Clinical, neuropathological and neuroimaging
research suggests that pathological changes in
Parkinson's disease (PD) start many years before
the emergence of motor signs. Since
disease-modifying treatments are likely to be
most effective when initiated early in the
disease process, there has been significant
interest in characterizing prodromal PD. Some
people with PD describe autonomic symptoms at
the time of diagnosis suggesting that autonomic
dysfunction is a common feature of prodromal PD.
Furthermore, subtle motor signs may be present
and emerge prior to the time of diagnosis.
The authors present a series of patients
who, in the prodromal phase of PD, experienced
the emergence of tremor initially only while
yawning or straining at stool and discuss
how early involvement of autonomic brainstem
nuclei could lead to these previously unreported
phenomena. The hypothalamic paraventricular
nucleus (PVN) plays a central role in autonomic
control including bowel/bladder function,
cardiovascular homeostasis and yawning
and innervates multiple brainstem nuclei
involved in autonomic functions (including
brainstem reticular formation, locus ceruleus,
dorsal raphe nucleus and motor nucleus of the
vagus).
The PVN is affected in PD and evidence from
related phenomena suggest that the PVN could
increase tremor either by increasing downstream
cholinergic activity on brainstem nuclei such as
the reticular formation or by stimulating the
locus ceruleus to activate the
cerebellothalamocortical network via the
ventrolateral nucleus of the thalamus. Aberrant
cholinergic/noradrenergic transmission between
these brainstem nuclei early in PD couldlead to
tremor before the emergence of other
parkinsonian signs, representing an early
clinical clue to prodromal PD.
Résumé
La recherche clinique, neuropathologique et
en neuroimagerie suggère que les
changements pathologiques de la maladie de
Parkinson (MP) commencent plusieurs
années avant l'apparition des signes
moteurs. Étant donné que les
traitements de fond sont susceptibles
d'être plus efficaces lorsqu'ils sont
initiés tôt dans le processus de la
maladie, il y a un intérêt
significatif pour caractériser la MP
prodromique.
Certaines personnes atteintes de MP
décrivent des symptômes autonomes
au moment du diagnostic, suggérant que le
dysfonctionnement autonome est une
caractéristique commune de la MP
prodromique. De plus, des signes moteurs subtils
peuvent être présents et
apparaître avant le moment du diagnostic.
Les auteurs présentons une
série de patients qui, dans la phase
prodromique de la MP, ont remarqué
initialement l'émergence de tremblements
uniquement en bâillant ou en allant
aux selles. Ils discutent de la façon
dont l'implication précoce des noyaux du
tronc cérébral autonome pourrait
conduire à ces phénomènes
auparavant non signalés. Le noyau
paraventriculaire hypothalamique (PVN) joue un
rôle central dans le contrôle
autonome, y compris la fonction intestinale /
vésicale, l'homéostasie
cardiovasculaire et le bâillement.
Il innerve plusieurs noyaux du tronc
cérébral impliqués dans les
fonctions autonomes (y compris la formation
réticulaire du tronc
cérébral, le locus ceruleus, le
noyau du raphé dorsal et le noyau moteur
du vague). Le PVN est affecté dans la MP
et les preuves issues de
phénomènes connexes
suggèrent que le PVN pourrait augmenter
le tremblement soit en augmentant
l'activité cholinergique en aval sur les
noyaux du tronc cérébral comme la
formation réticulaire, soit en stimulant
le locus ceruleus pour activer le réseau
cerebello-thalamo-cortical via le noyau
ventrolatéral du thalamus. Une
transmission cholinergique /
noradrénergique aberrante entre ces
noyaux du tronc cérébral au
début de la MP pourrait entraîner
des tremblements avant l'apparition d'autres
signes parkinsoniens, ce qui représente
un indice clinique précoce de la MP
prodromique.
Cartoon showing afferent and
efferent projections of the paraventricular
nucleus (PVN) salient to yawning (red), tremor
(blue) and parakinesia brachialis oscitans
(green). DA, dopamine; LRN, Lateral reticular
nucleus, OXT, oxytocin; VLpv, ventrolateral
nucleus of the thalamus pars
ventralis.
