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February 2018 | Volume 9 | Article 281
HYPOTHESIS AND THEORY
published: 05 February 2018
doi: 10.3389/fneur.2018.00028
Frontiers in Neurology | www.frontiersin.org
Edited by:
David Samuel Zee,
Johns Hopkins University,
United States
Reviewed by:
Dominik Straumann,
University of Zurich, Switzerland
Pierre-Paul Vidal,
Université Paris Descartes, France
*Correspondence:
Bernard Cohen
bernard.cohen@mssm.edu
Specialty section:
This article was submitted to
Neuro-Otology,
a section of the journal
Frontiers in Neurology
Received: 26May2017
Accepted: 12January2018
Published: 05February2018
Citation:
CohenB, YakushinSB and ChoC
(2018) Hypothesis: The Vestibular
and Cerebellar Basis of the Mal de
Debarquement Syndrome.
Front. Neurol. 9:28.
doi: 10.3389/fneur.2018.00028
Hypothesis: The Vestibular and
Cerebellar Basis of the Mal de
Debarquement Syndrome
Bernard Cohen1*, Sergei B. Yakushin1 and Catherine Cho2,3
1Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States,
2Department of Neurology, NYU School of Medicine, New York, NY, United States, 3Department of Otolaryngology, NYU
School of Medicine, New York, NY, United States
The Mal de Debarquement syndrome (MdDS) generally follows sea voyages, but it can
occur after turbulent flights or spontaneously. The primary features are objective or
perceived continuous rocking, swaying, and/or bobbing at 0.2Hz after sea voyages or
0.3Hz after flights. The oscillations can continue for months or years and are immensely
disturbing. Associated symptoms appear to be secondary to the incessant sensation
of movement. We previously suggested that the illness can be attributed to maladap-
tation of the velocity storage integrator in the vestibular system, but the actual neural
mechanisms driving the MdDS are unknown. Here, based on experiments in subhuman
primates, we propose a series of postulates through which the MdDS is generated:
(1) The MdDS is produced in the velocity storage integrator by activation of vestibu-
lar-only (VO) neurons on either side of the brainstem that are oscillating back and forth
at 0.2 or 0.3Hz. (2) The groups of VO neurons are driven by signals that originate in
Purkinje cells in the cerebellar nodulus. (3) Prolonged exposure to roll, either on the
sea or in the air, conditions the roll-related neurons in the nodulus. (4) The prolonged
exposure causes a shift of the pitch orientation vector from its original position aligned
with gravity to a position tilted in roll. (5) Successful treatment involves exposure to a
full-field optokinetic stimulus rotating around the spatial vertical countering the direction
of the vestibular imbalance. This is done while rolling the head at the frequency of the
perceived rocking, swaying, or bobbing. We also note experiments that could be used
to verify these postulates, as well as considering potential flaws in the logic. Important
unanswered questions: (1) Why does the MdDS predominantly affect women? (2) What
aspect of roll causes the prolongation of the tilted orientation vector, and why is it so
prolonged in some individuals? (3) What produces the increase in symptoms of some
patients when returning home after treatment, and how can this be avoided? We also
posit that the same mechanisms underlie the less troublesome and shorter duration Mal
de Debarquement.
Keywords: vestibular-only neurons, nodulus, baclofen, rocking, swaying, bobbing, gravity, orientation vector
Abbreviations: G, gravity; GIA, gravitoinertial acceleration; GABA, gamma amino butyric acid; Hz, persecond; MdD, Mal
de Debarquement, also sometimes known as “Land sickness”; MdDS, Mal de Debarquement syndrome; OKN, optokinetic
nystagmus; PAN, periodic alternating nystagmus; VO neurons, vestibular-only neurons; VPS neurons, velocity-pause-saccade
neurons; VOR, vestibulo-ocular reex.
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Cohen et al. Neural Model of MdDS
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DEFINITIONS
Brain fog disruption of ability to think clearly
Classic MdDS MdDS arising from travel on the sea or in the air
Spontaneous MdDS MdDS generally arising after exposure to motion, but
without known exposure to sea or air travel
Dutch roll flutter of wings and fuselage of aircraft when banking in
turbulent weather
Gravity pulling Sensation of being pulled in one particular direction
MdDS
Pitch orientation vector Vector generally directed toward the spatial vertical that
underlies balance
Rocking movement or sensation of movement forward and
back, generally at 0.2Hz
Swaying movement or sensation of movement from side-to-side,
frequently with a rotary component
Bobbing sensation of vertical movement of the head and body,
generally not associated with actual movement
Roll while rotating rotation of monkeys in darkness about a vertical axis at
60°/s for several hours while oscillating ±20° at 0.1Hz
in roll
Pitch while rotating rotation of monkeys in darkness at 60°/s for several
hours around a vertical axis while oscillating at 0.1Hz at
±20° in pitch at 0.1Hz
INTRODUCTION
e Mal de Debarquement Syndrome (MdDS) is composed of
primary and secondary symptoms. e major primary eects
are the continuous rocking, swaying, bobbing, or continuous
sensations of these phenomena at 0.2Hz aer being on the sea
or 0.3Hz aer turbulent ight (1, 2). ese symptoms cease briey
when riding in a car (1–8). e patients also frequently experience
a sensation of “pulling” in specic directions (“gravity pulling”)
(2). e MdDS pathology can be extended over months or years,
giving a sense of continuous oscillatory motion that seriously
aects the lives of the suerers, who are predominantly middle-
aged women. e incessant rocking, swaying, and/or bobbing are
frequently associated with a host of symptoms such as brain fog,
sensitivity to sound and uorescent lights, headaches, inability to
work, depression, and suicidal tendencies (2, 4, 6, 9, 10).
