ncbi.nlm.nih.gov/pubmed/23202153).

Armed with the knowledge that even short amounts of rTMS could yield symptom relief beyond the stimulation period, we then performed a double-blind, sham controlled, cross-over study that ran from 2012-2013. The individuals in this study were “the committed 8.” In this study, the individuals flew to UCLA on their own dime for two one-week blocks. In one block, they received 5 days of real rTMS. In the other, they received sham (placebo) rTMS. Neither they nor I knew which they were receiving on which week. Because the wash-out period between the two weeks was up to 4-months, and the individuals completed diaries before and after the treatments, any one participant could have been in the study for 6-months. They were the core of a committed team.

We learned that rTMS given back-to-back could induce long-term symptom relief from the feelings of motion and could also improve visual motion intolerance. We also learned about some important clinical features that are important in treatment response, such as the hormonal status at the time of treatment. The rich clinical detail from this study has informed all subsequent studies. This study was published in 2016 (www.ncbi.nlm.nih.gov/pubmed/27176615).

We learned from the prior two studies that both low frequency stimulation of the non-dominant hemisphere and high frequency stimulation of the dominant hemisphere could yield reductions in motion perception.

Thus, in the next study, running from 2013-2015 we enrolled “the tenacious 24.” In this study, we combined the two stimulation patterns into a single treatment week and also added maintenance treatment done at home with transcranial direct current stimulation (tDCS). Half of the group received real tDCS after rTMS and half the group received sham tDCS for 4 weeks. There was a 4-week washout period and then an open label period of 4 weeks followed by another wash-out period. Some people were thus in the study for over 6 months, a testament to their tenacity.

This study showed that tDCS can have a small augmenting effect on rTMS and that some people might even respond to tDCS when they didn’t respond to rTMS. However, the effect was not dramatic and it appeared that the timing of tDCS treatment relative to whether it was started during a ‘high’ symptom period or a ‘low’ symptom period was very important. This study was published in 2016 (www.ncbi.nlm.nih.gov/pubmed/27117283).

The MRI and EEG data generated from this study has both been published and is still undergoing analysis. We learned so much about MdDS from this study. First, we learned that when people respond to rTMS and feel better, long-range functional connectivity of the brain (essentially a measure of how synchronized two regions of the brain are) goes down. Second, we learned more specifically about where the functional connectivity changes were occurring as they pertain to brain regions that process visual and vestibular information. These studies were published in 2014 and 2017 as well as in many conference papers in between (www.ncbi.nlm.nih.gov/pubmed/24686227; www.ncbi.nlm.nih.gov/pubmed/28967282).

When looked at more specifically, in most brain frequencies, the synchronization went down as symptoms improved, but there was one specific exception. There was a narrow frequency band in which the synchronization actually went up with symptom improvement. Therefore, there may be something very particular about the role of this frequency band in the perpetuation of MdDS symptoms. A manuscript describing this analysis is currently being submitted for publication.

The change in the connectivity that was most relevant to treatment response to rTMS occurred in the posterior regions of the brain. Therefore, our next study, which ran from 2015-2017, tested a new form of rTMS called “theta burst stimulation” over these posterior brain regions. These individuals will be known as “the intrepid 24.” Theta burst stimulation (TBS) is a newer form of rTMS that uses very rapid pulses given in short bursts. If you weren’t awake before getting TBS, you surely would be after. It can hurt. The trade-off is that TBS has been shown to yield more durable changes in neural function than standard rTMS and is significantly shorter than regular rTMS. Our hope was to be able to give more treatments in the limited time frame in which the participants were in our study than we were able to previously.

These brave participants received stimulation to the posterior regions of the brain, specifically the occipital cortex, the cerebellum, and a control site. The response rate to TBS was about 3Xs better than that of stimulation over the prefrontal cortex with the prior standard rTMS protocol. The treatment response was also more rapid and the treatment itself was better tolerated because it was about 1/10^th the duration of the prior protocol. This data was quite exciting because the choice of this protocol was explicitly based on the use of fMRI and EEG as biomarkers of the MdDS brain state.

Once we finished that study, we immediately launched into the next study investigating the role of the specific frequency bands affected in MdDS mentioned earlier.

In the Fall of 2017, we began enrolling participants in a transcranial alternating current (tACS) protocol.

In tDCS, the current flows in just one direction whereas in tACS the current alternates between the two sites. The alternating current creates the possibility of entraining the baseline brain rhythm. We will enroll 24 participants in this study, whom we have called “the launching 24” because their data will be used to develop the paradigms that will be used in home therapy based on tACS.research recruiting

We can already see that tACS can modulate symptoms in real time and is clearly more effective than tDCS and significantly better tolerated than rTMS. Among the data that is needed to create a home protocol is an understanding of how response to ‘in-phase’ and ‘out-of-phase’ stimulation is related to treatment response and the baseline functional connectivity of each participant.

Once we have worked out these parameters, we will develop a ‘kit’ that is sent home to potential future participants that includes an EEG cap, the stimulation device, and necessary communication and teaching materials. This will be the “frontier” group. In the future, we want to be able to bring as many people into the frontier group as possible. This will be a very exciting study. However, it should be remembered that the contributions of every participant in our imaging studies and clinical trials to date has helped us to move towards this future. But, we are not there, yet.

The biological basis of MdDS is real. The suffering and the frustrations of people living with MdDS are real. Every study has been a stepping-stone towards gaining a better understanding of MdDS and of the people affected by it.

Throughout all of these efforts, our vision has been to advance our understanding of the biological basis of MdDS, to give people hope and a sense of meaning from their symptoms, and to evolve our treatment alternatives to address the variability in clinical experiences.

Whatever each of our roles in this effort, we move towards these goals as a team.