The diagnosis of Parkinson's disease (PD) is
centered on the identiÞcation of a
predominantly motor phenotype. Converging
evidence from clinical, neuropathological and
neuroimaging research, however, suggests that
pathological changes in people with Parkinson's
disease (PwP) start years before the emergence
of core motor signs [1, 2]. A recent
hypothesis in PD is that alpha-synuclein may
spread from the peripheral autonomic nervous
system to lower brainstem nuclei and only
thereafter to areas salient to movement
[2&endash;4]. In particular, a
body-Þrst subtype of PD has been recently
described whereby multimodal imaging supports
cardiac and colonic denervation which may occur
in prodromal PD [5]. Hence, it is not
surprising that PwP report autonomic symptoms at
the time of diagnosis [6]. Since
disease-modifying treatments are likely to be
most effective when initiated early in the
disease process, there has been interest in
identifying and character rising prodromal PD
[7]. REM-sleep behavior disorder (RBD),
the proto- typical prodromal syndrome in PD, has
complex pathophysiology involving GABAergic,
glutamatergic and cholinergic mechanisms
centered on a number of critical brainstem
nuclei [8]. Post-mortem, animal and
imaging studies suggest that cholinergicdegen-
eration of the mesopontine tegmentumplays a
central role in RBD [9, 10]. Other
prodromal markers of PD are regulated by the
autonomic nervous system and include
constipation, orthostatic hypotension, uri- nary
and erectile dysfunction [7]. In
parallel, some cholinergic, serotoninergic and
noradrenergic brain- stem nuclei which regulate
these autonomic functions are selectively
vulnerable in PD [11]. These include the
dorsal motor nucleus of the vagus, dorsal raphe
nuclei, locus ceruleus and subceruleus and
brainstem reticular formation.
Subtle motor signs are present before a
deÞni- tive diagnosis of idiopathic PD is
made [12, 13]. At diagnosis, rest tremor
is the most common present- ing symptom of PD
[14]. Charcot and Gowers both described
ephemeral tremors preceding the onset of
parkinsonism but this phenomenon has not been
well described in the modern era [15,
16]. Tremor has been identiÞed in two
studies as a prodromal sign of PD (in some cases
up to 10 years prior to diagnosis) [12,
17] but whether these represent the
well-documented relationship between essential
tremor and PD [18, 19] or distinct
prodromal parkinsonism is unclear. The
pathogenesis of tremor is poorly understood, and
serotoninergic, dopaminergic, noradrenergic and
cholinergic mechanisms may all contribute.
SpeciÞc brainstem nuclei implicated in the
generation of parkinsonian tremor include the
locus ceruleus [20], ventral tegmental
area [21], and dorsal raphe nuclei
[22]. Stress and cognitive load can
unmask tremor in PwP [23] and this may
be mediated by the locus ceruleus via
connections to the ventrolateral nucleus of the
thalamus [20]. The ability of other
activities to unmask parkinsonian tremor has not
been well described to date. We present a series
of patients who, in the prodromal phase of PD,
experienced the emergence of tremor while
yawning or straining at stool up to 20 years
prior to their diagnosis. We present a
hypothesis on how the early involvement of
critical diencephalic and brainstem nuclei could
lead to these previously unreported
phenomena.
Clinical cases
Discussion
We present a series of patients who, in the
prodromal phase of PD, experienced the emergence
of tremor initially only while yawning or
straining at stool. Although at Þrst
glance, yawning and straining appear to have
opposing physiological effects, the two
processes are not entirely at odds with each
other physiologically.
Studies have indicated that yawning leads to
an increase in heart rate, lung volume and skin
conductance and reduced venous return which may
be med- iated by mechanical stimulation of the
carotid body [24, 25]. The Valsalva
maneuvre engages both sympathetic and
parasympathetic pathways during four separate
phases of the response [26]. Hemodynamic
responses to the Valsalva maneuvre are well
deÞned and also include an increase in
heart rate and reduced venous return (mirroring
those which occur during yawning). This same
physiological response can also be stimulated by
carotid sinus massage. This suggests that
similar central autonomic activation may occur
during both yawning and Valsalva maneuver during
straining at stool [25]. The
baroreceptor reþex described above
activates a distributed central autonomic
network which includes the supraoptic and
paraventricular nuclei, posterior hypothalamus,
par- aventricular and dorsomedial hypothalamic
nuclei, preoptic-anterior hypothalamic region,
the periaqueductal gray, the central nucleus of
the amygdala, and the insular cortex
[27]. Of these, the area which may be of
most interest in PD is the paraventricular
nucleus of the hypothalamus, as outlined
below.
