Research into the Pathophysiology and Therapy Options of  Mal de Debarquement Syndrome


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Imagine getting off a boat, a plane or out of a car and feeling like you are still in motion. You may have experienced this unusual sensation once before, which typically resolves within a few hours. However, in some people this sensation becomes chronic, and is accompanied by a myriad of relentless symptoms, such as instability, anxiety and brain fog – this is Mal de Debarquement Syndrome (MdDS). MdDS is a complex, poorly understood condition which is life changing and currently has no cure. 

We are closer to finding effective treatments than ever before, help us conduct cutting-edge research that aims to further our understanding of the pathophysiology of MdDS and find a cure for this debilitating condition!

The aim of the research:

  1. Given the recent investigations into gonadal hormones and the female predominance of MdDS, this study aims to assess hormonal influences on neurotransmitter activity (e.g. GABA) in MdDS patients. This will allow us to understand the impact of hormones on this condition and also to observe if/and how MdDS subjects differ from migraineous patients and from healthy controls.
  2. This study aims to identify the most effective treatment available for MdDS patients considering their subtypes (i.e. motion-triggered or spontaneous / non motion-triggered). Three therapies will be compared; Vestibular Ocular Reflex Readaptation Treatment, Neuromodulation Treatment, and a Therapeutic intervention focused on hormones (antagonistic Calcitonin Gene-Related Peptide (CGRP)).

Benefits:

The research into MdDS is in its infancy and the underlying pathophysiology of MdDS remains unknown. Due to the lack of understanding many healthcare professionals are not even aware of the condition, let alone the symptoms that an individual with MdDS experiences. This has consequently led to a high rate of misdiagnosis, delayed diagnosis and poor patient management. Patients report negative diagnostic experiences with mental health consequences [11] and high socio-economic burden on patients and healthcare systems around the world [11].

Our research group aims to perform two novel studies to further advance our understanding of MdDS as well as providing treatment options for MdDS patients.

What is MdDS?

Mal de Debarquement (MdD) is French for ‘sickness of disembarkation’. In simple terms it defines the condition of a person that retains the sensation of motion after disembarking from a boat or other vehicle. This feeling can be described as “feeling like you are on a boat, despite being on land”. This phenomenon is often experienced by healthy individuals, however only transiently [1, 2], with the sensations of phantom motion (e.g. phantom feeling of swaying side to side) lasting from a couple of hours to up to a few days [3]. However when symptoms are prolonged for more than a month from onset, MdD becomes a pathological condition, named Mal de Debarquement Syndrome (MdDS) [5].

MdDS was only recognised and described as a medical condition in 1987 [1], therefore it can be considered a relatively new disorder, despite being described much earlier by Erasmus Darwin [5]. Given its rarity and lack of thorough investigation, MdDS is often misdiagnosed, with patients often suffering long diagnostic journeys which significantly impacts on their mental health [1]. Patients report that their symptoms have a negative impact on their relationships, careers and that they find it extremely challenging to go about their normal everyday activities, such as doing the groceries, hanging the washing, watching the TV, having a shower, etc [5]. Thus, MdDS has been described as a debilitating condition with a high level of intrusiveness in the lives of patients [6].

Which symptoms characterize MdDS?

MdDS is characterised by a persistent subjective perception of self-motion (i.e.rocking, bobbing, swaying) [6], which is in some cases is accompanied by other symptoms such as heightened visual sensitivity, unsteadiness, brain fog, cognitive slowing, and co-morbidities such as migraine, anxiety and depression [5]. Migraine seems to be dominantly present in MdDS patients [7].

Can anyone get it?

Unfortunately MdDS can affect anyone, however it seems to be more prominent in adult women (age range 30 and 65 years) [8, 9]. In most cases, the onset of MdDS occurs after exposure to passive motion (e.g. being on a boat, travel by car or plane or train) [8], these patients are referred to as having motion-triggered (MT) MdDS. However, MdDS can also develop spontaneously or following non-motion triggered events, such as surgeries or childbirth. Anecdotally, MdDS symptoms have been reported after the use of virtual reality experience [3]. These patients are referred to as having a spontaneous (SO) MdDS onset or non-motion triggered onset (non-MT) [10] (for facilitating the readers we will refer to SO patients in the text). SO patients have identical symptoms to patients with MT MdDS, however potential differences between these two subtypes are still unclear.

Figure from Mucci et al 2018 - Journal of Neurology

Figure from Mucci et al 2018 – Journal of Neurology

What do we know about MdDS pathophysiology and treatments options?

