ass JIDR Published on behalf of mencap and in association with IASSID Journal of Intellectual Disability Research doi: 10.1111).1365-2788.2010.01354 ‘YOUVE 55 FART 3 pp 255-262 MARCH 2611 Atypical sleep architecture and altered EEG spectra in Williams syndrome F. Gombos,' R. Bédizs'* & I. Kovacs'? | HAS-BME Cognitive Sconce Research Group, the Hungarian Academy of Sciences, Budopes, Hungory 2 Institute of Behavioural Sciences, Semmelies University, Budapest, Hungary 3 Deparment of Cognitive Science, Budapest Univesity of Tecnology and Economics, Bulapes, Hungary Abstract Background Williams syndrome (WS) is a new- rodevelopmental genetic disorder characterised by physical abnormalities and a distinctive cognitive profile with intellectual disabilities (IDs) and learn ing difficulties. Methods In our study, nine adolescents and young. adults with WS and 9 age~ and sexcmatched typi cally developing (TD) participants underwent poly- somnography, We examined sleep architecture, leg -movernents and the electroencephalogram (EEG) spectra of specific frequency bands at different scalp locations Results We found an atypical, WS characteristic sleep pattern with decreased sleep time, decreased sleep efficiency, increased wake time after sleep onset, increased non-rapid eye movernent percent- age, increased slow wave sleep, decreased rapid eye ‘movement sleep percentage, increased number of leg movements and irregular sleep cycles. Patients with WS showed an increased delta and slow wave activity and decreased alpha and sigma activity in the spectral analysis of the EEG. CConespondenc: De Rébere Bhs, HAS-BME Copnive Science Research Group ofthe Hungarian Acaemy of Seences, Depart. Budapest Hungary (emai Pbodsieogse be) Confit of Interest The ahors declare no cont of nest. Conclusions Sleep maintenance and organisation are significantly affected in WS, while EEG spectra suggest increases in sleep pressure, Keywords developmental disorders, BEG spectra, polysomnography, sleep EEG, sleep stages, ‘Williams syndrome Introduction Williams syndrome (WS) is a genetically de mined developmental disorder, linked to a microdeletion in chromosome 7431.23, characterised by distinct facial appearance, cardio- vascular abnormalities, mild to moderate ID, learning difficulties, high sociability and empathy (Meyer-Lindenberg «tal, 2006). The most interest- ing characteristic for cognitive research is their dis- tinctive cognitive profile: severe visual-spatial deficits and relative strength in expressive language (Karmilofi-Smith et al. 19975 Bellugi «tal. 2000). Overactivity and short attention span is typical in WS, More than 50% of WS individuals are disgnosed with attention deficit hyperactivity disor der (ADHD) (Morris etal. 2000; Leyfer otal 2006) ‘Sleep problems are common in developmental disorders, prevalence estimates vary from 13% 0 86%, dependent of age, physical and mental © 2010 The Authors, Journal of Intellectual Disability Revearch © 2010 Blackwell Publishing Lad256 Journal of Intellectual Disability Research VOLUME 55 PART 3 aancat 2031 F Gombor al = impairment and genetic syndrome (Lancioni etal 1999; Didden & Sigafoos 2002).'The few studies that have been published on WS so far do not cover the entire age range, and rely especially on question- naires, Polysomnography have been used only by a single research group in the past (Arens «tal. 19985 ‘Mason er al. 2009). Arens t al. questioned parents cof 28 children (mean age 4.7 + 2.3 years) with WS. ina telephone survey about their seep habits. Breathing arousal disorder was not diagnosed; however, movement arousal disorder was present in 57% of the cases. Seven of the 16 children with ‘movernent arousal sleep disorder and 10 typically developing (TD) participants underwent polysom- ‘ography. Children with WS had specifie sleep prob- lems, difficulties in initiating sleep, fragmented sleep ‘with long wake periods, as well as periodic limb -movernents during sleep. They spent more time awake, less time in sleep stages 1 and 2, and more time in stages 3 and 4 than TD participants (Arens al. x998), Mason et al, (2009) repeated Arens? study with more participants. They confirmed the results ofthe original study with respect to sleep dis- ‘urbance. Goldman et al. (2009) examined sleep in adolescents and young adults with WS. They used a sleep questionnaire and wrist actigraphy in their study, and found daytime sleepiness prolonged sleep Tatency, increased wake time, elevated movement index and fragmented sleep. The results support the continuity of sleep problems into adolescence and adulthood; however, studies, looking at sleep atchi- tecture by polysomnography in adolescents and adults with WS, are still missing, ‘Sleep quality is « relevant aspect of the WS phe- ‘notype; sleep problems may play an important role in cognitive and attention deficits and learning difi- culties. Our main objective was to determine ‘whether alterations in sleep architecture and sleep clectroencephalogram (EEG) spectra as measured by polysomnography, similar those that have been. found in children by Arens etal. are present in ado- lescents and adults with WS as well Methods Participants {Nine WS participants were recruited with the help of the Hungarian Williams Syndrome Association ‘Sleep architecture and