Neither the cause for nor the changes in neural activity pro-
ducing the MdDS are known (4, 6, 7), but there have been many
hypotheses to explain the source of the MdDS. ese include
“vestibular adaptation” or “defective readaptation” (3–5, 11),
although the specics of the vestibular adaptation were not
detailed. e MdDS has also been attributed to various cerebral
processes that involve the vestibular projections to the cerebral
cortex (7), overactivity of the hippocampus and entorhinal cortex
(7), interaction of cerebral processes (7, 12), increased sensitivity
of the cerebrospinal pathways (13), and modulation of general
activity following loss of gray matter in the prefrontal cortex,
entorhinal cortex, and cerebellum (14). ese studies led to the
use of transcranial magnetic stimulation that produced transient
relief of symptoms (7, 13) but not to prolonged disappearance of
the symptoms of the MdDS. It has also been proposed that the
MdDS is a vestibular analog of the Charles Bonnet syndrome,
with the recurrent oscillations reecting a loss of vestibular input
(15). However, the function of the semicircular canals is generally
intact in these individuals. us, there is an inherent dierence
between the Charles Bonnet suerers, in whom the loss of vision
is the precipitating cause for the visual hallucinations (16, 17) and
the MdDS where there is no loss of vestibular function.
ere have also been attempts to quell the symptoms with
medication. ese medications include GABAa agonists like
diazepam or clonazepam, nortriptyline, verapamil, and topira-
mate. Generally, these produced only mild or moderate reduction
of symptoms (4, 12). Vestibular rehabilitation has generally been
unsuccessful in stopping the sensed or actual movements of the
MdDS, and extensive medical workups that include MRI’s, tests
of vestibular function with video nystagmography, and tests of
auditory and otolith function have all been normal. It has been
estimated that the costs of these normal tests extend into the
thousands of dollars. Until recently, there has been no successful
treatment of the MdDS, nor is it clear how and where the process
is generated in the central nervous system.
In 2014, Dai etal. (1) introduced the rst successful treatment
of the MdDS, and several hundred patients have been success-
fully treated since that time (2). However, the succession of the
neural events that produce the MdDS is still relatively obscure.
In this paper, we present a hypothesis composed of a number of
postulates that presumably will explain the neural basis of the
internal structure responsible for this condition. Other than the
proposed maladaptation of the velocity storage integrator in the
vestibulo-ocular reex (VOR) (1), there is no theory detailing the
neural pathways involved in generating the incessant rocking,
swaying, and/or bobbing or a sense of these oscillations that are
the main features of the illness (1). ough important questions
remain, it is the rst such analysis of the vestibular and cerebellar
components that we believe are responsible for generating the
MdDS.
e vestibular basis for the treatment came from experiments
on the monkey (18). e monkeys were rotated for several hours
in darkness while oscillating in roll. Aerward, the animals
had horizontal spontaneous nystagmus and unusual vertical
positional nystagmus when their heads were rolled to either side.
e quick phases of the vertical nystagmus were upward when
the head was rolled to one side and downward when the head
was rolled to the other side (18), similar to the vertical positional
nystagmus with head roll in the MdDS patients (1). ese changes
persisted for about 18h and were never induced in monkeys that
had very short VOR time constants, i.e., in animals that had
appropriate vestibular responses to angular acceleration but no
velocity storage. is was modeled, and it was concluded that
the positional nystagmus had been produced by cross-coupling
of the pitch orientation eigenvector that had been shied in roll
aer exposure to roll while rotating. A similar shi in the pitch
orientation vector was not produced by pitch while rotating.
It was presumed that the pitch while rotating only strengthened
the pitch orientation vector in its alignment along the spatial
vertical (see Ref. (19–22) for a more complete description of
the characteristics of velocity storage). e striking similarities
between the reversal of vertical positional nystagmus with head
roll to either side in the monkeys and in the MdDS patients
FIGURE 1 | Frequencies of rocking (A) and swaying (B) in Mal de
Debarquement Syndrome patients (2). The frequencies were determined on a
Nintendo Wii board. The rocking frequencies were tightly centered around a
maximum at 0.2Hz, more for the rocking than the swaying. When there was
no actual rocking or swaying, the perceived frequencies were determined
with the elbow stabilized on a board, and the patient moved the forearm at
the frequency of the perceived movement.
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Cohen et al. Neural Model of MdDS
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suggested that a primate analog of the human disorder had been
created in the monkey by the roll while rotating. is included
vestibular imbalance, as shown by the tendency of the patients to
march to one side on the Fukuda stepping test, and the occasional
spontaneous nystagmus, which was observed consistently in
monkeys. In these subjects, the direction of the slow phases of
the nystagmus and the direction of the postural deviation in the
Fukuda test in the MdDS patients were always congruent, indicat-
ing that a vestibular imbalance had been created.
Long-lasting changes were never produced in monkeys by
pitch while rotating, specically implicating the roll system in
the MdDS. Similar vertical nystagmus had also been previously
produced in humans by extended exposure to a slow rotating
room for several days in which the subjects intermittently made
roll head movements. is induced vertical positional nystagmus
for several hours thereaer when they rolled their heads (23, 24).
Since only roll while rotating caused the abnormal eye move-
ments in monkeys, not pitch while rotating, and similar vertical
nystagmus with head roll was produced in humans (23), we pos-
tulated that the roll encountered during voyages was responsible
for the generation of the MdDS (1).
It can be questioned whether there is a signicant amount of
roll especially on cruise ships that are the most common source
of the MdDS patients. e stability of boats depends not only on
the size of the vessel but also on the extent of the wind and waves
as well as the direction of the boat’s progress. e sea is not always
calm, and there are multiple reports of vessels being capsized in
rough waters as reported by the Marine Accident Investigation
Branch. A search of the literature revealed measurements of roll
in the Bass Strait (between Australia and Tasmania) in a ship of
11,000t deadweight, 603.7 in length and 77.6 in width (25).
e ship had an average roll of ±6.3°, an average pitch of ±1.9°,
and an average heave of 7.2. e Bass Straight is 190 miles wide
and 120 miles long. is was likely to have been very rough condi-
tions, and the sea in cruises between Florida and the West Indies
might generally be calmer. Additionally, there are roll stabilizers,
i.e., planar strips of metal attached to the keel that can reduce roll.