Regarding MdDS pathophysiology, two main theories have been formulated [18] and these theories are associated with two distinct proposed therapeutic approaches.

Theory 1: According to one theory, MdDS pathophysiology has been considered to originate from a maladaptation of the Vestibular Ocular Reflex (VOR) and velocity storage caused by the exposure to passive motion. Based on this theory, a treatment using optokinetic stimuli (OKN) has been developed. The hypothesis of the maladapatation of the VOR supports the usage of OKN exposure to reduce MdDS symptoms [12] . As repetitive OKN exposure is able to adapt the velocity storage and modulate the VOR (see [13, 14]), this treatment has been proven to have the highest success rate in MdDS patients [15]. This treatment will be named in this project as VOR readaptation technique [12].

Optokinetic Chamber

Optokinetic Chamber

Theory 2: Another theory, following recent neuroimaging and neuromodulation studies [16, 17], describes MdDS as a disorder of abnormal functional connectivity [8, 18]. This theory has led to experimental neuromodulation treatments; such as transcranial Direct Current Stimulation (tDCS) [19], which is based on cathodal transcranial stimulations and low frequency repetitive Transcranial Magnetic Stimulation (rTMS) [20].

Although neuromodulation treatments have promising results [17] [21], their success rate remains lower than the use of the VOR readaptation technique [15] and it remains unclear how MT and SO patients respond to these two therapies.

tDCS Device

These two primary theories regarding MdDS pathophysiology, the maladaptive VOR and neuroplasticity disorder, may not be mutually exclusive [18]. However to date it remains unclear how they may be interrelated.

A new line of research – Hormones / Migraine and MdDS:

In addition to these two main theories, an additional hypothesis has been recently formulated [7]. Many questions remain to be addressed considering MdDS pathophysiology.

Thus, in the past year our research group has also focused on hormones, especially considering the great female dominance present in MdDS (80% of sufferers are female) [23]. Together with my colleagues, we have investigated whether gonadal hormones influence MdDS pathophysiology and/or symptomatology. We presented the data collected through a retrospective online survey on male and female patients from both MT and SO onset groups [23]. From our findings, we reported a predominance of female patients. Within this group, it was clearly reported that symptoms were aggravated during menstruation and around the mid cycle in female MT patients. This triggered us to propose a new theory where symptoms in female MdDS patients may be aggravated by estrogen withdrawal, similarly to what occurs in migranienous patients.

Fluctuations of estrogen, progesterone and luteinizing hormone during a typical 28-day menstrual cycle. Abbreviations EST- estrogen, PROG- progesterone, LH- luteinizing hormone.

We also ran a novel study specifically designed for pregnant MdDS patients [11]. From the data collected, most participants reported an improvement of symptoms during the 9 months of pregnancy [38]. We propose that this is due to the absence of estrogen withdrawal and high levels of estrogen and progesterone, which may alleviate MdDS symptoms. Despite being preliminary, we hope that the results will lead to more studies into the gonadal influence on vestibular symptoms.

From this reasoning, a new theory was created [7]. This theory considers how hormonal changes might influence neurotransmitters, rendering patients more predisposed to developing MdDS, as well as explaining their symptom fluctuation [7].

With regards to this concept, it is also important to consider the relationship between MdDS and migraine. Considering recent findings, CGRP has been implicated in the pathophysiology of migraine, mainly after observing that CGRP levels were higher during a migraine attack [35]. Additional studies have proved that CGRP can be influenced by hormonal changes [34]. CGRP is known to be involved in the “hot flashes”, occurring during perimenopause and menopause [36], by acting centrally on the thermoregulatory centre of the hypothalamus as well as peripherally to cause vasodilation and sweating [37]. Similarly CGRP is also known for being able to influence the trigeminal nociceptive system [35], possibly involved in migraine. Thus, from these recent findings new therapeutic options are emerging by developing antagonistic CGRP drugs [33] to help managing migraine and hormonal changes. By considering the strong link between migraine and MdDS [9], it is possible that CGRP may equally hold some relevance with regards to MdDS pathophysiology. This hypothesis needs further assessment and investigation.

a) representation of normal distribution of CGRP and b) representation of higher distribution of CGRP (i.e. during migraine attacks)

What remains to be addressed?

Our research group aims to perform two relevant studies to further advance our understanding of MdDS pathophysiology a well as identifying the most effective treatment options for MdDS patients.