Yawning and the paraventricular nucleus
of the hypothalamus
In order to understand how yawning could
activate tremor in a patient with prodromal PD,
the physiology of yawning must be considered.
Yawning is a common physiological phenomenon
occurring up to 20&endash;30 times per day in
healthy humans [28]. However, the
pathophysiology of yawning is poorly understood,
as is its role in neurological disease. Several
hypotheses have been proposed as to why we yawn.
These include regulation of arousal and sleep,
thermoregulation, brain perfusion/oxygenation
and a communicative/social tool
[29].
The precise underlying neuroanatomical
structures which mediate yawning are also
unknown. Anencephalic infants yawn suggesting
that the structures which execute the motor
action of yawning reside in the brainstem
[30]. Other lesion studies have
localized this to near the reticular activating
system [31]. It is clear that a number
of structures modulate the yawning mechanism in
a top-down fashion, most notably, the
hypothalamic paraventricular nucleus (PVN)
[28]. The PVN is located in the ventral
diencephalon and is composed of magnocellular
neurons, parvocellular neuronsand
long-projecting neurons. These long-projecting
neurons include oxytocinergic cells which
project to the hippocampus, spinal cord and
brainstem, including multiple autonomic
brainstem nuclei (e.g., nucleus of the solitary
tract, reticular formation, locus ceruleus,
dorsal raphe nuclei and motor nucleus of the
vagus). The pro- posed roles of the PVN are
therefore wide-ranging from cardiovascular,
gastrointestinal and respiratory homeostasis,
through feeding and metabolism, to penile
erections and sexual behavior [32,
33].
Yawning in Parkinson's disease
Yawning has been reported in parkinsonism as
early as initial reports of encephalitis
lethargica, both in acute and post-encephalitic
stages [34]. However, its role in
idiopathic PDis predominantly related to
dopaminergic therapy. Goren & Friedman
Þrst reported yawning as an aura signaling
the levodopa- induced "on" period in two PwP
[35]. Transient yawning preceded the
clinical transition from "off" to "on" by
approximately 5 minutes in a reproducible
fashion. The authors hypothesized that
dopaminergic and cholinergic mechanisms may be
at play [36, 37]. This letter prompted
responses from other groups stating that the
majority of PwP who are administered
subcutaneous apomorphine (a direct D1/D2
dopamine receptor agonist) experience transient
yawning coincident with onset of the motor
response [38, 39] and in some patients,
with transient penile erections [40].
Given that oxytocin release from the PVN
mediates yawning and penile erections in rats
following apomorphine administration, the PVN is
assumed to play a similar role in
apomorphine-induced yawning in these PwP
[33, 41]. The number of oxytocinergic
neurons in the PVN is reduced (by over 20%) in
PwP [42]. The nuclear volume of the
remaining neurons is increased suggesting a
compensatory activation. This may result in
altered sensitivity of these remaining neurons
to dopaminergic stimulation. Initial studies
examining ubiquity nation suggested that Lewy
bodies were not present in the PVN [42],
however more recently alpha-synuclein
immunohistochemistry has demonstrated that the
PVN is directly involved, not only in
conÞrmed PD cases but also in the
incidental Lewy body disease group (Braak
stage< = 2) [43]. Importantly this
suggests that Lewy body aggregation may occur in
the PVN in the prodromal phase of PD.
Apomorphine injected into the PVN can induce
yawning at concentrations 5&endash;40 times
lower than that required to induce yawning at
the level of the striatum implying that the PVN
is the primary site of action for dopaminergic
yawning [44]. Furthermore, lesioning of
the PVN and administration of oxytocin
antagonists suppresses apomorphine-induced
yawning [41, 45]. D2-like antagonists do
not sup- press oxytocin-induced yawning,
suggesting that the dopaminergic effect is
upstream from oxytocin [46, 47]. Yawning
induced by D2-agonists is sup- pressed by
D2-like antagonists as expected. However,
D2-agonist-induced yawning is also inhibited by
anticholinergics [35, 48].
