Ambulatory thermoregulatory system identification in relation to vigilance disturbances.

*Vigilance disturbances*, among which fatigue, sleepiness and sleeplessness,
are a common denominator of functional impairments that affect quality of life
in disorders of the central nervous system. The brain areas involved in sleep
and wakefulness regulation are sensitive to temperature, which in an
evolutionary sense is among the oldest cyclically varying physical aspects of
the environment. They include the hypothalamic suprachiasmatic nucleus (SCN)
and preoptic area (POAH); key players in the regulation of both temperature and
vigilance * with demonstrated response overlap even for single neurons. Indeed,
we have recently observed that the spontaneous time-variance of skin
temperature * determined by thermoregulatory cardiovascular blood flow control
- is a significant predictor for fluctuations in vigilance both in healthy
controls and narcoleptic patients.1 Also, we demonstrated a prominent response
of sleep and vigilance parameters to very mild manipulations of skin
temperature.2-4
It is often forgotten that the major thermoregulatory effector in humans, the
skin, is in fact the largest organ of the body. Not surprisingly therefore, a
large proportion of the paravertebrate sympathetic chain ganglion motorneurons
is dedicated to the regulation of skin blood flow. And, other than suggested by
the older handbooks, studies during the last decades,5 have clearly shown that
autonomic outflow is somatotopically differentiated rather than generalized.
Indeed, the paravertebrate sympathetic chain motorneurons innervating the skin
vasculature are small and consequently show little integration, allowing for
topographic specificity of skin vasoconstriction. Thus, there is good reason to
suppose that the spatiotemporal characterization of spontaneous fluctuations
and evoked responses in skin vasoconstriction, and consequently skin
temperatures, could provide a magnifying glass view on subtle abnormalities in
autonomic function.
These spatiotemporal fluctuations and responses are part of a closed loop that
includes the POAH, as mentioned an area that is strongly involved in vigilance
regulation. In brief, the POAH controls skin vasoconstriction by acting,
through the medulla, on paravertebrate sympathetic chain ganglion motorneurons.
In turn, skin temperature changes associated with changes in skin blood flow
are sensed by a dense network of nerve endings, ascending to project back to,
among others, the POAH. Consequently, we obtained considerable evidence for a
hypothesized1, 6 causal effect of spontaneous and evoked skin temperature
fluctuations on the normal and abnormal variation in vigilance level and sleep
in health and disease.1-4, 7-10

Recent unpublished interesting findings support the validity of focusing on the
thermoregulatory system. Firstly, we found a redistribution of topographical
coupling of thermoregulated skin areas after sleep deprivation. Traditionally,
the skin is subdivided into distal areas characterized by arteriovenous
anastomoses (AVAs) and a proximal area without. AVAs are constricted under
sympathetic control, and if released, a manifold increase in skin blood flow
results, facilitating the transfer of heat from the core of the body, by
radiation and convection from the skin to the environment. Therefore, a
dichotomy is usually presumed, with the distal AVA-rich areas as primary
targets for thermoregulation regulated and fluctuating independently from the
proximal area. Our new results suggest that the distinction between the two is
flexible and co-varies with sleepiness. In brief, temperature was continuously
measured at 15 sites along the proximal to distal axis of the body in twelve
healthy volunteers for two whole days controlled to be identical with regards
to environment, behavior and food intake; once after a normal night of sleep
and once after a night of total sleep deprivation. The multivariate time series
of the two days were subjected to principal component analysis in order to
quantify co-varying skin areas. Interestingly, there appeared to be a shift in
the border between proximal and distal; the temperature of the lower legs and
feet started to co-vary with proximal skin areas. This suggest that the
sleepiness of a person may be reflected in the topographical profile of skin
temperature fluctuation coupling under controlled yet relatively normal
ambulatory conditions.

