PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache

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Abstract

The interaction between sleep and primary headaches has gained considerable interest due to their strong, bidirectional, clinical relationship. Several primary headaches demonstrate either a circadian/circannual rhythmicity in attack onset or are directly associated with sleep itself. Migraine and cluster headache both show distinct attack patterns and while the underlying mechanisms of this circadian variation in attack onset remain to be fully explored, recent evidence points to clear physiological, anatomical and genetic points of convergence. The hypothalamus has emerged as a key brain area in several headache disorders including migraine and cluster headache. It is involved in homeostatic regulation, including pain processing and sleep regulation, enabling appropriate physiological responses to diverse stimuli. It is also a key integrator of circadian entrainment to light, in part regulated by pituitary adenylate cyclase-activating peptide (PACAP). With its established role in experimental headache research the peptide has been extensively studied in relation to headache in both humans and animals, however, there are only few studies investigating its effect on sleep in humans. Given its prominent role in circadian entrainment, established in preclinical research, and the ability of exogenous PACAP to trigger attacks experimentally, further research is very much warranted. The current review will focus on the role of the hypothalamus in the regulation of sleep-wake and circadian rhythms and provide suggestions for the future direction of such research, with a particular focus on PACAP.

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The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

Harald Schrader, Emmanuel Mignot, S Nevsimalova … (2002)

Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels. To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy. Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels. Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif. There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders). Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies. Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features. HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n = 194). Intermediate (n = 30) and low (n = 3) levels were observed in various acute neuropathologic conditions. Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).

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PACAP38 induces migraine-like attacks in patients with migraine without aura.

Steffen Birk, Jes Olesen, Troels Wienecke … (2008)

Experimental studies have shown that infusion of vasoactive neurotransmitters may trigger headache or migraine-like attacks in man. Pituitary adenylate cyclase activating peptide-38 (PACAP38) is a strong vasodilator found in trigeminal sensory and parasympathetic perivascular nerve fibers. We therefore hypothesized that infusion of PACAP38 would cause headache in healthy subjects and migraine-like attacks in migraine patients. Twelve healthy subjects and 12 migraine patients were examined in two separate studies. All subjects were allocated to receive 10 pmol/kg/min PACAP38 and placebo in a randomized, double-blind crossover study design. Headache was scored on a verbal rating scale (VRS) during hospital (0-2 h) and post-hospital (2-12 h) phases. Mean blood flow velocity in the middle cerebral artery (V(MCA)) by transcranial Doppler (TCD) and diameter of the superficial temporal artery (STA) by high resolution ultrasonography were recorded during hospital phase in migraineurs. PACAP38 infusion caused headache in all healthy subjects and 11 out of 12 migraine patients. Seven migraine patients experienced migraine-like attacks after PACAP38 and none after placebo (P = 0.016). Most of attacks (6 out of 7) occurred during the post-hospital phase [mean time 6 h (range 2-11)]. Two healthy subjects reported migraine-like attacks after PACAP38 during the hospital phase and none during the post-hospital phase. In the hospital phase, the area under the curve (AUC) for headache score was larger during PACAP38 infusion compared to placebo in healthy subjects (P = 0.005) and tended to be larger in migraineurs (P = 0.066). In the post-hospital phase, the AUC for headache was larger after PACAP38 infusion compared to placebo in both healthy subjects (P = 0.005) and migraine patients (P = 0.013). In migraine patients, PACAP38 caused a peak decrease of 16.1% in V(MCA) and a 37.5% increase in STA diameter at 20 min after start of infusion. In conclusion, PACAP38 infusion caused headache and vasodilatation in both healthy subjects and migraine patients. In migraine sufferers, PACAP38 caused delayed migraine-like attacks. The findings stimulate further investigation of the neuronal and vascular mechanisms of PACAP38.

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Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden.