However, many although not all of the trips are in the Atlantic,
and there can be strong weather that produces larger waves in any
sea. Even large ships will roll if they encounter waves obliquely.
us, there can be substantial roll, depending on the size of the
waves despite the cruise ship’s roll stabilizers. While it is true that
people walk around the deck in cruise ships, nevertheless, they
are in stable positions for 6–8h when they sleep at night or when
they are sitting down for meals or in chairs to relax. erefore,
there can be adequate exposure to roll in cruise ships on the sea,
particularly in heavy weather.
ere have been no recent studies specically on roll during
ight in turbulent air, to our knowledge, although Dutch roll
was described in light planes when banking in rough weather
(26). Flutter of the wing tips and fuselage at 3–3.5Hz has been
generated in transport aircra in turbulent conditions. See
more details in the link provided (https://www.youtube.com/
watch?v=kOBbAFzXrRg). Similar oscillations could contribute
to the 0.3 Hz body oscillations in some MdDS patients aer
extended ights in turbulent weather.
A striking nding was that there was a sharp peak in the aver-
age frequency of rocking and the perceived rocking in both our
2014 and 2017 papers at 0.2Hz (Figure 1A). ere was more
spread in swaying (Figure1B), probably due to the variation in
determining the period of swaying, i.e., pitching was easier to
observe and sense than swaying. e signicance of the relatively
conserved 0.2Hz frequency (1 cycle/5s) is that it signies that a
similar process is likely to be producing the rocking in virtually
all of the MdDS patients aer sea voyages. is implies that the
frequency is being internally generated and is sensitive to an
external stimulus of 0.2Hz. e 0.2Hz frequency is too slow to be
produced by lesions of the inferior olive, since frequencies of such
phenomena like palatal myoclonus typically have frequencies of
about 1 Hz (27). erefore, there should be another, separate
source for the 0.2 and 0.3Hz signals in the brainstem and cerebel-
lum to account for the changes that are presumed to arise in the
velocity storage integrator.
Modulation of roll depends heavily on the integrity of the
cerebellar nodulus (28–31). is suggests that the nodulus may
play an important part in the generation of the MdDS. In normal
monkeys and humans, the orientation of the axis of eye velocity
is always aligned with the spatial vertical or the gravitoinertial
acceleration (GIA) during rotation, regardless of the position of
the head in space (20, 21, 30–35). e underlying postulate for
the generation of the MdDS was that the pitch orientation vector
of the system had been transformed from its original position
along gravity to a tilted position in roll (1). e purpose of the
treatment was to bring the orientation vector back to the spatial
vertical by activating the velocity storage integrator with an opto-
kinetic stimulus that rotated around the spatial vertical. us, the
proposed treatment was to roll the head of the aected subjects
at the frequency of their perceived or actual rocking, swaying, or
bobbing, while activating the velocity storage integrator with a
low-frequency, constant velocity, full-eld, optokinetic stimulus
rotating around the spatial vertical against the direction of their
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vestibular imbalance. Presumably, this reoriented the integrator
back to gravity or the GIA. If the correct direction of the ves-
tibular imbalance was not chosen during the treatment, the body
oscillations became worse, supporting the postulate that it was
the conict between the tilted orientation vector and the spatial
vertical that had produced the MdDS.
As a result, it was possible to relieve the constant rocking,
swaying, and/or bobbing in 70% of the original 24 patients aer
the second week of treatment, an improvement that was gener-
ally maintained in the original group when they returned home,
and at follow-up aer a year (1). In an additional 141 MdDS
patients, the 2-week success rate was 80% (2); however, the rate
of symptom reduction fell to 44% aer 1year, possibly due to
stress experienced by these patients during long ights or rides
home aer treatment. is drop in ecacy must be addressed in
future studies, but it should be emphasized that this was the rst
and only successful treatment for the MdDS.
e implication of these results is that the underlying cause
for the MdDS is a disturbance in the control of roll at a specic
direction and frequency, which is approximately 0.2Hz aer sea
voyages and 0.3Hz aer turbulent ight. e fact that there was
a dierence in the sensed or actual oscillations implies that an
external 0.2 or 0.3Hz component of the roll on the sea or in the
air was provoking the prolonged response to roll, but the highly
specic oscillation frequencies across a wide range of MdDS
patients strongly implies that those frequencies were recognized
and perpetuated in the central nervous system. As will be shown
below, we think that it is likely that the storage mechanism
involves the nodulus of the vestibulocerebellum.
e treatment devised by Dai etal. (1) signicantly reduced
the symptoms by readapting the velocity storage mechanism to
normality. is indicates that there had been no primary struc-
tural lesions in the vestibulocerebellar system that had caused
the symptoms. is was essentially veried by the rapid return to
normality, even aer having suered with the major symptoms
for up to 20years (2). However, the neural basis of the process
that involved the velocity storage mechanism in the VOR has
remained unclear. Here, a hypothesis composed of a number of
postulates is proposed to explain how these ndings are produced
in the brainstem and cerebellum. First, however, we consider
some of the requirements of such a proposal.
