Original Article Thalamic contribution to Sleep Slow Oscillation features in humans: A single case cross sectional EEG study in Fatal Familial Insomnia Angelo Gemignani a,b,c,⇑ , Marco Laurino a,b , Federica Provini d , Andrea Piarulli b,c , Giorgio Barletta d , Paola d’Ascanio a,b , Remo Bedini b,c , Raffaele Lodi e , David Neil Manners e , Paolo Allegrini b,c , Danilo Menicucci b,c , Pietro Cortelli d a Department of Physiological Sciences, University of Pisa, Pisa, Italy b Extreme Centre, Scuola Superiore Sant’Anna, Pisa, Italy c Institute of Clinical Physiology, National Research Council, Pisa, Italy d Department of Neurological Sciences, University of Bologna, Bologna, Italy e Functional MR Unit, Department of Internal Medicine, Aging and Nephrology, University of Bologna, Bologna, Italy article info Article history: Received 8 December 2011 Received in revised form 9 March 2012 Accepted 13 March 2012 Available online 19 May 2012 Keywords: Sleep Slow Oscillation NREM sleep Spindles Thalamus Fatal Familial Insomnia Humans abstract Objective: Studying the thalamic role in the cortical expression of the Sleep Slow Oscillation (SSO) in humans by comparing SSO features in a case of Fatal Familial Insomnia (FFI) and a group of controls. Methods: We characterize SSOs in a 51-year-old male with FFI carrying the D178N mutation and the methionine/methionine homozygosity at the polymorphic 129 codon of the PRNP gene and in eight gen- der and age-matched healthy controls. Polysomnographic (21 EEG electrodes, two consecutive nights) and volumetric- (Diffusion tensor imaging Magnetic Resonance Imaging DTI MRI) evaluations were carried out for the patient in the middle course of the disease (five months after the onset of insomnia; disease duration: 10 months). We measured a set of features describing each SSO event: the wave shape, the event-origin location, the number and the location of all waves belonging to the event, and the grouping of spindle activity as a function of the SSO phase. Results: We found that the FFI individual showed a marked reduction of SSO event rate and wave mor- phological alterations as well as a significant reduction in grouping spindle activity, especially in frontal areas. These alterations paralleled DTI changes in the thalamus and the cingulate cortex. Conclusions: This work gives a quantitative picture of spontaneous SSO activity during the NREM sleep of a FFI individual. The results suggest that a thalamic neurodegeneration specifically alters the cortical expression of the SSO. This characterization also provides indications about cortico-thalamic interplays in SSO activity in humans. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction Electrophysiological studies in animal models have revealed that, during Slow Wave Sleep (SWS), cortical neurons show slow (<1 Hz) rhythms characterized by a coordinated switching behavior of the membrane potential: they synchronously alternate between a state of hyperpolarization (down state) and a state of wake-like depolarization (up state) [1,2]. This behavior, which represents the fundamental cellular phenomenon underlying different slow neural activities in SWS, such as K complexes and delta waves [3], has also been described in humans and referred to as Sleep Slow Oscillation (SSO) [4,5]. From an EEG stand point SSO (i) corresponds to a sharp negative peak (related to the down-state) followed by a shallow positive half wave (related to the up-state), (ii) originates mainly in frontal regions [4,5], and (iii) propagates across variable cortical territories [4,5]. It has also been observed in animal models and in humans that up-states group spindle and faster activities, which reflects the influence of the neural mechanism underlying SSO on thalamo-cortical cells [6,7]. Despite a deep electrophysiological and EEG characterization of SSOs, an issue is still under debate: is the human SSO generated in the neocortex and then imposed on thalamic territories or is it gen- erated by a mutual interplay between the thalamus and the cere- bral cortex? 1389-9457/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2012.03.007 ⇑ Corresponding author. Addresses: Department Physiological Sciences, Univer- sity of Pisa, via San Zeno 29, Pisa, Italy; Extreme Centre, Scuola Superiore Sant’Anna & Institute of Clinical Physiology, CNR, Pisa via Moruzzi 1, Pisa, Italy. Tel.: +39 050 315 2686; fax: +39 050 2213 527. E-mail address: gemignan@dfb.unipi.it (A. Gemignani). Sleep Medicine 13 (2012) 946–952 Contents lists available at SciVerse ScienceDirect Sleep Medicine journal homepage: www.elsevier.com/locate/sleep