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2 Models of Comorbidity 27
Regarding potential mechanisms, Borsboom and colleagues [1]found
that many of the highly overlapping psychiatric symptoms in their DSM-
4 analysis were linked to basic homeostatic brain functions, including
eating, sleeping, sex and mood regulation. In particular, the four most
highly connected psychiatric symptoms in the analysis were insomnia,
psychomotor-agitation, psychomotor-retardation, and depression, which
were collectively linked to 60–71 other DSM-4 symptoms and 29–35%
of the symptoms in the giant component, for GAD and MD, respectively.
Thus, impaired sleep/insomnia, changes in activity levels, and depression
were the most highly connected symptom groups, which were highly cor-
related with each other, other symptom groups (e.g. anxiety), and changes
in behaviour (e.g. eating, sex). These computational results are generally
consistent with the observation that homeostatic processes are involved
in mediating at least some of the comorbid relationships, for example
between impaired sleep andfatigue, bothof whichare symptoms of depres-
sion [14].
On thebasis of theresults, Borsboom andcolleagues [1, 15] positedthat
the most highly connected symptoms may be ‘causally-coupled variables’
that play a crucial role in maintaining the structure of the psychiatric
symptom network. That is, activating a single node (e.g. anxiety) in the
network may indirectly contribute to the activation of other nodes (e.g.
depression) to cause other symptom group(s). For example, anxiety may
propagate via the network structure to contribute to insomnia, which, in
turn, may contribute to depressed mood, via anxious and/or depressive
rumination, which delays sleep onset and shortens sleep, and over time,
this may contribute to tiredness and depressed mood [9]. Thus, the shared
symptoms of anxiety and depression (e.g. impaired sleep, fatigue) may
‘function as bridge symptoms that transfer symptom activation from one
network to the other, like a virus may spread from one community to
another via people who are in contact with both’ (p. 9) [13].
Taken together, the results suggest that the computational model has
substantial utility in explaining the tendency of people to develop comor-
bid anxiety and depression, either concurrently or sequentially, potentially
via a number of different mechanisms. Several other aspects of the model
are also appealing: (1) there may be several or more potential causal path-
ways contributing to a particular disorder; (2) the symptom networks may
28 R. Brown and E. Thorsteinsson
be different in different individuals and they may tend to change over
time; (3) this might result in different comorbidity pathways in different
individuals or in the same person at different times; and/or (4) multiple
different causation events may contribute to comorbid illnesses in some
individuals [1, 13, 15].That is to say,there may be different possible paths
to comorbidity, and the pathways occurring in particular individuals may
depend upon the characteristics of the person (e.g. life experiences, coping
methods) and their specific life situation.
As detailed above, so-called causally coupled variables or causal chains
have already beenposited to underpin the common co-occurrenceof anxi-
ety and depression [16] and fatigueand depressed mood [17],via impaired
sleep and rumination [8]; for more discussion, see Chapter 6.Borsboom
and colleagues [1] also posited that comorbidity between depressive and
anxiety disorders will likely arise from causal chains of directly related
symptoms (e.g. impaired sleep). Consistent with this assertion, Kim and
Ahn [18] have shown that clinical psychologists tend to interpret their
clients’ symptom patterns in terms of the particular causal networks in
their clinical practice.
However, most ‘causal chains’ that have been described in the litera-
ture are singular in their focus. For example, they typically investigate a
single specific mechanism (e.g. impaired sleep leading to depression via
rumination) but exclude other clinically relevant factors or comorbidities
(e.g. emotional eating, overweight/obesity), which are also known to be
linked to impaired sleep [19] and affective distress (e.g. depression) [20,
21]. Thus, again, there is a crucial need to employ a more holistic theoret-
ical approach to the problem of disease comorbidity, which incorporates
multiple highly concurrent symptoms, disorders, and behaviour together,
so that a range of coexisting phenomena and potential intervening factors
can be considered together.
To address the aforementioned issues, the authors of this book have
recently developed a new clinical theory of concurrent symptom development
[22] which seeksto explain the mechanisms by which comorbidity is likely
to arise in people with concurrent overweight/obesity, impaired sleep, eat-
ing disorders, affective distress (e.g. anxiety, depression), and other dis-
orders (e.g. diabetes mellitus type-II). A specific biological mechanism—
dysregulation of nocturnal body temperature (BT) and the circadian rhythm
2 Models of Comorbidity 29
of BT —is proposed to explain comorbidities between the aforementioned
disorders, andthroughout the book, weexamine the modelfor its utility in
explaining the co-occurrence of highly connected conditions. A detailed
analysis of the relevant literatures pertaining to the relationships between
the disorders, symptoms, and behaviour, and perturbations in BT will be
provided, as appropriate, in the following chapters.
