ARTICLE IN PRESS

Sleep Medicine Reviews (2007) 11, 71–79

www.elsevier.com/locate/smrv

THEORETICAL REVIEW

Insomnia: Pathophysiology and implications

for treatment
Thomas Roth, Timothy Roehrs, Ron Pies

Sleep Disorders and Research Center, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit,
MI 48202, USA

KEYWORDS Summary Interest in developing a greater understanding of the pathophysiogical

Insomnia; mechanisms underlying primary insomnia has increased. Recent evidence indicates
HPA axis; that there may be some neuroendocrine and clinical similarities between primary
Hyperarousal insomnia and major depressive disorder, that abnormal corticotropin releasing factor
(CRF) activity occurs in major depression, and that CRF hyperactivity appears to
mediate the hyperarousal seen in primary insomnia. These findings all point to the
possibility of hypothalamic–pituitary–adrenal (HPA) axis and CRF overactivity in both
disorders. More recent findings have strengthened the evidence that primary
insomnia may be linked with mood disorders and is associated with HPA axis
overactivity and excess secretion of CRF, adrenocorticotropin releasing hormone,
and cortisol. These insights have implications for managing chronic primary
insomnia, such as use of antiglucocorticoid agents.
& 2006 Elsevier Ltd. All rights reserved.

Introduction medical or psychiatric disease may be modulated

Despite more than 30 years of research into the
nature of insomnia, our understanding of its basic
pathophysiology has lagged behind that of other
sleep disorders, such as narcolepsy and sleep
apnea.1 In part, this discrepancy stems from the
heterogeneous nature of insomnia, which is both a
primary condition with a pathophysiology, and a
condition co-existing with numerous medical and
psychiatric disorders. The course of the co-existing
Corresponding author. Tel.: +1 313 916 5171;
fax: +1 313 916 5167.
E-mail address: troth1@hfhs.org (T. Roth).
by the course of the sleep disturbance.2–4 In
addition, insomnia has been found to precede the
onset of major depression.5–7
The Diagnostic and Statistical Manual of Mental
Disorders, fourth edition, text revision (DSM-IV-TR)
defines the term primary insomnia as difficulty
initiating or maintaining sleep, or non-restorative
sleep, that results in clinically significant distress or
impairment in social, occupational, or other im-
portant areas of functioning (American Psychiatric
Association, 2000). DSM-IV-TR specifies that pri-
mary insomnia cannot occur exclusively during the
course of narcolepsy, breathing-related sleep dis-
order, circadian rhythm disorder, or a parasomnia,

1087-0792/$ - see front matter & 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.smrv.2006.06.002
 ARTICLE IN PRESS
72 T. Roth et al.

Table 1 DSM-IV-TR diagnostic criteria for primary insomnia.

(A) The predominant complaint is difficulty initiating or maintaining sleep, or non-restorative sleep, for at least
1 month.
(B) The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
(C) The sleep disturbance does not occur exclusively during the course of Narcolepsy, Breathing-related Sleep
Disorder, Circadian Rhythm Sleep Disorder, or a Parasomnia.
(D) The disturbance does not occur exclusively during the course of another mental disorder (e.g., Major
Depressive Disorder, Generalized Anxiety Disorder).
(E) The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition.

Reprinted with permission from American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th
edition, text revision. Washington, DC: 2000; 604.