THEORETICAL DEMANDS OF AN MdDS
GENERATION HYPOTHESIS
e recurrent direction-changing nystagmus in periodic alter-
nating nystagmus (PAN) aer cerebellar lesions oers a potential
scheme to explain the continuous sensations of rocking, swaying,
and bobbing of the MdDS patients. PAN occurs aer cerebellar
lesions and causes a reversal of the direction of the slow and
quick phases of nystagmus at frequencies of about once every
2–3min (36). is has been interpreted as recurrent activation
of groups of neurons on each side of the brainstem, i.e., as an
adaptive process that can continuously reverse the direction of
the nystagmus (37, 38). We have also reproduced the continuous
reversal of the direction of horizontal nystagmus in the monkey
by ablation of the nodulus and uvula (31, 39). In both studies,
the recurrent cycle was terminated by an IM injection of the
GABAB agonist baclofen, similar to the eect of baclofen on the
PAN (36). e PAN is, of course, considerably slower than the
recurrent oscillations in the MdDS, but this analogy shows that
there can be oscillation between neural groups on each side of
the brainstem.
MdDS GENERATION HYPOTHESIS
Based on new ndings from a three-dimensional study of the
characteristics of vestibular-only (VO) neurons in the medial
and superior vestibular nuclei (40), it is proposed that there is
a similar situation that produces the MdDS, namely, oscillation
between the VO neuronal groups on each side of the brainstem
at frequencies of 0.2 or 0.3Hz, controlled by output from the
cerebellar nodulus that produces the MdDS.
RELEVANT QUESTIONS
Previous studies of velocity storage have primarily been done on
oculomotor aspects of vestibular activation, while the current
interest is in head, neck, body, and leg movements or the per-
ception of such movements. erefore, there should be specic
activation of the neural elements that would cause excitation of
the body and limbs rather than the eyes. ere should also be
neurons that control dierent neural groups on either side of
the brainstem to activate dierent parts of the body and limbs.
If such an arrangement exists, these neural groups should have
substantial connections between them that could monitor and
maintain the oscillations. e VO neurons characteristically
have a time constant during rotation of 15–25s (40, 41), but these
neurons are capable of responding at a much faster rate, i.e., up
to 450 impulses/s (42, 43). As suggested earlier, there should be
adaptable elements in these structures to account for the pro-
posed shi in the pitch orientation vector that drives them into
oscillation when confronted with exposure to head roll on the sea
or in the air. Finally, there should be access to a 0.2 or 0.3Hz signal
from a structure that directly connects to these neural groups and
sequentially drives them.
e VO neurons in the medial and superior vestibular nuclei
meet these criteria. ey are the neural structures that convert the
time constant of the hair cells in the cupula of 4–4.5s (42) into
the VOR time constants of 15–25s or longer (19–22, 44). e
VO neurons receive direct input from the semicircular canals and
output to the neck, body, and limbs through vestibulo- and retic-
ulo-collic and vestibulo- and reticulospinal pathways (45–48).
ey have little direct output to the oculomotor system, and pre-
sumably contact the oculomotor system primarily through the
VPS neurons (48), although there are also some direct vestibulo-
oculomotor projections. As shown by Boyle and McCrea etal.,
the VO neurons reect the imposed accelerations on the head and
body, but do not go into action during volitional turns of the head
(45–47). ere are other vestibular neurons related to eye veloc-
ity that are activated during volitional head or head and body
oscillations (49–51). us, there is a clear separation between the
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vestibular neurons that respond to passive head or head and body
oscillations, as against a complex set of neurons in the vestibular
nuclei that respond to visual input, volitional turns of the head or
eerence copy (45).
e VO neurons, however, are out of volitional control, and
we postulate that the rocking, swaying and bobbing during the
MdDS is generated by the VO neurons that similarly are not
subject to eerence copy, volitional control, or response of corti-
cal or visual input. is is consistent with the nding during the
MdDS that the patients have little or no active control of imposed
rocking, swaying, and/or bobbing, or of the sensations associated
with these movements. Of interest, drowsiness does not aect the
rocking, swaying, or bobbing of the MdDS patients, and these
oscillations or the perception of these oscillations persist even
when the MdDS patients are not alert (Yakushin, Cohen, persoal
communication).
e mixture of neurons that respond to passive head move-
ment, voluntary head movement, and eerence copy demonstrate
that activity generated in the vestibular system can be overt or
silent when viewed in terms of muscular activity. us, we
assume that perceived rocking, swaying, and bobbing that is not
observable in many of the MdDS patients does not mean that
vestibulospinal and reticulospinal tracts are not active, but simply
that the activity is not always manifest.
e VO neurons have extensive axonal connections to VO
neurons on the other side of the brainstem and use GABAB as
the primary inhibitory agonist (52–54). Injections of baclofen
caused a dramatic reduction in activity of VO neurons (22, 40,
55), and when the crossing axons were severed, velocity storage
permanently disappeared (54, 56). Since we propose velocity
storage is intimately involved in production of the MdDS (1),
the disappearance of velocity storage when the connecting VO
neurons in the brainstem were inhibited or severed supports our
hypothesis that the VO neurons are involved in the production
of the MdDS.
When examined in three dimensions, a majority of VO
neurons on each side of the brainstem are primarily activated
by rotation to the contralateral side and fail to respond to ipsi-
lateral rotation (40). ey also receive vertical canal and otolith
inputs. Since these neurons project to the head, neck, body, and
limbs through dierent components of the reticulospinal and
vestibulospinal pathways, they each can activate a dierent set
of head, neck, body, and limb movements, which could result in
the rocking, swaying, and bobbing as well as the “gravity pull-
ing” of the MdDS. Exactly how this is done is still not known,
however.
EVIDENCE THAT THE ORIENTATION
VECTOR CAN BE MODIFIED BY
EXPOSURE TO ROLL
e experiments in monkeys using roll while rotating pro-
duced modication of the pitch orientation vector for up to
18h (18). In other experiments, Eron etal. (57, 58) also have
demonstrated that it is possible to condition the polarization
vector of VO neurons by putting monkeys on their sides (in
roll) for 30–60min. is shis the otolith polarization vector
toward gravity in the side-down or rolled position. e shi in
the habituated orientation of the neuron persisted for periods
of several hours. us, the orientation of the VO neurons can
be altered for substantial periods by exposure to roll. Changes
in their polarization vectors, while not as profound, were also
found in canal-related neurons that were located in the direct
pathway of the VOR (59). Such changes could also be involved
in the “gravity pulling” by altering the vertical canal and otolith
inputs to the VO neurons.