In short, the clinical theory posits that when certain symptoms (e.g.
anxiety) or sleep-disrupting behaviour (e.g. stress-related eating) are expe-
rienced atnight, this can result inan elevatednocturnal BT thatis sufficient
to interrupt sleep, occurring via a phase shift in the circadian rhythm of
BT. Furthermore, once a person’s sleep is disrupted, they may tend to
engage in similar (or different) sleep-disrupting behaviour (e.g. night-
eating, electronic device use) while they wait for sleep to come, and over
time, this may worsen their sleep and contribute to new disorders (e.g.
overweight/obesity) [23]. Inthis way, a person’s late night-eating may con-
tribute to a new disorder (e.g. insomnia, obesity) and/or the worsening or
perpetuation of existingbehaviour (e.g. night-eating) via thedelayed onset
of sleep at night, and as detailed in Chapter 3, the relationship appears to
be indirect, complex, and bidirectional.
That is, we propose that a bio-psycho-behavioural mechanism—an ele-
vated nocturnal BT that interferes with sleep onset —can parsimoniously
explain the presence and development of highly concurrent disorders
including insomnia/impaired sleep and overweight/obesity, via the prac-
tice of sleep-disrupting behaviour(e.g. latenight-eating) atnight.That isto
say, sleep-disrupting behaviourmay be a behavioural mechanism by which
disease comorbidity occurs, because of its tendency to raise a person’s BT
[22], and thepremise is examined in greater detail in Sect. 2.2. Simply put,
we propose that impaired sleep may play a pivotal and bidirectional role
in contributing to the causation, worsening, and/or perpetuation of other
disorders, symptoms, and behaviour, as well as being the consequence of
other disorders, symptoms, and behaviour. A pictorial representation of
our model is presented in Fig. 2.1.
Detailed empirical evidence will be provided to support this assertion
throughout the book, as appropriate to the specific disorders, symptoms,
and behaviour discussed in each chapter. However, it is worthwhile briefly
30 R. Brown and E. Thorsteinsson
Fig. 2.1 Symptoms, states, and behaviour that can increase nocturnal body tem-
perature, and if practiced at night, thereby potentially interfere with sleep onset
reiterating that the study results of Borsboom and colleague’s [1]net-
work simulations showed that the most highly connected of all the psy-
chiatric symptoms were insomnia, psychomotor-agitation, psychomotor-
retardation,and depression. Itis appreciatedthat all fourof these symptom
groups are substantially correlated with elevated BT, especially high noc-
turnal BT, as indeed are most of the concurrent symptoms, disorders, and
behaviour discussed in this book, including overweight/obesity, night-
eating, and other sleep-disrupting behaviour.
2.2 Sleep, Body Temperature, and Circadian
Rhythm Function
We posit that a complex bio-psycho-behavioural mechanism that results
in an elevated nocturnal BT which interferes with sleep onset can explain
the high degree of comorbidity that exists between the aforementioned
disorders, symptoms, and behaviour, as detailed in Fig. 2.1. To more fully
explain thispremise, a detailed explanationof the preciserelationships that
2 Models of Comorbidity 31
exist between sleep onset, sleep offset, and BT in clinical and non-clinical
human samples is provided below.
First, changes in core BT are thought to signal the onset and offset of
sleep [24, 25], as shown in Fig. 2.2 [25]. In particular, before a person
can fall asleep, they typically need to cool down; specifically, sleep onset
is putatively triggered by a precipitous fall in core BT that occurs in the
early evening. In people who live a conventional lifestyle, core BT tends
to stabilise between 2:00 PM to 8:00 PM; then it precipitously declines
(on average 41 minutes before elderly people report wanting to go to bed)
[26]; it reaches a minimum at approximately 4:00–5:00 AM, after the
mid-point of sleep; and then it starts to increase before the end of sleep,
reaching its peak in the late afternoon [25–29]. As a result, most sleep
tends to occur in a rather narrow temporal window from 6 hours before
the temperature nadir and 2 hours after it (≈10 PM–7 AM) [25].
Thus, sleep typically begins when the rate of BT drop and body heat
loss is maximal, that is, when BT is falling most precipitously, a process
Fig. 2.2 Original caption reads: “Diagrammatic representation of normally
entrained endogenous rhythms of core body temperature (solid curve), plasma
melatonin (dotted curve), and objective sleep propensity (dashed curve) placed in
the context of the 24-h clock time and normal sleep period (shaded area).” Figure
is from Lack et al. [25]
32 R. Brown and E. Thorsteinsson
that is reported to take about 60 minutes in a naturalistic setting. On the
basis of this research, it is asserted that BT and the circadian rhythm of
core BT play a key role in regulating the sleep-wake cycle, such that a
sharp decrease in nocturnal BT is thought to signal an approaching sleep
episode and an increase in BT heralds the end of a persons’ sleep [28, 29].