or during the course of another mental disorder
(e.g., major depression), and it cannot be due to a
general medical condition or substance use dis-
order (Table 1). Primary insomnia has been con-
ceptualized as sleep disturbance not arising from a
medical, psychiatric, circadian, behavioral, or
pharmacologic cause, or from a primary sleep
disorder.8
The DSM-IV-TR criteria inform clinicians what
primary insomnia is not, but do not define what it
is, beyond a complaint of difficulty initiating or
sustaining restful sleep lasting more than a month.
It is unclear what pathophysiologic mechanisms
drive primary insomnia and what implications these
have for insomnia morbidity and treatment. This
paper provides a brief overview of the epidemiol-
ogy, morbidity, and risk factors associated with
insomnia, and will also briefly highlight the specific
research still needed in each of these areas. Next
the paper discusses the question of primary
insomnia etiology, focusing on the critical role of
hyperarousal and abnormal corticosteroid regula-
tion—a pathophysiology that may be the unifying
link between primary insomnia, depression, and
perhaps other disorders. Finally, the implications of
this new research will be explored as it relates to
insomnia pharmacotherapy.
population-based chronic insomnia is associated
with psychiatric and medical diseases, or with
primary sleep disorders and primary insomnia
accounts for approximately 25% of all chronic
insomnia.11 Thus, primary insomnia is estimated
to occur in 1–2% of the general population,11 while
it accounts for as much as 25% of all chronic
insomnia cases.8
Insomnia generally does not resolve sponta-
neously. Half the adult population experience
trouble sleeping at some time in their life, and
approximately one-third report that the problem
has lasted more than a year12. For those with
insomnia characterized by poor sleep at least 3
nights/week and subjective daytime impairment,
the problem persists from 2 to 6 years;12 durations
over 2 years were typical for more than half of
those reporting moderate to severe symptoms.12 In
retrospective reports, individuals with severe
symptoms report having sleep difficulties for at
least 1 year, with 40% suffering for more than
5 years. In various longitudinal reports, up to 80% of
individuals with severe insomnia experienced no
remission over time.70
Morbidity