A POTENTIAL CEREBELLAR SOURCE OF
THE 0.2 OR 0.3Hz BODY OSCILLATIONS
A large body of experimental data indicates that the nodulus
and part of the uvula exert powerful control of the VO neurons
and the velocity storage integrator. e VO neurons receive
substantial input from the nodulus (31, 60–63). Pathways from
the lateral portions of the nodulus cause disappearance of veloc-
ity storage and electrical stimulation of the nodulus, presumably
activating these pathways, also causes a loss of velocity storage
(64). is region of the nodulus is likely to discharge activity
in velocity storage during visual suppression (19, 65) as well as
loss of stored activity in velocity storage during “tilt-dumps”
(20, 33, 39). In contrast, pathways from the central portions of the
nodulus provide activity responsible for orienting the axis of eye
velocity to the spatial vertical (20, 66). ese functions are lost
aer nodulus lesions (30, 31). Habituation of the dominant time
constant of the VOR is also controlled by the nodulus and is lost
aer nodulus lesions (67, 68). erefore, there is extensive neural
control of the VO neurons and of the velocity storage integrator
through this structure (30, 31). Lesions of the nodulus also result
in alternating nystagmus every 5min (31, 39). us, the nodulus
has a role in maintaining temporal adaptation of processes in the
vestibular nuclei, that presumably can identify the source of the
drive on neuronal groups in the brainstem that produce the PAN.
Of note, this alternating nystagmus is eliminated by the action of
baclofen, similar to the elimination of activity in VO neurons by
the IM injection of baclofen (40, 55).
Nodulus lesions also cause a loss of roll eye movements and
torsional nystagmus (28, 29), conrming the close association of
the nodulus to roll. us, the tilted state of the pitch orientation
vector in roll during the MdDS would be a natural function of the
neural structure of the nodulus, as would the ability of the roll
component of the nodulus to be modied by extensive exposure
to roll on water or in the air.
Although the origin of the 0.2 and 0.3Hz signal driving the
VO neurons has yet to be discovered in monkeys or humans, this
signal is present in the nodulus of the rabbit. In a comprehen-
sive series of experiments, Barmack and Shojaku etal. (69–74)
showed that there was a massive input from the vestibular nerve
to the nodulus (73). A striking aspect of this is that about 70%
of vestibular bers in Scarpa’s ganglion project directly to the
nodulus through the inferior olives, bypassing the vestibular
nuclei. is input arises predominantly in the anterior and
posterior canals that sense active or passive roll movements of
FIGURE 2 | (A) Site of recording of the neuron of the nodulus shown in (B).
(B) Climbing Fiber-driven Purkinje cell activity from the site shown in (B). The
Purkinje cell fired three to five times. Each time, the animal was rolled into the
left side-down position. The oscillation in roll is shown by the bottom trace.
The oscillation amplitude is shown by the bar on the right, and the time base
by the lowest trace. This figure is reprinted with permission. For further
details, see the article by Barmack and Shojaku (70).
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the head and/or of the head and body. is activity is also trans-
mitted through the medial and inferior vestibular nuclei to the
inferior olives, where the individual planes of one anterior and
the contralateral posterior semicircular canals are represented
in individual neurons. e combined anterior and posterior
canal activation in roll is also separately represented in another
inferior olive nucleus (69). e combined activity that represents
roll head and/or head and body in space is then transmitted by
climbing ber and mossy ber inputs to the Purkinje cells in
the contralateral nodulus. us, there is a powerful input to the
nodulus continuously detailing the passive and active head and/
or head and body movements in roll. Otolith neurons also sense
the roll position of the head and/or the head and body relative
to gravity and the GIA, and transmit this activity to the inferior
olives and thence to the nodulus. e nodulus also receives a
mossy ber input from the dorsal cap of Kooy in the inferior olive
that originates in the subcortical visual system in the nucleus of
the optic track that carries optokinetic-generated activity to the
vestibular nuclei and the nodulus.
In their experiments, coordinated ring of the nodular and
uvular Purkinje cells (Figure2A) was produced by rolling the
head and body statically and dynamically around the long axis
at 0.2Hz (Figure2B). e 0.2Hz oscillation in roll was chosen
because it was the frequency that gave the best coordinated
responses in the Purkinje cells on repeated testing at dierent fre-
quencies of oscillation (Barmack, personal communication). e
coordinated ring of the Purkinje cells at 0.2Hz ceased in most
cells, when the roll stimulus ended, and the cells returned to their
irregular spontaneous activity. In about 15% of the Purkinje cells,
however, the 0.2Hz ring frequency faded and then returned for
300–400s. us, it was possible to induce aer-activity in some
neurons at the preceding 0.2 Hz frequency that considerably
outlasted the exciting 0.2Hz roll oscillation (70). If such activity
were present in the human nodulus, and if it were suciently
prolonged, presumably it could supply activation of the output
pathways to the VO neurons, and initiate the sense of swaying,
rocking, and/or bobbing. Moreover, in a smal l number of Purkinje
cells, it was possible to change the frequency of the aer-activity
to 0.3Hz, as experienced in the MdDS aer turbulent ight. A
0.1Hz frequency was also induced that could be related to the
spread in frequencies shown in Figure1. ey also encountered
Purkinje cells that had a continuous 0.2Hz ring rate that could
maintain the preference of the Purkinje cells to oscillate at 0.2Hz.