Nevertheless, sleep initiation is also linked to an increase in melatonin
secretion and an increase in sleep propensity (e.g. sleepiness) [24, 25].
Figure 2.2 illustrates the typical daily changes in melatonin secretion,
BT, and sleep propensity over 24 hours; the optimal time for a person
to sleep (i.e. 11 PM–7 AM); and the periods of wakefulness when it
is typically difficult to fall asleep (i.e. wake maintenance zone) [25]. The
model indicates that good sleepers will tend to go tobed several hours after
the wake maintenance zone has ended, which is likely to facilitate a shorter
sleep onset latency [30]. In contrast, sleep tends to be disrupted when
the expected nocturnal decline in BT is uncoordinated with the time the
person tries to fall asleep. For example,high ambient temperature (e.g. hot
summer’s night) is known to interfere with the onset of sleep by increasing
a person’s BT [31].Thus, changes in the circadian rhythm of core BT have
been linked to dysregulation of the sleep-wake cycle, especially a difficulty
in falling asleep [32]. Key circadian rhythmchanges including core BT are
known to be regulated by the human circadian clock or ‘pacemaker’ that
is located in the suprachiasmatic nucleus of the anterior hypothalamus
(SCN). It is thought that ambient light acts as the primary timekeeper
for the human circadian clock; such that the retina sends impulses to the
SCN when incident light falls upon it [33, 34].
Clinically, people with sleep problems are reported to show higher core
BT acrossthe sleepperiod, relative to good sleepers[35]. Similarly,patients
with sleep-onset insomnia are reported to experience a delayed circadian
rhythm of core BT that occurs about 2.5 hours later than in good sleepers,
as assessed by polysomnography and rectal temperatures over 26 hours
[30]. As a result, if a person with insomnia tries to fall asleep early in the
night, they may be unableto do so if they are still in the wake maintenance
zone of the sleep-wake cycle. However, if they went to bed 2–3 hours later,
they may have less trouble sleeping, but this may be impractical if there
is a need for them to wake up early for work or study. Thus, as shown in
Fig. 2.3 [30], people with insomnia (or impaired sleep) tend to experience
2 Models of Comorbidity 33
Fig. 2.3 Original caption reads: “Fitted Fourier curves to the control group and
insomniac group mean 24-h temperature data in the constant routine relative to
subjects’ usual sleep onset times (vertical solid line). The usual mean lights out
times (LOT) for each group are indicated as vertical dashed lines. The estimated
mean wake maintenance zone (WMZ) for each group is indicated as shaded area.”
Figure is from Morris et al. [30]
a smaller and later decline in their BT, indicating that a phase-shift (i.e. to
the right) has likely occurred in the circadian rhythm of core BT [30]. As
a result, they will tend to experience a relatively elevated nocturnal (i.e.
night-time) BT or will lack the normal drop in BT that occurs at night,
and this can interfere with the onset of sleep [24–26, 28].
As detailed in Chapter 7, myriad factors have been shown to potentially
impact on sleep quality including environmental factors such as high or
lowambient temperature[36, 37]and night-time exposure tobright lights,
which can increasealertness and interfere with sleep [38]. Ambient heating
sources (e.g. electric blankets) can also disrupt sleep via an increase in
nocturnal BT[39]. For example,high blanket temperaturehas beenshown
to result in less total sleep time (i.e. more wakefulness), more Stage 1
sleep, more sleep stage changes, and less sleep efficiency in one study
[39]. Other studies have reported a reduced amount of Stage 1 sleep and
rapid eye movement (REM) sleep [40] and more frequent and longer
awakenings, more shifting between sleep stages, less REM and Stages 3
and 4 non-REM (NREM) sleep, and the delayed onset of Stages 3 and 4
sleep, even in healthy individuals [41]. Normally, a person’s BT decreases
34 R. Brown and E. Thorsteinsson
to about 34.5–36 °C at night, whereas electric blankets tend to keep BT
at a relatively constant 37 °C, and elevated heart rate is linked to the
elevated BT. Thus, an electric blanket can promote sleep in low ambient
temperature conditionsand may exert modest effects on sleeparchitecture,
but it can lead to significant overheating, thereby promoting wakefulness
and potentially reducing sleep efficiency [39, 40].