Studies using standardized assessment instruments

Insomnia: epidemiology, morbidity, and
risk factors
Epidemiology
Prevalence estimates for insomnia range from 10%
to 50% of the adult population. Summaries of the
epidemiologic evidence conclude that 10–13% of
the adult population suffers from chronic insomnia,
and an additional 25–35% has transient or occa-
sional insomnia.9,10 It is estimated that 75% of
show that insomnia patients consistently report
significantly decreased daytime functioning, with
deficits across a large number of emotional, social,
and physical domains and with a severity similar to
other chronic diseases.13–15 They describe difficul-
ties with memory, concentration, attention, and
reasoning.16 Objective measurements, as described
below, have failed to confirm these patient reports
and demonstrate variable or no impairment with
objective assessment.
Patients with chronic insomnia generally show
signs of hyperarousal, with normal to prolonged
 ARTICLE IN PRESS
Insomnia: Pathophysiology and implications for treatment
daytime sleep latencies on multiple sleep latency
tests compared with normal sleeping control sub-
jects.17–19 Patients with insomnia also perform as
well as normal sleepers on a wide variety of tasks.
In small cohort studies, no difference was noted
between these groups in cognitive, psychomotor, or
memory tasks. Specifically, results for insomniacs
and controls were similar on digit-symbol substitu-
tion tests, pegboard testing, card sorting, addition,
logical reasoning, divided attention, and visual
vigilance tasks.20 What does appear to differ
between insomniacs and aged-match normals is
the ability to accurately self-rate performance.
Good sleepers are better judges of how well they
have or will perform on tasks following a good or
poor night’s sleep, while people with insomnia
typically overestimate their impairment and under-
estimate their performance.21
Insomnia is an important covariate of poor
physical and emotional health. For example,
comorbid sleep disturbance in dementia or Parkin-
son’s disease is problematic for both the patient
and the caregiver. Conversely, it is possible that
appropriate treatment of sleep disturbances in
these patients may aid in delaying institutionaliza-
tion, may help reduce nursing care costs, and may
improve quality of life for both patient and
caregiver.22 With respect to psychiatric disorders,
a large body of data suggests that sleep disturbance
and depression may be associated,5,6 and insomnia
associated with major depression increases the risk
of adverse outcomes, such as depressive relapse or
suicide.23–25
Beyond the individual sufferer, chronic insomnia
adversely affects society in both direct and indirect
ways. The estimated total direct cost attributable
to insomnia in the United States was approximately
$14 billion in 1995.26 Healthcare services for
insomnia constituted approximately $12 billion of
the direct costs; the use of sleep-promoting agents
accounted for the remaining $2 billion.26 Insomnia
is linked to increased rates of hospitalization,
healthcare use, and absenteeism at work,24 as well
as increased healthcare costs.27 The cost of
insomnia in terms of lost productivity and accidents
was estimated as $80 billion.28
Risk factors for insomnia
Increasing age, female gender, medical and psy-
chiatric disease, and shift work all independently
predict risk for developing chronic insomnia in
epidemiological studies as summarized by Roth
and Roehrs.8 In one large-scale population study
(N ¼ 9851), women were 1.6 times more likely
73
to suffer from insomnia than men. Although specific
risk factors differed somewhat by gender, that is,
risk factors in women included being a housewife
and being divorced, while in men they included
having less education and being retired. Prevalence
increased with age in both sexes.29
Insomnia is more prevalent in older populations,
and several authors have noted that the elderly are
prone to a number of concomitant risk factors, such
as increased prescription drug use, somatic dis-
orders, neurological decline, reduced exposure to
outdoor light, and polyphasic sleep-wake pat-
terns.30 Lack of physical activity also may play a
role in the age-related increase in insomnia
prevalence.31 Longitudinal data suggest that re-
duced physical activity, independent of social
engagement or interaction, represents a strong risk
factor for development of insomnia in elderly
individuals.31
In addition to female gender and advancing age,
psychosocial factors, such as family quarrels and
illness, and excessive home or workplace demands
independently predict insomnia.32 Finally, poor
physical health was associated with insomnia in
several epidemiological studies.33,34
Hyperarousal in insomnia
Chronic primary insomnia has been characterized
as a state of hyperarousal. The hyperarousal can be
seen in various signs of peripheral and central
activation (see Table 2) and with various symptom
and behavioral manifestations such as excessive
worry and reactivity.10 An underlying pathophysiol-
ogy for the hyperarousal, as described below, has
been hypothesized. The hyperaroused state of
insomnia differs from the daytime sleepiness and
impaired performance that results from sleep
restriction, fragmentation, and deprivation in
non-insomniacs.
In a previous paper, Richardson and Roth1
proposed a model suggesting that increased corti-
cotropin releasing factor (CRF) activity is respon-
sible for the pathogenesis of primary insomnia. The