Cholinesterase inhibitors and muscarinic
receptor agonists can also induce yawning which
can be suppressed by anticholinergics but not
dopamine receptor antagonists [36, 48].
Thus, the dopaminergic effect on yawning is
likely executed by downstream cholinergic
transmission, probably via M1 muscarinic
receptors. In summary, the primary yawning
mechanism is likely via oxytocinergic
long-projecting neurons in the paraventricular
nucleus enhancing cholinergic transmission in
the hippocampus and multiple brainstem sites
including the reticular formation.
Defecation, valsalva and Parkinson's
disease
Our fourth patient experienced prodromal
emergence of tremor while straining at stool.
Bowel dysfunction is a common prodromal feature
of PD. During defecation in PwP, paradoxical
sphincter con- traction occurs, leading to
signiÞcantly higher anal pressure than
occurs in control subjects [49]. As a
result, a greater rise in intra-abdominal
pressure is required for evacuation in PwP.
Abdominal straining and hence, Valsalva can
achieve this. The degree of paradoxical
sphincter contraction on defecation is similar
in early and late PD, indicating that this
phenomenon is an early Þnding in PD and
may even occur in the prodromal phase
[50]. However, straining is impaired in
PwP due to poorly coordinated glottal closure
[51]and Valsalva maneuvers in PwP lead
to a smaller increase in intraabdominal pressure
com- pared with controls [52],
suggesting a greater degree of straining is
required for defecation in PwP. Furthermore, the
vagal response to Valsalva maneuver is reduced
in PwP, particularly in the setting of ortho-
static hypotension (another prodromal PD
syndrome) [53]. This implies abnormal
and possibly aberrant vagal responses may occur
during straining at stool and Valsalva
maneuvers, even in the prodromal phase of
PD.
The PVN, which densely innervates the dorsal
vagal nuclei, clearly plays a central role in
yawning but it may also play a crucial role in
vagal control of gut motility. Stimulation of
the PVN modulates the activity of gut-sensitive
neurons in the vagal com- plex and may also
modulate vago-vagal reþexes [54].
Excessive PVN activity may therefore be required
to compensate for the deÞcient downstream
regulation of defecation. Furthermore, vagal
afferents can stim-
ulatePVNneuronsinthesettingofchangesinvolume
load as occurs during a Valsalva maneuvre
[55]. In this way, straining at stool in
PD could lead to similar activation of the
PVN-brainstem axis as we have hypothesized
occurs during yawning above. However, we have
yet to discuss how either process could lead to
the emergence of tremor in these patients.
Unmasking paradoxical movement and
tremor
The striking feature of our cases is that
they developed yawning- or straining-associated
rest tremor ears before a diagnosis of PD was
made. The emergence of tremor while yawning or
straining at stool in PwP has not been
previously described. However, involuntary
movement occurring synchronously with yawning
has been previously described herein patients
with acute hemiplegia may experiencere þex
elevation of the paralyzed arm during yawning
[56&endash;59]. This phenomenon of
parakinesia brachialis oscitans has been
reported in patients with vascular,
demyelinating, infectious and degenerative
lesions affecting the corticospinal tract, basal
ganglia or brainstem and consists of
reproducible involuntary elevation or abduction
of the paretic limb coincident with jaw opening
during yawning [59]. The paretic limb
falls again when the yawn ends. The most com-
mon causes are lesions of the internal capsule
and lentiform nucleus/caudate nucleus or ponto
medullary lesions. The precise pathophysiology
is unknown but it is hypothesized to occur as a
reþex activity of brain- stem structures
when released from rostral inhibitory control,
similar to the emergence of palatal tremor with
uncontrolled activity of the olivary nucleus
[59]. Walusinski has presented a number
of possible hypotheses for parakinesia
brachialis oscitans [29, 56, 59, 60].
