Author's personal copy Original Article Insomnia cycling with a 42-day infradian period: Evidence for two uncoupled circadian oscillators? Luca Vignatelli a,b, * , Simone Masetti c , Mario Amore d , Caterina Laterza d , Katia Mattarozzi e , Giulia Pierangeli b , Pietro Cortelli b , Stefano Vandi b , Roberto Vetrugno b , Giuseppe Plazzi b , Pasquale Montagna b a Ambulatorio di Neurologia, Polo Sanitario ‘‘Barberini” di Crevalcore, AUSL di Bologna, Italy b Dipartimento di Scienze Neurologiche, Università di Bologna, Italy c Dipartimento di Fisica, Università di Bologna, Italy d Divisione di Psichiatria, Dipartimento di Neuroscienze, Università di Parma, Italy e Dipartimento di Psicologia, Università di Bologna, Italy article info Article history: Received 10 June 2009 Received in revised form 8 September 2009 Accepted 14 September 2009 Available online 4 February 2010 Keywords: Sleep initiation and maintenance disorders, Bipolar disorder Chronobiology disorders Circadian rhythm Suprachiasmatic nucleus Theoretical models abstract Objective: To describe the unique case of a middle-aged woman with severe insomnia recurring with a regular infradian period without any other significant clinical condition. To infer the existence of a circa- dian dysfunction modeled according to the physical phenomenon of the ‘‘beats.” Patient/Methods: A two-year prospective observation by means of a sleep log was performed during the patient’s normal life. She underwent one month of motor activity recording and also polysomnography, circadian rhythm of body core temperature and psychiatric evaluation during periods with and without insomnia. Results: Visual inspection of the 293-day plot of the sleep log disclosed a regular 42-day rhythm of insomnia recurrence confirmed by a Discrete Fourier Transform. During the periods of insomnia, lasting 5–7 days, only moderate mood symptoms (depressive overlapping hypomaniac symptoms) were present. Treatment with sodium valproate was effective in curtailing insomnia. Conclusion: The wax and wane infradian modulation of the sleep length suggested the presence of a basic mechanism similar to the physical phenomenon of the ‘‘beats,” i.e., a long period modulation of the amplitude of an oscillating system due to the interference of two uncoupled oscillators with a slightly different oscillation frequency. Hypothesizing a dysfunction of the circadian component of sleep, namely two uncoupled circadian cycles, a simple mathematical model estimated the difference of their periods of oscillation |34 ± 2 min| and reproduced the sleep-log data of the drug-free period of observation. Ó 2010 Elsevier B.V. All rights reserved. 1. Introduction Complex behaviours may manifest with regular infradian peri- odicity both in healthy people and in patients with psychiatric dis- orders [1–4]. Menstrual migraine has, by definition, a monthly repetition, and cluster headache may recur with infradian regular- ity [5]. Some cyclic disorders have been described in the field of hematology, and cyclic neutropenia, the most studied, has a regu- lar periodicity of 21 days [6]. Insomnia, the commonest sleep complaint and symptom of sev- eral neurological and psychiatric disorders, may display an infra- dian recurrence if driven by mood symptoms in a rapid-cycling bipolar disorder [7]. Insomnia cycling with regular infradian recur- rence, however, has never been reported as a dominant complaint. We describe the case of a middle-aged woman with a severe cyclic insomnia whose original points were (1) the regular infra- dian period of recurrence demonstrated upon extensive prospec- tive clinical observation and neurophysiological monitoring, (2) the presence of moderate mood symptoms following the insomnia, (3) a good overall clinical response to treatment with sodium val- proate. In this patient we hypothesized a dysfunction of the circa- dian component of sleep, which we modeled according to the physical phenomenon of the ‘‘beats,” i.e., a long period modulation of the amplitude of an oscillating system as the result of two uncoupled oscillators cycling with slightly different frequency. 2. Case description 2.1. Subject In June 2001, a 43-year-old woman with no history of neurolog- ical or psychiatric disorders came to the Sleep Center of the Depart- 1389-9457/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2009.09.006 * Corresponding author. Address: Dipartimento di Scienze Neurologiche, Univer- sità di Bologna, 40123 Bologna, Italy. Tel.: +39 0512092950; fax: +39 0512092963. E-mail address: vigna@interfree.it (L. Vignatelli). Sleep Medicine 11 (2010) 343–350 Contents lists available at ScienceDirect Sleep Medicine journal homepage: www.elsevier.com/locate/sleep