theory was based on three interwoven strands of
evidence: (1) observation of some clinical and
neuroendocrine similarities between primary in-
somnia and major depressive disorder (MDD); (2)
abnormal CRF regulation in the pathogenesis of
major depression; and (3) findings showing that
hyperactivity of CRF neurons (specifically those
innervating the locus coeruleus) can account for
several clinical features of insomnia, including
hyperarousal and sleep disturbance.
 ARTICLE IN PRESS
74
Table 2 Physiologic evidence of sympathetic
nervous system hyperarousal in insomnia.
Parameter Recent studies
Elevated levels of Vgontzas et al.35
circulating
catecholamines
Increased basal Bonnet and Arand36
metabolic rate
Increased body Lushington et al.37
temperature
Altered heart rate Lichstein et al.38 and
variability/reduced Bonnet and Arand39
RSA
Elevated beta EEG Nofzinger et al.40
frequency/cortical Perlis et al.41
activation on EEG Nofzinger42
Abbrevations: EEG ¼ electroencephalograph;
RSA ¼ respiratory sinus arrhythmia.
 Reduced RSA indicates reduced parasympathetic tone,
associated with increased stress.
With respect to the third point, hyperarousal
appears to distinguish patients with primary in-
somnia from controls, as evidenced by prolonged
sleep latency during the day despite fragmented
and decreased nocturnal sleep.18,38 Furthermore,
patients with chronic insomnia show a variety of
physiologic markers suggesting sympathetic ner-
vous system hyperarousal (Table 2). Also, both
animal and human data suggest that the hypotha-
lamic–pituitary–adrenal (HPA) axis is overactive in
insomnia.1 For example, patients with primary
insomnia show elevated levels of urinary free
cortisol, which correlates with the amount of
nighttime wakefulness.35 Based on these findings,
it is hypothesized that (1) CRF hyperactivity, arising
through either a genetic diathesis or early stres-
sors, leads to an exaggerated CRF response to
stress; (2) subsequent re-exposure to stress leads to
amplification of the abnormal stress response,
perhaps via pathological changes in the hippocam-
pus; and (3) this sequence leads to marked
difficulty sleeping when stressed, exaggerated and
prolonged sleep disturbance following stress, and
ultimately to chronic primary insomnia.1
Pathophysiology of the HPA axis: findings
in primary insomnia
Two findings in healthy, normals suggest a linkage
between primary insomnia and mood disorders. The
T. Roth et al.
first finding demonstrated that in normal male
subjects infusions of either cortisol or adrenocorti-
cotropic hormone (ACTH) reduced rapid eye move-
ment (REM) sleep compared with placebo
infusions.43 The second result suggested that
intravenous CRF may lead to blunted growth-
hormone secretion and reduced slow-wave sleep
in normal men.44 Importantly, these effects re-
sembled effects seen among hypercortisolemic
depressives; setting the stage for subsequent
hypotheses linking primary insomnia with mood
disorders.44 These findings in healthy normals
indicate that experimentally induced elevations in
ACTH and CRF are disruptive of sleep.
In patients with primary insomnia elevated HPA
neuroendocrine levels have been found. A recent
investigation studied plasma cortisol levels in seven
men (age 40.078.2 years) with severe, chronic
primary insomnia compared with seven healthy
male controls (age 35.9711.2 years).45 The pa-
tients with insomnia had significantly increased
evening and nocturnal plasma cortisol concentra-
tions and reduced duration of the quiescent period
of circadian cortisol secretion compared with
controls. The authors viewed these findings as
‘‘ya neuroendocrine counterpart of the postu-
lated psychophysiological hyperarousal’’ of primary
insomnia. The increased plasma cortisol in these
insomniac patients was perpetuated by diminished
negative feedback inhibition of cortisol on CRF, a
finding also seen in elderly subjects and patients
with depression.46,47 The authors further proposed
that the reduced negative feedback may lead to
chronically increased CRF levels, thus inducing and
maintaining elevated cortisol levels in people with
insomnia.45
Chronic insomnia is also associated with in-
creased plasma levels of ACTH and cortisol.48 In
fact, higher cortisol levels were correlated with
reduced sleep efficiency.48 These results are con-
sistent with insomnia being a central nervous
system hyperarousal disorder rather than simply a
disorder of sleep loss. Thus, the goal of insomnia
treatment should not only be to improve nighttime
sleep, but also to decrease the overall level of
physiologic and emotional arousal.48 These data
indicate that basal levels of ACTH and cortisol are
elevated in insomniacs relative to normals.
Insomnia, hyperarousal, and mood
disorders
The most common comorbidity associated with
chronic insomnia is psychiatric disorder, specifically
 ARTICLE IN PRESS
Insomnia: Pathophysiology and implications for treatment
depression.8 Recent epidemiological studies
provided strong evidence that insomnia is an
independent predictor of incident depression.5,6
The occurrence of insomnia symptoms for a
period of more than 2 weeks is predictive of
increased risk for depression over the subsequent
1–3 years.49
The question remains, however, whether insom-
nia causes depression or depression causes insom-
nia, or if either condition may cause the other.
It is also likely that an individual is vulnerable to
both insomnia and depression because of some
similarities in pathology. Specifically, the over-
activation of the HPA axis appears to underlie both