us, there was activity in the rabbit nodulus and uvula that could
have potentially caused activation of VO neurons that outlasted
the roll stimulus that had induced the original activity. If this
activity existed in humans, it could explain the frequency of the
body rocking (Figure1).
is work provides a potential neural basis for the 0.2 and
0.3Hz oscillations in Purkinje cell ring that could be respon-
sible for the 0.2 and 0.3Hz oscillations in rocking, swaying, and
bobbing of the MdDS patients. One may question whether results
in rabbit as well as in monkey can be appropriately applied to
humans. e rabbit’s eyes are centered ±85° from the midline of
the head; whereas, the monkey and human have the fovea centered
±7° from the midline. Of course, there are many other dierences
between rabbits and humans. However, the vestibular system does
not follow this rule. Baker and Straka and other colleagues have
done extensive studies of the vestibular and oculomotor systems
in sh and frogs (75–80). ey note that “although the projec-
tions of the neurons vary among species, similar subgroups of
major vestibular projection neurons originate from homologous
segmental positions in the hindbrain of mammals, birds, and
amphibians.”
us, it is striking that the semicircular canal to vestibular
nuclei and inferior olive connections are very similar across
mammalian species. For example, the angles of the planes of the
semicircular canals and the insertions of the eye muscles driven
by the semicircular canals lie in the same planes in humans, mon-
keys, goldsh, and sharks (81–83). Moreover, the eye movements
induced by the canals are also the same across species in rabbits,
dogs, cats, and monkeys (81, 82, 84). A striking example of the
similar morphology of the end organs is that the planes of the
semicircular canals are the same in monkeys and humans as in
a brachiosaurus dinosaur that has been extinct for 155 million
years (85). Of course, the dinosaur labyrinth is magnitudes bigger
than the monkey labyrinth, but the planes of the canals are the
same.
Baker and Straka conclude: “these comparative attributes
among vertebrates suggest that, from basic wiring through func-
tion, the vestibular blueprint was established quite early during
vertebrate evolution and, from the viewpoint of structure more
than function, has been largely conserved throughout ~400
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Cohen et al. Neural Model of MdDS
Frontiers in Neurology | www.frontiersin.org February 2018 | Volume 9 | Article 28
million years of vertebrate phylogeny (75).” From this, we pos-
tulate that the ndings in the rabbit can be applied to monkeys
and humans and that the driving frequency established in the
nodular Purkinje cells are manifest in the VO neurons to produce
the rocking, swaying, and bobbing of the MdDS in humans.
DISCUSSION
In this paper, we posit that the MdDS is produced by a devia-
tion of the pitch orientation vector from the spatial vertical to
one side in roll. Further, the deviation of the pitch orientation
vector occurs as a function of contextual learning aer prolonged
exposure to roll on the sea or in the air. If the pitch orientation
vector is displaced in roll, it should cause positional nystagmus.
Consistent with this, many of the MdDS patients had a unique
type of vertical positional nystagmus when their heads were put
in roll on either side; the quick phases were up when the head
was on one side and down when the head was on the other side
(1). Most patients also had a vestibular imbalance, manifested by
marching to one side in the Fukuda stepping test. e unusual
vertical positional nystagmus was also produced in monkeys
aer extensive exposure to roll while rotating. is occurred in
association with a vestibular imbalance manifested by sponta-
neous nystagmus in darkness (18). is provided the basis for
recognizing that a similar process had produced the MdDS in
monkeys as in humans. Such vertical positional nystagmus was
also produced in humans aer long exposure to a slow rotating
room when they rolled their heads to the side (23, 24). e experi-
ments in monkeys also demonstrated that such responses to roll
while rotating only occurred in monkeys with a long VOR time
constant, that considerably outlasted the 4.5–5.0s input from the
hair cells in the semicircular canals to steps of rotational velocity
(42). Such time constants are produced in the velocity storage
integrator, providing evidence that the MdDS was generated in
velocity storage.
From this, it was postulated that the pitch orientation vector
had been transformed from its original position along gravity to
a lateral position in roll. It was further postulated that this shi
had been produced by cross-coupling that had altered the position
of the pitch orientation vector. e failure of pitch while rotating
to cause a shi in the pitch orientation vector was interpreted as
having strengthened, not modied, the pitch orientation vector.
Model predictions were consistent with this hypothesis.
e nding that modication of the pitch orientation vector,
i.e., its return to the spatial vertical, was produced by viewing
low velocity, full-eld optokinetic stimulation oriented around
the spatial vertical conrmed this hypothesis. us, there was
internal consistency between the conditions in both the MdDS
patients and the response to roll while rotating. e ability to
reverse the MdDS symptoms with a low velocity, full-eld,
optokinetic stimulus rotating against the direction of the
vestibular imbalance, further strengthened the hypothesis that
the optokinetic nystagmus (OKN) stimulus had countered the
lateral tilt of the pitch orientation vector in roll. is conclu-
sion was also supported by the disappearance of the rocking,
swaying, and bobbing and the subjective symptoms aer such
treatment (1, 2).
EVALUATION OF SPECIFIC ASPECTS
OF THE HYPOTHESIS
e mechanics of the basis for oscillation were also considered:
namely, it was proposed that the MdDS is produced by repetitive
oscillation of groups of VO neurons on either side of the medial
and superior vestibular nuclei. ese neurons project excitatory
activity to muscles in the head, neck, body, and limbs that could
produce the repetitive rocking, swaying, and/or bobbing or the
sensation that these motions have occurred (40). is could
explain why spontaneous nystagmus was not prominent in the
MdDS patients. Instead they generally manifested their vestibu-
lar imbalance through the body and limbs, as evidenced by the
lateral movement on the Fukuda stepping test. is would be
expected if the primary site of activation of the MdDS movements
was in the VO neurons that primarily project to the head neck,
limbs, and body, and not to the oculomotor system. Rather, it is
believed that the major projection of the VO neurons that are
sensing body rotation is to the body, and not to the eyes (48). e
proposed link to the oculomotor system from the VO neurons is
through the VPS neurons, and these neurons become inactivated
during drowsiness along with the eye movements, whereas the
VO neurons continue their activity unchanged (13, 43). Similarly,
in agreement with this, the perceived rocking, swaying, and bob-
bing continue even when the MdDS patients are drowsy. ese
ndings are consistent with the clinical state and support the
conclusion that the VO neurons are at the basis of the MdDS.