Regulation of automatic respiratory activity
such as diaphragmatic movement and stretching
occurs via the coordinated activity of the
pre-Botzinger complex in the ventral medulla and
the adjacent lateral reticular nucleus (under
modulatory control from the hypothalamus)
[61, 62]. The lateral reticular nucleus
(LRN) plays a crucial role in integrating
descending and ascending signals to regulate
limb movements [63]. The Þbers
which project from the LRN to the deep
cerebellar nuclei exert a direct excitatory
effect on descending motor pathways via the
reticulospinal and vestibulospinal tracts
[63]. Even when corticospinal motor
control is lost, the LRN continues to receive
afferent stimulation from the ventral
spinocerebellar tract. A strong afferent signal
from contraction of respiratory muscles during
yawning (or a strong Valsalva maneuver during
straining at stool), could therefore lead to
involuntary automatic limb movement through this
spinoreticulocerebellar pathway
[59].
Although parkinsonian tremor is a much more
common phenomenon than parakinesia brachialis
oscitans, its precise pathophysiology is equally
poorly understood. Unlike rigidity and
bradykinesia, parkinsonian tremor often takes
longer to respond to
dopaminergictherapyandsomecasesrequiredhigher
doses [64]. Animal studies of selective
dopaminergic basal ganglia lesions (e.g., MPTP)
do not pro- duce the characteristic parkinsonian
tremor [65] and involvement of other
brainstem areas such as the locus ceruleus or
ventral tegmental area may be required to cause
tremor [21]. Tremor severity is not
related to nigral dopamine deÞciency
making dop- amine unlikely to be the sole
neurotransmitter involved in tremor generation.
Serotoninergic deÞcits in midbrain raphe
nuclei have been demonstrated with positron
emission tomography (PET) and these correlate
with tremor scores [22]. Importantly,
the raphe nuclei receives input from the PVN.
However, the effect of anticholinergic agents on
parkinsonian tremor cannot be ignored.
Antimuscarinic agents were the Þrst
pharmacological treatment for PD and still
widely used for management of tremor.
NeostriatalM4muscarinicreceptorshavebeenimpli-
cated in generation of this tremor in rat models
and tropicamide (which has a modest effect on M4
receptors) suppresses the tremor [66,
67]. Multiple brainstem areas can be
involved in generation of parkinsonian and
non-parkinsonian tremor (includ- ing
dentate-rubro-olivary pathways [68, 69],
dorsal raphe nuclei [70], bulbar
reticular formation [71], nucleus
ambiguous [72], locus ceruleus and
ventral tegmental area [21]). Many of
these regions receive projections from the PVN
(Fig. 1). In particular, the PVN projects to the
reticular nuclei, raphe nuclei, ventral
tegmental area, locus ceruleus and nucleus
ambiguous [32].
Ephemeral tremors prior to the emergence of
PD have been described by both Charcot and
Gowers, however these were predominantly in the
setting of acute stressors (emotional shock,
prolonged anxiety, trauma or cold weather)
[15, 16].
Gowers noted that "the tremor subsides when
the alarm is over" suggesting a brief
physiological change may mediate these tremors.
Trauma was noted to be the inciting cause in a
number of cases, in particular trauma at the
site in which tremor subsequently persisted.
Although there may be a bias here (tremor in the
traumatized limb being more notable than tremor
elsewhere), it raises the possibility of sensory
feedback modulating tremor thresh- olds. The
spinoreticular pathway and brainstem ret- icular
formation may play a role in parakinesia
brachialis oscitans. However, this pathway is
also in- volved in processing emotional response
to pain [73]. Hence, the reticular
formation may provide a com- mon pathway to
explain those tremors caused by emotional stress
and those cause by physical trauma. Gowers also
described the remarkable case of young lady, who
when startled by water suddenly pouring onto her
hand, developed tremor in that hand which
subsequently spread, developing into typical PD.
It is worth noting that in all of our cases, the
tremor which occurred during yawning or
straining was on the side in which persistent
tremor eventually emerged. This supports the
idea that our patients were displaying true
prodromal parkinsonian tremor rather than an
unrelated phenomenon.
Cognitive load is another common exacerbator
of tremor. Dirkx and colleagues examined the
effect of cognitive load on tremor in PwP using
synchronous electromyography and functional MRI
[20]. In a similar manner to what we
observed, parkinsonian tremor can emerge or be
ampliÞed when patients experience a
cognitive load such as being asked to carry out
mental arithmetic under pressure in the
consulting room. Dirkx and colleagues
demonstrated that cognitive load correlated with
tremor amplitude, pupillary diameter, heart rate
and activity in the cog-
nitivecontrolnetwork[20].