conditions.8
The insomnia literature tends to regard depres-
sion as a homogeneous entity. Yet, the history of
psychiatry is replete with attempts to delineate
subtypes of depression, for example, unipolar/
bipolar; endogenous/reactive; melancholic/non-
melancholic; psychotic/non-psychotic; and typi-
cal/atypical. There is no a priori reason these
clinical syndromes, to the extent that they repre-
sent discrete nosological entities, should have
identical pathophysiologies, much less identical
alterations in HPA function. Yet the study of HPA
dysfunction in the major subtypes of depression has
been quite limited. A recent review noted that
psychotic depression is specifically associated with
HPA dysfunction.50 In particular, patients with
psychotic depression tend to show high rates of
non-suppression on the dexamethasone suppression
test (DST), markedly elevated post-dexamethasone
cortisol levels, and high levels of 24-h urinary free
cortisol. These findings do not appear to result
merely from high levels of depression or from the
presence of endogenous features, such as absence
of a precipitant.51,52 In contrast, the rates of DST
non-suppression in dysthymic disorder have gener-
ally been similar to those observed in control
subjects,50 though not all studies support this
conclusion.53
Previous research indicated that melancholic
depression is a syndrome in which the stress
response is hyperactive; patients are anxious,
anorectic, unresponsive to psychosocial stimuli,
more depressed in the morning, and exhibit
insomnia symptoms. Melancholic patients tend to
show an overactive CRF system and decreased
growth hormone. In contrast, patients with atypical
depression tend to be lethargic, fatigued, hyper-
phagic, reactive to the environment, more de-
pressed in the evening, and exhibit
hypersomnia.54,55 A recent study assessed HPA
function in these two types of depression, and
found both phenomenological and neuroendocrine
75
distinctions. Atypical depression was generally
characterized by down-regulated HPA axis and
CRF deficiency.56 In effect, melancholic depression
can be viewed as a prolonged and intensified stress
response that is not susceptible to the usual
counter-regulatory restraints. Atypical depression,
on the other hand, can be viewed as a state of
stress system hypoactivity that is too easily
susceptible to counter-regulatory restraints. Inter-
estingly, reduced cortisol levels and down-regula-
tion of the HPA axis also exist in posttraumatic
stress disorder.57
HPA hyperfunction: treatment
implications for depression and insomnia
As HPA overactivity is a common factor in
primary insomnia and some subtypes of depression,
it seems reasonable to ask whether both dis-
orders might respond to the same therapeutic
intervention. Two important questions related
to these issues come to mind. First, would
strategies that reduce HPA activity and/or gluco-
corticoid effects ameliorate both major depression
and primary insomnia? Second, as HPA over-
activity is an integral feature of insomnia, how
effective are the currently available pharma-
cologic and behavioral treatments at reducing this
overactivity?
To answer the first question, an examination
of the growing body of literature on the use of
antiglucocorticoid agents in the treatment of
psychotic depression is warranted. Mifepristone
(RU-486), a potent glucocorticoid receptor antago-
nist, rapidly reversed psychotic symptoms in a
study of patients with delusional depression.58
Other antiglucocorticoid agents, such as aminoglu-
tethimide, metyrapone, and ketoconazole, have
shown some efficacy in heterogeneous depressed
populations.50 For example, a double-blind study
of depressed patients found that ketoconazole
was superior to placebo.59 This was true, however,
only in the subset of patients with hypercortisole-
mia. The relatively rapid onset of glucocorticoid
receptor antagonists (1 week or less) is an
advantage compared with the more gradual im-
provement seen with antidepressant/antipsychotic
combinations.60 Although the literature describ-
ing the use of antiglucocorticoid strategies in
bipolar disorder is limited, successful treat-
ment of a patient with refractory bipolar II
depression was achieved through addition of
ketoconazole to a regimen of lithium and phenel-
zine.61 Interestingly, improvement was correlated
 ARTICLE IN PRESS
76
with decreases in urinary free cortisol levels, and
discontinuation of ketoconazole was associated
with relapse.
To our knowledge, no published placebo-con-
trolled studies exist that examine the sleep efficacy
of antiglucocorticoid agents in depressed patients.
However, one study assessed 29 patients diagnosed
with treatment-resistant major depression, of
whom 17 completed treatment with one or more
antiglucocorticoid agents (aminoglutethimide, ke-
toconazole, or either of these plus metyrapone).62
Eight completers were psychotic; nine were
nonpsychotic. Improvement was noted on overall
Hamilton Depression Scale scores, including
improvement of the three sleep-related items.
Somewhat surprisingly, nonpsychotic patients im-
proved more than psychotic patients. A follow-up
study described the neuroendocrine responses in
this same cohort.63 Improvement in depression
was not consistently correlated with changes
in serum cortisol, but was associated with
declines in levels of dehydroepiandrosterone. In
summary, while the therapeutic effects of anti-
glucocorticoid agents in depression is not very
strong and have not been tested in insomnia