Finally, we propose that the signal driving the 0.2 and 0.3Hz
oscillations impinges on the VO neurons through projections
from the nodulus. Since the nodulus has been shown to have a
close association with roll (28, 29, 69–74), the exposure to repeti-
tive roll while on the sea or in the air is presumably the trigger for
the syndrome. As yet, the source of the 0.2Hz signal, postulated
to come from the nodulus, has not been found in humans or
subhuman primates, but the ndings by Barmack and Shojaku
indicate that a preferred 0.2Hz oscillation is present in the nodu-
lus of the rabbit, and that the climbing ber-driven Purkinje cells
are readily excited by a 0.2 or a 0.3Hz oscillation in roll. Such a
signal may also be present in the human nodulus.
e same organization is probably also responsible for the
generation of the commonly experienced Mal de Debarquement
(MdD). It is likely that the less intrusive MdD is also produced by
a transient shi of the orientation vector in roll, but fortunately,
this is short-lived in most individuals. e underlying basis for
the dierence in durations of the MdD and the MdDS are not
known, but presumably involve dierent tendencies for continued
activation of nodulus Purkinje cells in the two conditions. Nor
is it obvious why women are much more susceptible to develop-
ment of MdDS than men. A similar propensity is also prevalent in
migraine and motion sickness. If our postulate that the changes in
the underlying frequency of nodular Purkinje cells is at the heart
of the syndrome, then experiments in male and female monkeys
and rabbits could prove interesting. It would also be important to
determine if the eects of tilt of the body axis and exposure to brief
ashes of light during recording of optokinetic aer-nystagmus
cause discharge in velocity storage (19, 65) Both of these functions
have been demonstrated to originate in the nodulus (19, 30, 65).
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Cohen et al. Neural Model of MdDS
Frontiers in Neurology | www.frontiersin.org February 2018 | Volume 9 | Article 28
POSSIBLE EXPERIMENTAL
INVESTIGATION OF UNPROVEN
ASSUMPTIONS
e postulate that the VO neurons were set into oscillation
through an inhibitory link across the brainstem is presented
without specic evidence that this actually occurs in the MdDS
patients. For that reason, it would be important to have registra-
tion of VO neurons in monkeys with long VOR time constants
aer they had been exposed to several hours of roll while
rotating that produced the vertical positional nystagmus when
their heads were put in roll on either side of the midline. is
preparation could also be useful in determining if the 0.2Hz
oscillation in the Purkinje cells in the rabbit were similar to
those in primates. It is also possible to determine if the pitch
orientation axis is aligned with the spatial vertical in recordings
of neurons in the nodulus. If so, then it could be determined
if the pitch orientation vector was tilted aer generation of an
MdDS analog in monkeys and whether it was possible to reori-
ent the pitch orientation vector by exposure to a slowly moving,
full-eld OKN stimulus moving about the spatial vertical. It also
might be possible to force a shi in the pitch orientation vector
by exposure to roll while rotating, and to determine how much
tilt of the OKN axis was sucient to produce a tilt in the pitch
orientation vector. Finally, it might also be possible to determine
if the pitch orientation vector is actually strengthened aer
exposure to pitch while rotating (18).
Similarly, the hypothesis that exposure to an optokinetic
stimulus oriented to gravity induces reversion of the pitch orien-
tation vector could explain the nding that the body oscillations
disappear briey when the MdDS patients ride in cars (3–5).
Presumably, some aspect of the visual streaming or the oscilla-
tions of the automobile temporarily restore the orientation vector
back to the spatial vertical. is could be studied experimentally
by blocking vision during the car rides, or by determining if rides
on smooth, at surfaces in well sprung cars fail to aect the sensa-
tions of the MdDS.
It would also be of interest to tilt the axis of rotation of the
OKN when treating MdDS patients to determine whether tilts
of the axis of the OKN stimulus failed to induce abolition of the
MdDS, and if so, by how much tilt of the axis of rotation. e
importance of the vestibular imbalance could also be studied by
combining rotation at various velocities with the MdDS to deter-
mine whether it made the perception or actual oscillations better
or worse, as does rotating the OKN stimulus during treatment
against or in the direction of the vestibular imbalance. Finally, it
would be of interest to reduce the time constant of the velocity
storage integrator using the paradigm that was used to reduce
velocity storage in motion sickness (66), and test the hypothesis
that the MdDS could be improved by habituating or shortening
the time constants of the VO neurons.
A critical experiment would also be to determine if the yaw
axis orientation vector was tilted from the spatial vertical during
o-vertical axis rotation (OVAR) in patients with the MdDS,
and whether such a tilt reverted to its orientation to gravity
aer the patients had been successfully treated (20, 66). Such an
experiment could provide proof of the tilted orientation vector
hypothesis.
e syndrome considered in this manuscript is dependent
on the presence of a velocity storage integrator and does not
exist in monkeys and presumably in humans with a short VOR
time constant. Velocity storage, as noted above, is not a recently
developed phenomenon, since it is also present in the goldsh,
evolved hundreds of millions of years ago (75). Ernst and
omas have shown that it is possible to activate cross axis ring
of neurons on each side of the vestibular nuclei of the goldsh
with continuous rotation, as in humans (37, 38). e goldsh
also have prominent cerebella with many similar connections as
in mammals (75). Consequently, it could also be of interest if it
were possible to produce cross-brain stem activation of vestibular
units by roll while rotating in the goldsh. e point is that this
type of cerebellar-driven oscillation of neurons in the vestibular
nuclei may be a very old phenomenon. If so, then it would be of
interest to determine if cerebellar-driven vestibular activity is an
intrinsic phenomenon crossing species from sh to man.