EEG spectra in Willams syndrome and nine age-matched healthy TD participants were recruited by personal contacts, Pasticipants were matched also by sex, with the exception of one ‘wwin-pair of different gender, where the male was a ‘WS participant and his healthy fraternal (dizygotic) twin sister was his TD control participant. WS par- ticipants (three males and six females) ranged in age from 14 to 28 years, with a mean age of 20.5 * 5.5 years and TD participants (two males and seven females) ranged in age from 14 to 29 ‘years, with a mean age of 20.3 * 5.3 years. A simi- larly large age range was used in a study by; e.. Godbout etal. (2000), and precise age- and gender- matched TD participants were used to overcome this problem. We employed the same precisely matched TD participants in order to deal with the relatively large age range. Body mass index was in the normal and under the normal range in the WS group (between 13.9 and 26 with an average of 19.4) and in the normal range in the TD group (between 17.4 and 23.3 with an average of 20.5). Fluorescence in situ bybridisa- tion (FISH) test and clinical evaluation confirmed the diagnosis of WS patients, Participants were free of drugs or medications, except for one WS patient ‘who was on stable medication: clonidine (250 mg! day), enalapril (5 mp/day), acenylsalicylic acid (500 mg/day), betaxololi hydrochloridum (20 mg/ day) and amlodipine (15 mglday). Exclusion criteria for'TD participants were medical diagnosis of sleep problems or psychiatric, neurologic or other medical disorder. The retearch protocol was approved by the Ethical Committee of the Budapest University of Technology and Economies and all participants or the parents of the underage partici- pants signed informed consent to take part in the experiment. Recording Participants underwent two consecutive full-night polysomnography in a sleep laboratory. One parent ‘had the possibilty to remain and sleep in the same room on another bed for the whole night. The timing of lights off was determined by the partici= ‘pants, and morning awakenings were spontaneous Only the second night was evaluated, the first night supported the adaptation to the conditions. Poly- somnographic recordings included 18 EEG chan- © 2010 The Authors, Journal of Intellectual Disability Revearch © 2010 Blackwell Publishing Ladast Journal of Intellectual Disability Research VOLUME 55 PART 3 aancat 2031 F Gombor al = nels (Fp, Fp2, F3, F4, Fz, Fy, F8, C3, C4, Cz, Ts, T4, 1, T6, P3, P4, Or, O2), scalp electrodes were Tocated using the International 10-20 electrode placement with mathematically linked mastoid ref erence, Bilateral electrooculograms, bipolarly linked chin electromyogram and electrocardiogram chan- nels were monitored also. Leg movements were monitored with accelerometers over the ankles. We hhave not recorded respiratory variables because significant breathing difficulty during sleep in the study by Arens eal (1998), and in a more recent study by Mason etal (2009). Moreover, this would have caused further inconveniences for the participants because of the recording instruments. However, one participant, ‘whose sleep was one of the most fragmented in our study, underwent a fllnight polysomnography in a clinical sleep laboratory after our examination. The results of clinical respiratory monitoring did not show sleep apnea or hypopnea in this participant. All channels were digitised at a sampling rate of 249 Hz by using the 30 channel Flat Style SI La Mont Headbox with an active 50 Hz notch ‘filter, Signals were high-pass filtered at 0.5 Hz and low-pass filtered at 70 He. ‘Sleep was scored according to the modified Recatschaffen & Kales methods (Rechtschaffen and Kales 1968; Himanen & Hasan 2000) wsing 20 epochs. Periodic leg movements (PLM) in sleep ‘were scored according to standard criteria (Ameri- can Academy of Sleep Medicine 2005): at least four repetitive episodes of muscle contraction lasting 0.5 to $4 separated by an interval of § to 90 s. PLM. index was defined as the number of PLM per hous, A PLM index greater than 5 was considered patho- logical and called periodic limb movement disorder. ‘The following definitions were used for sleep architecture evaluation: time in bed (as the time fom lights out to final awakening), sleep time (defined as the amount of sleep from sleep onset to final awakening), wake time after sleep onset CWASO, excluding wakefulness after the final awak- ening), sleep efficiency (calewlated a¢ the percent of sleep time without WASO divided by the time in bed), sleep latency (defined as the period between, lights off and the first appearance of stage 2 sleep), pon-rapid eye movement (NREM), Stage 1 (St), Stage 2 (S2), slow wave sleep (SWS, defined as the amount of time in Stages 3 and 4), rapid eye move ‘Sleep architecture and EEG spectra in Willams syndrome ment (REM), REM latency (defined 2s the period between sleep onset and the firs epoch scored as REM), number of sleep cycles (number of REM periods separated from each other by more than 15 min), average REM period duration (duration of REM sleep divided by the number of REM periods) and average sleep cycle duration in ‘minutes (sleep time from the sleep onset to the end of the last REM period divided by the number of sleep cycle). Spectral analyses After visual artifact rejection, 4 s epochs (50% overlap) from sleep stages 2-3-4 and REM were Hanning-tapered and mixed-radix “Transformed in order to get the average power spectra in NREM and REM. The spectral bins were summed in specific frequency domains to get the band power for the slow oscillation (0.5-1 Hz), as ‘well as delta (2.25-4.5 Hz), slow wave (SWA, 0.75~ 4.5 Hz), theta (4.75-7.25 Hz), alpha (7.5-10.75 Hz), sigma (11-15 Hz) and beta (15.25-30 Hz) activities. To standardise absolute power across participants, relative power was also calculated, Relative power ‘was calculated as the ratio of band powrer to total power. Each channel’s absolute and relative band power was compared between the WS and the TD groups. 