Theauthorshypothesized that cognitive load can
increase tremor through a bottom-up
noradrenergic ascending arousal system which
activates the ventrolateral nucleus of the
thalamus pars ventralis (VLpv) and hence the
cerebel- lothalamocortical network driving
tremor. Tremor- predominant PwP show less
degeneration of the locus ceruleus than other
PwP [74] and the locus ceruleus sends
noradrenergic projections to the VLpv as well as
other nodes of the cerebellothalamocortical
network [75, 76]. Dirkx and colleagues
therefore con- cluded that the locus ceruleus
mediates the increase in tremor amplitude, as
well as the pupillary and heart rate changes.
Since the PVN is a major sym- pathetic premotor
nucleus of the pupillary reþex (via the
intermediolateral column of spinal cord)
[77] and modulates heart rate, it is
possible that this nucleus may play a role in
their Þndings. Given the dense
connectivity between the PVN and the locus
ceruleus, a similar activation of the
cerebellothalamocortical network might enhance
tremor during yawning or Valsalva while
straining at stool in our patients.
Hence, it is possible that aberrant
brainstem trans- mission during yawningor
Valsalva maneouvre could activate the
cerebellothalamocortical network either via the
lateral reticular nucleus (and the deep
cerebellar nuclei) or via the locus ceruleus
(and the VLpv). The brainstem reticular
formation and locus ceruleus have previously
been implicated in the pathophysiology of RBD,
the only well characterized prodromal syndrome
in PD.
Horsager et al. recently used the presence
or absence of premotor RBD to dichotomize PD
patients into "brain-Þrst" and
"body-Þrst" subtypes [5].
Body-Þrst patients demonstrate a wide
range of abnormalities on functional imaging
including cardiac denervation and cholinergic
denervation of the colon. Given the widespread
role of the PVN both in cardiovascular
homeostasis as well as well as regulation of
bowel function, it seems likely that the PVN may
be involved in many of these "body-Þrst"
patients.
Our hypothesis is speculative and future
work is required to clarify the involvement of
the PVN in prodromal PD and its clinical
correlates. Only a single study to date has
examined alpha-synuclein immunohistochemistry in
the PVN. It is clear that well-designed
neuropathological studies examining the
frequency and extent of involvement of the PVN
in clinically well-characterised patients with
PD (such as body-Þrst subtypes) as well as
patients with idiopathic RBD are needed. As we
are on the thresh- old of diagnostic tests for
the synucleinopathies, in particular with
respect to Real-Time Quaking- Induced Conversion
(RT-QuIC) in tissues such as skin and
cerebrospinal þuid, it may be able to test
this hypothesis in vivo in patients such as
those presented herein [78, 79]. With
potential disease modifying treatments in
evolution, this may also have impor- tant
implications in helping to deÞne prodromal
PD patients who may beneÞt from early
treatment with such agents. Although the exact
mechanisms under- lying the emergence of tremor
in prodromal PD are undeÞned, it clearly
represents an important Þnding as it may
help identify PwP at an earlier stage of disease
than is currently possible. Vigilance for this
phenomenon, for example in newly diagnosed PwP
or in patients with idiopathic RBD, may lead to
greater appreciation of its prevalence and the
breadth of its spectrum.
Conclusions
The identiÞcation of a new clinical
syndrome in prodromal PD has important
implications for target- ing early therapeutic
interventions. The emergence of tremor
coincident with yawning and straining at stool
up to 20 years before a diagnosis of PD in our
patients represents an important therapeutic
window. A greater understanding of the
pathophysiology of this phenomenon is required.
The PVN likely plays a central role, either by
increasing downstream cholinergic activity on
critical brainstem nuclei such as the reticular
formation, by stimulating the locus ceruleus to
activate the cerebellothalamocortical network or
by another autonomic mechanism. Aberrant
cholinergic/noradrenergic transmission between
these non-dopaminergic brainstem nuclei early in
PD could lead to tremor before the emergence of
other (dopaminergic) parkinsonian signs,
representing an early clinical clue to incipient
PD.