QUALIFICATIONS TO THE MdDS
HYPOTHESIS
Two major qualications could invalidate the hypothesis pre-
sented in this paper. First, there has been heavy emphasis on
the speculation that the syndrome produced in the monkey by
roll while rotating is essentially the same as that of the MdDS in
humans. is was based primarily on the nding of abnormal
positional nystagmus and a vestibular imbalance in both humans
and monkeys. However, there were signicant dierences
between these two that were encountered. Namely, there was
more activation of spontaneous nystagmus in the monkeys than
in humans in whom spontaneous nystagmus was rarely present.
is suggested that the vestibulo-ocular component was larger
in the monkeys than in humans. It could have been related to
the dierences in generation of the mdDS. e monkeys were
rotated in yaw for several hours, whereas the humans presum-
ably got their MdDS aer prolonged exposure to roll, without the
concomitant yaw axis rotation. More important, perhaps, was the
dierence in body movements. Rocking, swaying, and or bobbing
was never observed in the monkeys aer roll while rotating, but
such movements or the perception of such movements were a
cardinal feature of the MdDS. Of course, there was no manifest
movement in many of the humans, only the sensation of move-
ment, and it could not be ascertained whether the monkeys also
had a sensation of movement, not manifest by rocking, swaying,
and/or bobbing. If the VO neurons were driven by the nodulus,
such activity would be expected. However, the monkeys studied
in the 2009 paper were always chaired when out of their cages,
so that it is possible that weak oscillations of limbs were never
observed (18). If monkeys were to be used in Future studies,
it would be important to have implanted EMG electrodes to
determine if weak oscillations were present in the muscles aer
exposure to roll.
Second, heavy emphasis was placed on the origin of the
role of the nodulus in perpetuating the body oscillations or the
9
Cohen et al. Neural Model of MdDS
Frontiers in Neurology | www.frontiersin.org February 2018 | Volume 9 | Article 28
perception of the body oscillations. is postulate depended on
data from the rabbit. However, there was little direct evidence
that such activation of nodular Purkinje cells was also present
in the individuals with the MdDS. If such activity does not exist
in humans, then an important part of this hypothesis would be
invalidated.
Despite these dierences, the hypothesis that the pitch ori-
entation vector had been tilted in roll that led to the treatment
generated a therapy that was successful in a majority of the MdDS
patients, for the rst time (1, 2). If the study using OVAR can be
performed, then it could potentially provide support for this por-
tion of the hypothesis. However, these qualications must be kept
in mind in evaluating whether the hypothesis is generally valid.
OTHER TREATMENT NECESSITIES
A major criticism of the therapeutic results is that they were
obtained without adequate controls. is largely accrued because
there was no signicant support for such a study. e patients
were desperate for relief aer having had the MdDS for years
without relief, and some were even suicidal. Also, this was the rst
successful treatment for the MdDS, and the results in the initial
study were statistically signicant (1). Moreover, the patients were
coming for treatment from all over the country and the world and
were not able to return for motor studies without support. e
fact that many of the patients had had their illness for many years
without relief despite a wide range of investigative steps, extensive
drug treatment, and prolonged physiotherapy without signicant
improvement rendered treatment, even without controls to be
a necessity. Presumably, given the strong positive results, even
though they were largely reported by telephone, provide the
preliminary data to support a complete, controlled study. Such a
study is now under consideration.
A signicant problem remains in the treatment of the MdDS,
namely, that there was a substantial reversion back to the rock-
ing, swaying, and/or bobbing aer treatment. is was generally
attributed to oscillations during the ride home (2). Initial eorts to
reduce this reversion with oral baclofen have not been successful.
is might be due to its limited ability to cross the blood–brain
barrier (86–89).
Intramuscular injections of baclofen in monkeys caused the
disappearance of any vestige of velocity storage in the VO neurons
(22, 40, 55). If our hypotheses that the MdDS is produced by VO
neuronal activity are correct, suppression of VO neuron activity
could stop the uncontrollable oscillations of the body during the
MdDS. If the 0.2 or 0.3Hz signals are coming from the cerebellum,
however, we do not have the appropriate drugs to aect cerebellar
circuitry, aside from the GABAA and GABAB inhibitory agonists,
and more research is necessary on this subject.
Since cruises on the sea continue to be an attractive vacation,
it is likely that we will continue to have numerous people who
are aicted by this malady. However, while it was originally
considered to be untreatable, and people have even been driven
to suicide by this condition, there appears to be the possibility
of nally correcting the position of the pitch orientation vector
so that it stays permanently on its appropriate orientation to the
spatial vertical. Of course, adequate therapy demands reduction
in the host of associated symptoms such as brain fog, sensitivity
to sound and uorescent lights, headaches, inability to work,
depression, and suicidal tendencies that accompany the MdDS
(2, 4, 6, 7, 9, 10, 13–15), but this must be addressed in detail
when the uncontrolled body movements or the sensation of these
movements ceases.
AUTHOR CONTRIBUTIONS
All authors contributed to the generation of this manuscript.
ACKNOWLEDGMENTS
We thank Larry Cornman at the Aviation Applications Program
of the UCAR for information on aircra characteristics in turbu-
lent weather. We thank Richard Lewis, MD, for helpful criticisms,
and Rupa Mirmira for editorial assistance.
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Conict of Interest Statement: e authors declare that the research was con-
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construed as a potential conict of interest.
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