A second example concerns an abnormality in the thermoregulatory changes
response to a postural *perturbation* in a neurological disease, narcolepsy. We
previously published that the distal skin temperature of narcoleptic patients
measured under ambulatory conditions is increased during the day, and that the
amount of increase correlates with the difficulty to stay awake.1 In a recently
completed, unpublished lab study where both narcoleptic patients and controls
were kept in a supine position, narcoleptic patients and controls however
reached the same high level of distal skin temperature that is normal in a
supine position. Together, these two studies suggest a possible deficiency in
narcolepsy of the cardiovascular vasoconstrictive response (and consequent
temperature decrease) of the skin that normally occurs with orthostasis.
Whereas in healthy controls an upright position reduces the central venous
pressure, unloads cardiopulmonary baroreceptors and consequently leads to
strong distal vasoconstriction and the consequent decrease in skin blood flow
and temperature, this response appears to be attenuated in narcolepsy. A third
example indicates that deficiencies in regulation of skin temperature and its
relation to daytime sleepiness are not limited to distal sites, neither to
narcolepsy. We recently completed ambulatory skin temperature recordings in 45
patients with early stage Alzheimer*s disease, as well as in matched healthy
controls and disease controls, i.e. subjects with only subjective memory
complaints. On top of the normal changes with aging11 only Alzheimer patients,
but not disease controls, showed a significant increase in daytime, but not
nocturnal proximal skin temperature. Of note, the increase correlated with
daytime sleepiness.

Concertedly, our published results as well as our new unpublished findings
illustrate how spatiotemporal characteristics of skin temperature may be
disease-specific and possibly have diagnostic value and provide clues towards
autonomic nervous system abnormalities that may lead to a better understanding
of the vigilance disturbances that are so common to nervous system disorders.
The present protocol aims for an extensive spatiotemporal characterization of
skin temperature regulation and fluctuation both in controlled laboratory
conditions and under unconstrained ambulatory conditions. A validation of the
ambulatory profile against the laboratory profile will provide insight in the
applicability of the ambulatory approach as a cost-efficient tool to aid
neurological examination.

The present study aims to systematically investigate whether the
thermoregulatory profile of spontaneous fluctuations and responses to
perturbations differs in association with diagnosis and with individual
differences in the severity of vigilance complaints.

Secondary objective is to determine whether the profile of thermoregulatory
parameters of spontaneous fluctuations and responses to perturbations as
obtained in the laboratory can be approximated using a more cost-efficient
ambulatory assessment approach.
To determine the relative contribution of the baroreceptor and skin temperature
to the drop in vigilance that results from changing from an upright to a supine
posture.

A within-subject 7 day ambulatory observation period and 2 lab days, one of
which will be a randomized laboratory protocol of 1 day. The lab protocol
includes manipulation of light (dim, bright), temperature (mildly cool, mildly
warm), posture (seated, supine) applied across time of day. The other lab day
will be used to explain the protocol and do some short tests.

Eight of the non-active duty pilots will be requested to shorten their habitual
sleep duration by 1 hour in the 4 nights preceding the lab measurements.
Another eight non-active duty pilots will be requested to lengthen their
habitual sleep period with 1 hour in the 4 nights precending the lab
measurements. The remaining pilots will be instructed not to change their
habitual sleep pattern.

During the intervention study in the lab, participants will be admitted to the
institute from 9:00 in the morning and stay until approximately 18:00 in the
afternoon. Each participant will sequentially be subjected to 12 manipulation
blocks. Each block will consist of one of the following manipulations: change
of posture (supine, seated), mild warm versus cool skin temperature
manipulations within the thermoneutral zone or no skin temperature
manipulation, bright and dim light exposure.

To allow for an assessment of skin temperature responses and fluctuations the
thermosuit should not contain any heated or cooled water. Therefore, all free
running temperature conditions are presented sequentially in a 2 (light) x 2
(posture) full factorial design. A separate 2 (light) x 2 (posture) x 2
(temperature) full factorial design will be applied that includes the
temperature manipulations. The order of the blocks and the designs is
randomized across subjects within the same clinical population.

Each manipulation block will last 30 minutes. The first 19 minutes of a block
allow for the consumption of an isocaloric snack (60 kcal and 100ml ice tea)
and adaptation to the new conditions. From time t = 00:19 to t = 00:26 of each
manipulation the participant performs the psychomotor vigilance task. At time
t = 00:26 participants rate their subjective fatigue, sleepiness, stress,
thermal comfort and sensation and arousal. Each block concludes with a 2
1-minute eyes-open and eyes-closed resting state EEG recordings.

The burden of participating filling out questionnaires multiple times a day for
7 days as well as wearing the small ambulatory sensors. The burden of the lab
protocol will mainly be attaching the sensors (including a rectal temperature
sensor) and wearing the body suit for skin temperature manipulations.