Jennifer R. Fishman, Todd Rozen (2011)

To present results from the United States (US) Cluster Headache Survey including data on cluster headache demographics, clinical characteristics, suicidality, diagnostic delay, triggers, and personal burden. There are few large-scale studies looking at cluster headache patients and none from the USA. This manuscript will present data from The US Cluster Headache Survey, the largest survey ever completed of cluster headache patients living in the USA. The total survey was composed of 187 multiple-choice questions that dealt with issues related to cluster headache including demographics, clinical characteristics, comorbid medical conditions, family history, triggers, smoking history, and personal burden. The survey was placed on a Web site from October through December 2008. A total of 1134 individuals completed the survey (816 male, 318 female). Some key highlights from the survey include the following: (1) diagnostic delay: there remains a significant diagnostic delay for cluster headache patients on average 5+ years with only 21% receiving a correct diagnosis at time of initial presentation. (2) Suicidality: suicidal ideations are substantial, occurring in 55%. (3) Eye color: the predominant eye color in cluster headache patients is brown and blue, not hazel as suggested in previous descriptions. (4) Laterality: cluster headache has a right-sided predominance. (5) Attack profile: in US cluster headache sufferers, most attacks occur between early evening and early morning hours with peak time of headache onset between midnight and 3 am; the circadian periodicity for cluster headache is present but is not as predominant in the population as previously thought. (6) Triggers: beer is the most common type of alcohol trigger in US cluster headache patients; noted migraine triggers such as weather changes and smells are also very common cluster headache triggers. (7) Medical comorbidities: peptic ulcer disease does not have a high prevalence in US cluster headache patients as suggested by previous literature; cluster headache is associated with a low prevalence of cardiac disease as well as cerebrovascular disease even though the majority of patients are chronic heavy smokers. In US cluster headache sufferers, there appears to be comorbidity with restless leg syndrome, and this has not been demonstrated in non-US cluster headache populations. (8) Personal burden: cluster headache is disabling to the individual as almost 20% of cluster headache patients have lost a job secondary to cluster headache, while another 8% are out of work or on disability secondary to their headaches. Some findings from the US Cluster Headache Survey expound on what is currently known about cluster headache, while some of the results contradict what has been previously written, while other information is completely new about this fascinating headache disorder. © 2011 American Headache Society.

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Author and article information

Contributors

Philip R. Holland: Philip.holland@kcl.ac.uk

Mads Barloese: christian.johannes.barloese@regionh.dk

Jan Fahrenkrug: Jan.fahrenkrug@regionh.dk

Journal

Journal ID (nlm-ta): J Headache Pain

Journal ID (iso-abbrev): J Headache Pain

Title: The Journal of Headache and Pain

Publisher: Springer Milan (Milan )

ISSN (Print): 1129-2369

ISSN (Electronic): 1129-2377

Publication date (Electronic): 5 March 2018

Publication date PMC-release: 5 March 2018

Publication date Collection: 2018

Volume: 19

Issue: 1

Electronic Location Identifier: 20

Affiliations

[1 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, Department of Basic and Clinical Neuroscience, Headache Group, , Institute of Psychiatry, Psychology and Neuroscience, King’s College London, ; London, UK

[2 ]Department of Clinical Physiology, Nuclear Medicine and PET, 70590 Rigshospitalet, Copenhagen, Denmark

[3 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Department of Clinical Biochemistry, Faculty of Health and Medical Sciences, Bispebjerg Hospital, , University of Copenhagen, ; Copenhagen, Denmark

Article

Publisher ID: 844

DOI: 10.1186/s10194-018-0844-4

PMC ID: 5838029

PubMed ID: 29508090

SO-VID: 9a7bdd30-aa6d-496b-b44c-9de6a36d277e

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 10 November 2017

Date accepted : 12 February 2018

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ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: migraine,cluster headache,circadian,circannual,hypothalamus,pituitary adenylate cyclase-activating peptide

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ScienceOpen disciplines: Anesthesiology & Pain management

Keywords: migraine, cluster headache, circadian, circannual, hypothalamus, pituitary adenylate cyclase-activating peptide

PACAP in hypothalamic regulation of sleep and circadian rhythm: importance for headache

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Irish Journal of Paramedicine

Most cited references 71

The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias.

PACAP38 induces migraine-like attacks in patients with migraine without aura.

Cluster headache in the United States of America: demographics, clinical characteristics, triggers, suicidality, and personal burden.

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