It remains unclear how hormonal fluctuations may influence MdDS symptoms as well as if gonadal hormones influence specific neurotransmitters (e.g. GABA). Assessing central changes in MdDS patients and in patients with migraine, and comparing them with healthy age matched controls may help us to further understand MdDS pathophysiology.

The second aspect that remains to be addressed is treatment options. We aim to investigate which one is the most effective treatment for the different subtypes of MdDS patients (SO versus MT). This will be done by comparing different types of treatments between each other. Comparisons between the VOR readaptation technique treatment [12, 13] and neuromodulation therapies (such as: transcranial direct current stimulation (tDCS)) [39], as well as additional therapeutic intervention focused on hormones (e.g. antagonistic Calcitonin Gene-Related Peptide (CGRP)), and how effective they are in treating the symptoms of patients with MT and SO MdDS.

Objectives

This project aims to advance the current understanding of MdDS pathophysiology and subtypes differences between MT and SO MdDS with a particular focus on female patients.

Further assessing therapeutic options for MdDS will not only provide more information about which treatment is the most effective for the different MdDS subtypes but also explore potential pathophysiological differences present between MT and SO MdDS patients.

Why is this research important?

Currently it is unknown why there is such a great gender predominance of female patients affected by MdDS. This study will be the first of this kind to assess in great detail the hormonal profile of MdDS female patients. Additionally, this study for the first time will try to evaluate further the interaction between the GABAergic system, hormonal fluctuations and neuro-vestibular symptoms in MdDS patients.

Gaining information about whether hormonal levels correlate with brain alterations found in MdDS patients and, perhaps more practically, whether further treatment should consider these hormonal fluctuations on therapeutic choices may be of great relevance to ease MdDS symptoms and develop successful treatments.

Considering the lack of therapeutic options for MdDS subjects, this project for its second phase aims to implement the VOR readaptation treatment, which is considered the treatment with the highest success rate; and simultaneously to propose to the patients who report aggravation of symptoms during menses to try CGRP antagonist drug therapy. While another independent group will be assessed with tDCS neuromodulation treatment.

This project is extremely relevant to further investigate how different therapies may affect MdDS patients and which one is the most effective for the different subtypes (MT versus SO).

Further research into the therapeutic options for MdDS will not only provide more information about the most effective treatment, but also teach us about potential pathophysiological differences present between MT and SO MdDS subtypes.

(Male subjects will also be considered for the treatment section).

What do you think are the potential outcomes of the work?

  • We will gain more information about the hormonal profiles in female patients with MT and SO MdDS.
  • We may potentially understand if MdDS patients differ from migraineous and healthy control subjects with regards to GABAergic changes.
  • We will be able to compare the outcomes of the three different types of treatments in MT and SO patients.
  • We may potentially identify which treatments is the most effective for patients with MT and SO MdDS.

Budget

In order to perform this study, we need to acquire new equipment, purchase consumables, and most importantly allow patients to join the treatment for free (usually ~$2500 USD/patient).

The budget estimation for the whole project is of: $264,000 (USD) =  £207,745 

Through this campaign we are aiming to raise money at first for the first phase (phase 1) and to support our team, so the amount we are aiming to collect is $178,000 (USD) =£140,070  by February 2020.

Where will the money go? At this stage, we are not able to provide this information. This project proposal intends to collect money and raise awareness about MdDS. The purpose of using the Crowd Science platform was to ensure we will be able to create a deal with the most appropriate university, department, and settings to perform this study once we will have the right funding. Only when and if we will reach the target proposed we will then decide where to settle the research. This will be most likely between the USA and Australia. So donors from all over the world are welcomed.

How about ethical issues? The study will be performed following the highest standard of care and following the Declaration of Helsinki for Ethical Principles for Medical Research. Before the study will take place an ethical committed from the government body where the study will be performed will evaluate the study as per every other clinical research.

Why do we donate in pounds (£)? The amount for the donations is shown in pounds because CrowdScience is a UK based organization, it does not mean the research will take place in the UK.

What happens if we don’t reach our target?

If the target is not met we will revise the project, if we have enough money, we will consider running a pilot study; or we may extend the deadline.

What happens if we raise more money than what planned?

In the amazing event that we will be able to receive larger donations than what we have foreseen we will consider to promote fellowships programs for Ph.D. and MSc students interested in contributing to MdDS research.