Similarly, higher ambient temperature (e.g. hot summer’s night) has
been reported to increase BT [42] and interfere with sleep. For exam-
ple, raising ambient temperature from 13 to 25 °C is linked to shorter
REM cycle length, but not an alteration in REM duration, REM period,
and REM sleep latency [43], suggesting that warmer nocturnal ambient
temperature can interfere with sleep. However, the greatest disruptions
in slow-wave and REM sleep are thought to be linked to cold ambient
temperature [36]. For example, Haskell and colleagues [37] found that
colder temperatures impacted adversely on sleep in men, as assessed via
polysomnography. However, the men wore only shorts to bed and they
did not use a blanket, whereas most people sleep with at least some form
of bedding. Thus, it is evident that extremes in cold and heat can interfere
with sleep, whereas moderate ambient temperatures can facilitate sleep,
although sleepers typically manage their nocturnal BT by using more or
less blankets or other bedding, as appropriate.
Several physiological processes that are entrained to the circadian
rhythm also promote sleep in humans, including a change in melatonin
secretion [33]. Melatonin is an endogenous sleep-promoting hormone
that is secreted by the pineal gland; along with BT, it is thought to assist
in initiating and maintaining sleep during the night such as suggested
through its importance in treating sleep disorders [44]. As Fig. 2.2 shows,
melatonin secretion begins to increase in the evening, when a person may
start to feel a little drowsy, and it reaches a maximum during the night
before it starts to wane before the person wakes up. However, its secretion
is inhibited by exposure to light [45], at which time a message is sent to
the SCN to restrict its secretion [45, 46], which in turn reducessleepiness.
Clinically, melatonin preparations have been used to treat sleep problems,
and a meta-analysis [47] showed that there is at least some clinical evi-
dence indicating that the preparations can reduce sleep onset latency and
2 Models of Comorbidity 35
improve sleep efficiency, suggesting that it may have some clinical utility
in treating sleep problems.
Additionally, sleep onset is thought to be triggered by external cues,
called zeitgebers (i.e. social ‘time-givers’), which assist animals and humans
to maintain a 24-hour behavioural schedule, consistent with the body’s
physiological processes. Zeitgebers include habitual behaviour such as
brushing one’s teeth, setting the alarm clock, and putting on pyjamas.
Thus, the presence of salient conditioned cues (i.e. social zeitgeber theory)
[48], such asthe sun/dawn, low light at night, falling ambient temperature
at night, and social time-givers are thought to collectively promote a good
night’s sleep and potentially normalise the circadian rhythm of sleep and
core BT [46, 48, 49]. As a result, people who live a conventional lifestyle
and keep to a regular schedule tend to show better circadian rhythm
functioning than those who do not [50, 51]. Thus, it is clear that sleep,
especially the onset of sleep, involves a complicated set of circadian neuro-
regulatory dynamics that include changes in BT, melatonin secretion, and
a complex array of associated behaviours [52].
In summary, a precipitous drop in BT, increased melatonin secretion,
and the presence of zeitgebersare thought to collectivelytrigger the subjec-
tive sense that it is time to sleep. Responding promptly to these internal
and external signals is likely to assist people in falling asleep faster and
experiencing a more restful sleep. That is, if a person lives a conventional
lifestyle, keeps to a regular schedule, and respectfully obser ves good sleep-
hygiene practices, including habitual sleep-preparation behaviour, they
are likely to experience good quality sleep and optimal circadian rhythm
functioning. However, if they do not keep to a regular schedule and/or
they engage in sleep-disrupting behaviour at night, they may find it difficult
to fall asleep at night, and this latter premise will be examined in more
detail in Chapters 3 and 7.
Specifically, in Chapter 3, behaviour that is linked to over-
weight/obesity, including a sedentary lifestyle, physical inactivity, night-
eating, and binge-eating, will be explored in regards to impaired sleep
in overweight/obese individuals. That is, overweight/obese people tend
to practice a range of unhelpful behaviour at night that can potentially
interfere with sleep, and once impaired, their sleep problem may adversely
impact upon their physical and/or mental health, including an increase
36 R. Brown and E. Thorsteinsson
in weight. As detailed in Chapters 3 and 7, all of the aforementioned
behaviour can potentially increase a person’s BT; thus, if they are prac-
ticed at night, they will tend to increase nocturnal BT thereby potentially
interfering with the capacity to fall asleep.
Finally, as discussed in Chapter 9, the clinical model presented in this
chapter posits that a complex bio-psycho-behavioural mechanism is likely to
underpin the development of disease comorbidity. Simply put, the model
suggests that a range of states, symptoms, and sleep-disrupting behaviour
may interact with each other to result in circadian rhythm dysfunction,
as indexed by a relative increase in BT at night, which may increase the
risk of comorbid disorder development. As detailed in Chapter 9,wehave
principally focused on perturbations in BT (rather than melatonin secre-
tion or other biological mechanism/s) as it provides a readily measurable
index of circadian rhythm function and a parsimonious explanation of the
comorbidities detailed in the book.
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