these do suggest that strategies to reduce HPA
activity and/or glucocorticoid warrant study in
insomnia.
The answer to the second question is simple;
there are no published, placebo-controlled studies
examining HPA axis and hypercortisolemia in people
with well-defined chronic or primary insomnia.
However, the effects of loprazolam (a benzodiaze-
pine not available in the US) (1 mg) and triazolam
(0.5 mg) were studied in nine poor sleepers over a
3-week period.64 Total overnight urinary cortisol
was lower during active treatment, and cortisol
levels significantly rebounded to above-baseline
upon drug discontinuation. Similarly, a placebo-
controlled study found that temazepam (20 mg)
significantly inhibited peak serum cortisol levels
and ACTH after CRF administration in healthy
volunteers, but not in patients with Cushing’s
syndrome.65
Although there are no published data examining
the effect of non-benzodiazepine hypnotics on HPA
function in insomnia, there are some related data.
Zolpidem (10 mg) use did not appear to affect
plasma cortisol levels in a study of hormonal
response to exercise after partial sleep depriva-
tion.66 Similarly, the popular over-the-counter
agent melatonin does not appear to significantly
affect glucocorticoid secretion.67
While the sedating tricyclic antidepressants are
not approved for the treatment of insomnia,
several studies using these agents have shown
T. Roth et al.
effects on the HPA axis. The effects of oral
and intravenous doxepin (25 mg) on nocturnal
sleep and plasma cortisol secretion were studied
in 10 patients with chronic primary insomnia.68
Both doxepin formulations improved sleep
and reduced mean cortisol levels from 9.071.7
to 7.571.6 mcg/l (single IV infusion) and
7.072.0 mcg/l (oral doxepin for 3 weeks). The
authors concluded that normalization of HPA
axis function partially mediated the sleep-improv-
ing effects of doxepin. Similarly, another study
hypothesized that the atypical tricyclic trimipra-
mine may be of value in primary insomnia because
of its ability to inhibit nocturnal cortisol secre-
tion.69 Clearly, more controlled studies of hypnotic
agents as well as behavioral treatments are
necessary to determine their effects on HPA
function.
Conclusion
Chronic insomnia is a highly prevalent, yet incom-
pletely understood condition. People with insomnia
report significantly impaired daytime function
across a number of emotional, social, and physical
domains. These deficits reported by insomnia
sufferers are additionally associated with enormous
personal and societal costs. Several studies show
that insomnia is an important predictor of poor
physical and emotional health and that insomnia
may independently alter the course of affective
disorders.
Recent evidence suggests that insomnia and
some types of depression may have common
pathological processes that make an individual
vulnerable to both conditions. Specifically, over-
activation of the HPA axis appears to underlie both
insomnia and depression. If confirmed in large,
well-controlled studies of primary insomnia, these
findings may have important therapeutic implica-
tions. We may find that some currently available
hypnotic agents are better able to reduce inap-
propriate HPA activation and thus may be more
effective than others for insomnia and comorbid
depression. Since no randomized, controlled, head-
to-head studies of hypnotic agents and their effects
on HPA overactivity/hyperarousal exist, this should
be a priority for future research. It remains to be
seen whether benzodiazepine receptor agonists
reduce HPA overactivation in insomnia. If so, such
agents may play a more important role than
previously thought in the management of both
primary insomnia and insomnia comorbid with
depression.
 ARTICLE IN PRESS
Insomnia: Pathophysiology and implications for treatment
Practice points
1. In managing insomnia it is important to
recognize that insomnia is not merely a
symptom of another disorder but a disorder
of hyperarousal. Hence, treatment should
be directed at the insomnia AS WELL as the
comorbid disorder.
2. Patients with insomnia are at increased risk
of developing affective disorders. Hence,
monitoring depressive symptoms in insom-
nia patients may help identify depression
early in its evolution.
3. As hyperarousal may precede the full blown
manifestation of insomnia, treating transi-
ent sleep problems may help stop the spiral
to chronic insomnia.
*10. Drake CL, Roehrs T, Roth T. Insomnia causes, consequences,
Research agenda
1. Treatment studies in insomnia need to focus
not only on measures of sleep induction and
maintenance but also on measures of
physiological function during sleep espe-
cially those impacted by the HPA system.
2. Studies are needed to determine the
impact of insomnia therapy on the efficacy
and timing of an antidepressant response.
Can improving sleep augment antidepres-
sant response or even prevent depressive
relapse in patients with insomnia and
comorbid depression?
3. Research is needed to determine if hyper-
arousal is unique to primary insomnia or is
common to all insomnias including those
that are co-morbid with another medical or
psychiatric disorder.
Acknowledgements
The authors would like to acknowledge that they
received compensation from Sepracor for the
services they provided in support of the develop-
ment of this manuscript. The authors wish to
acknowledge H. Heith Durrence for his assistance
in preparing this manuscript.
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