Team

Dr. Viviana Mucci performed her Ph.D. on studying and researching Mal de Debarquement Syndrome. She is currently continuing her research in Switzerland. She successfully implemented the VOR readaptation treatment in Belgium and now in Geneva, CH. Since her Ph.D. she has been treating several patients from all over Europe and performed a sham study demonstrating that no placebo effect is involved with the VOR readaptation specific rehabilitative therapy. As evidenced from her publication [13], she obtained therapeutic results matching the New York team, who developed the VOR readaptation treatment [14], with a 70% success rate in MT MdDS subjects. Similarly the co-applicant for this funding Dr.Yakushin Sergei from Mount Sinai Hospital in New York has an extended experience in treating MdDS patient’s with teh VOR readaptation protocol for more than 7 years, as his lab is the first in the world to have developed and implemented this therapy.

In 2018 Dr.Mucci, Dr.Yakushin, Dr.Browne and a team of MdDS researchers launched the largest survey on MdDS, where they performed the first ever study on hormonal influences on MdDS symptoms. In early 2019 Dr.Mucci and Dr.Browne published their work on MdDS women who underwent pregnancy. Dr. Browne is a lecturer in Human Anatomy at Western Sydney University 
and a conjoint Lecturer at the School of Medical Sciences, UNSW Sydney. She is also head of the MdDS research lab, Australia. She has an extended knowledge about MdDS and she co-promoted Dr.Mucci’s Ph.D.  In addition to this, Dr. Choi Deblieck from KU Leuven, Belgium, will support the team with the implementation of tDCS therapy. Dr.Deblieck is a major expert in neuromodulation (rTMS and tDCS) (https://www.upckuleuven.be/nl/artsen-therapeuten/choi-deblieck-phd) and she will be the primary supervisor for the tDCS part of the study.

A picture of the Barany Conference 2018 with Dr.Dai (Assistant Professor Ichan School of Medicine, Mount Sinai, NYC, USA),  who we honour and remember after he sadly passed away last February. Dr.Dai has dedicated his life to research Motion Sickness and MdDS, and it is because of his work that patients can access OKN treatment. On the right side of the picture are Dr. Mucci and Dr.Yakushin.

The team will also be supported by MDs and specialised migraine experts to perform the CGRP study. Together this team will be capable of successfully continuing to research  MdDS and developing innovative approaches to this complex and debilitating disorder.

More about each team member:

Dr. Viviana Mucci

Dr. Viviana Mucci (Ph.D) is a postdoc researcher from University of Zurich and currently affiliated to the Swiss Concussion Centre, Schulthess Klinik in Switzerland. Viviana won the Future Science Early Career Research Award in 2018, following her work on Mal de Debarquement Syndrome performed during her Ph.D. She completed her Ph.D. program in the field of Neurotology in July 2018 from Antwerp University, Faculty of Medical Science. Her background involves a BSc in Medical Physiology (University of East London, UK), which she completed with distinction in 2012 and a MSc in Space Physiology and Health from King’s College London (UK), where she graduated in 2013. Since her Ph.D. Viviana’s work has been focusing on continuing to investigate Mal de Debarquement Syndrome. She currently treats MdDS patients in Switzerland (Zurich and Geneva). At the same time she is also bringing forward a new frontier of sensory integration in patients affected by post concussion syndrome. She is assessing specifically the presence of Visually Induced Dizziness and a visual sensitivity in professional athletes after multiple concussions, at the Swiss Concussion Centre. Although the neuro-vestibular knowledge has grown over the last few decades there are still many pieces of this remarkable system that remain to be addressed. This lack of knowledge is a strong drive for Viviana to continue pursuing research in this particular field.

Viviana and the other team members have worked together in previous project, Viviana is planning to conduct this study in New York working alongside Dr.Yakushin.

Dr. Sergei Yakushin

 

Over the first six years of my research career, I worked for the Russian Space program at the Institute of BioMedical Problems (IMBP, Moscow, Russia) in the department Neurophysiology headed by Dr. Inessa B Kozlovskaya. We studied adaptation of vestibulo-ocular reflex (VOR) (a key component of the balance system) to microgravity. In 1991, I was invited to come to the United States to work on a similar NASA project in Dr. Cohen’s laboratory at Mount Sinai School of Medicine. In 1998 I got my First Award, an R29, to study effects of semicircular canals plugging on adaptation of VOR. I also worked as a Co-Investigator on Drs. Cohen and Raphan’s grants. Since than I received my R01 grant that was renewed and supplemented by equipment grant. I also was a mechanical Core Grant director for 10 years. Over that extensive period, I gained administrative scale to train and supervise technicians and post-docs working simultaneously on various projects.

Over the last 5 years I have been working with Dr. Dai on experimental treatment of patients suffering from Mal de Debarquement Syndrome (MdDS). Over that time, we treated over 500 patients. At present 100% of my research is related to patients’ treatment. Our lab works closely with several neurologists in particular, with Drs. Joanna Jen, Susan Shin and Catherine Cho (NYU). We recently develop a new collaboration with Dr. Viviana Mucci, where hormonal fluctuations were assessed in MdDS patients.

Dr. Choi Deblieck

I graduated with an MSc degree in Psychology from the University of California, Los Angeles, CA, USA in 2001 as valedictorian of my class. I subsequently earned my Ph.D. in Cognitive Neuroscience, studying the representation of language using fMRI, from the University of Milan, Italy in 2006. In the last year of my Ph.D. program, I returned to UCLA to work in Drs. Iacoboni and Wu’s TMS Laboratory, expanding my knowledge of brain mapping using functional magnetic resonance imaging (fMRI) and learning TMS methodology. I proved exceptional at understanding and conducting TMS experiments and rapidly became an integral part of the laboratory’s efforts in studying patients with movement disorders using TMS. As such, following my Ph.D., I was appointed as a postdoctoral fellow in the laboratory in 2006. After my postdoctoral years, I held a supervisory role over all practical aspects of TMS Laboratory training, function, and operation while being the primary Research Associate advancing the translational rTMS research program. I oversaw training of research assistants who were learning to conduct TMS studies, and I supervised day-to-day development and testing of existing and novel TMS protocols. I conducted independent TMS sessions, gathered outcome measures, maintained regulatory and research data and analysed data in the TMS Laboratory. In addition, I gave support group talks and made outreach attempts for recruitment of patients in Parkinson’s disease studies, something not traditionally undertaken by researchers.

In 2015, I moved to Belgium to become the non-invasive neuromodulation expert at UPC KU Leuven. Currently, next to continuing my research work, I am providing TMS and tDCS as alternative treatments to patients with psychiatric and neurologic disorders, ranging from depression, OCD, auditory halluciantions, PTDS, alcohol craving, autism to Tourette’s syndrome, neuropathic pain, MS.

Dr. Cherylea Browne

 

Dr.Cherylea Browne is a lecturer in Human Anatomy at Western Sydney University 
and a conjoint Lecturer at the School of Medical Sciences, UNSW Sydney. She completed a Bachelor of Medical Science with honours at The University of Sydney in 2007 majoring in Cell Pathology, Anatomy and Neuropathology, and completed her PhD in Auditory Neuroscience in 2013 at Western Sydney University. She is an anatomist with ~9 years’ experience teaching a broad range of units to medical, clinical health science and 
postgraduate students, across various educational and training institutions 
She has also a broad background in neuroscience researcher with ~12 years’ experience – currently focusing on investigating the underlying 
mechanisms of Mal de Debarquement Syndrome specifically focussing on the hormonal influences and sympathetic nerve activity; and is involved with the Translational Neuroscience Facility at UNSW Sydney working on the use of pulsed electric 
fields for gene delivery to stimulate neural regeneration. She is the head of the Mal de Debarquement Syndrome Research Group, in Australia. She is also a member of the Mal de Debarquement Syndrome Australia Medical Advisory Board. She is actively involved in community outreach programs and events promoting science and higher education 
as well as promoting Mal de Debarquement Syndrome research.

Thank you note

Thanks to Enea Ferrari (www.eneaferrari.ch , Instagram: eneaphotography) who has contributed to the creation of the video contents and to Jared A. Shaw for providing writing assistance.

Thank you to Action for Mal de Debarquement Syndrome UK for the help and assistance in promoting the project.

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  41.      Cha Y, Cui YY, Baloh RW (2018) Comprehensive Clinical Profile of Mal De Debarquement Syndrome. Frontiers in Neurology 9:1–10 . doi: 10.3389/fneur.2018.00261
  42.      Garcia-Segura L (2009) Hormones and Brain Plasticity. In: Behavioral Neuroendocrinology. Oxford University Press., pp 53, 148, 118
  43.      Cha Y-HY-H, Cha (2015) Mal de debarquement syndrome: new insights. Ann N Y Acad Sci 1343:63–68 . doi: 10.1111/nyas.12701.Mal

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