1 Fourier Statistical analysis, Statistical analyses of differences in sleep architec ture parameters and in power spectra between the WS and the TD participants were performed using the one-way ANOVA test with staTistica 8.1 (Stat- soft Inc., Tulsa, OK, USA), Results ‘As demonstrated by the representative hypnogram examples of Fig. 1, sleep in WS is more fragmented general, with moze awakenings and less cyclic sleep architecture than in the TD participants ‘Table t displays the mean values of sleep archi- tecture variables in patients with WS and TD par Licipants, and also the ANOVA results for group differences. Compared with TD participants, WS participants showed significantly decreased sleep © 2010 The Authors, Journal of Intellectual Disability Revearch © 2010 Blackwell Publishing Lod28 Journal of Intllecrual Disability Research ‘voUUME 55 nas 3 saReH 2011 FF Gombos eal. + Sleep architecture and EEG spectra in Williams syndrome al Pa ha Ural Fmt Figure 1 Hypnogram cxmples. Tye Hypnogram of 5 ear oi female Wiliams syndrome paricpant Boo: Hypaogram of 4 Years old pealy developing female partipat. REM, rp eve time as well as decreased sleep efficiency. WASO vas significantly increased in WS (the group aver- ages being 68.6 min vs. 16.4 min) with larger indi vidual differences in the WS group (SD 52.2 vs. 9.7 min). Sleep latency and REM latency was increased in WS; however, these differences were not significant. WS participants presented a signifi- cantly higher amount of NREM sleep percentage and a decreased amount of REM sleep percentage. Increased NREM percentage was mainly because of the increased SWS, there were no differences between the groups in stage 1 and stage 2. Average sleep eycle duration was homogeneous and in the normal range in the TD group (mean 96.2 min, SD 5.9), while among WS participants enormous indi- vidual differences were present (mean 98.0, SD 36.7, see Fig. 2) ‘The analysis of leg movements showed a signifi cantly higher number of leg movements per hour in the WS groups however, these leg movements were not periodic. The PLM index was low in both groups, without a significant difference between the ‘wo groups. The patterns of significant differences in the sleep EEG spectra of WS and TD partici pants were similar for the NREM and REM phases, but spatially more extended for NREM and charac- terised by increases in absolute and relative power of frontopolar (Fpt and Fp2) delta and SWA, as well as by a region-independent decrease in relative alpha and sigma power (Fig. 3).'There were no ‘other power spectra differences between the groups in the examined frequency ranges. Discussion In the present study, we proved the continuity of sleep problems in WS into adolescence and adult- hhood, and found an atypical, WS-characteristic sleep pattern with decreased sleep time, decreased sleep efficiency, increased WASO, increased NREM. percentage, increased SWS, decreased REM sleep percentage, irregular sleep cycles and increased ‘number of leg movements Difficulties in maintaining sleep and decreased sleep time were found to be characteristic features of our post-pubertal WS sample. This finding is coherent with results of polysomnographic studies ‘on pre-pubertal WS participants (Arens er al. 1998; ‘Mason er al. 2009) and with actigraphic ones on adolescents and adults (Goldman er al. 2009) Sleep cycles are disconcerted in WS as you can see in the hypnogram examples (Fig. 1) and in the large individual differences in the sleep cycle dura- tions (Fig. 2). There is a possibilty that fragmented sleep and frequent awakenings are behind the decreased REM percentage, and an awakening or stage shift occurs before reaching a REM phase uring the sleep cycles. However, WS participants hhave not presented a significantly fewer number of REM periods than TD participants Decreased sleep efficiency and decreased REM ratio are characteristic symptoms also in other developmental disabilities like Down syndrome (Diomedi «ral. 19995 Miano et al. 2008), autism (iomedi eal. 1999) and Angeiman syndrome (Miano er al. 2004) and in ADHD (Sobanski etal 2008). ADHD like symptoms are common in the above-mentioned developmental disabilities and in WS as well. Gau et al, (2009) examined ADHD participants and found relationships between sleep problems and ADHD. It is possible that ADHD like symptoms in WS are caused by decreased sleep effi- ciency and REM percentage. Clonidine, taken by ‘one of our WS participants, may induce changes in dreams. It has been applied in the treatment of ightmares associated with Post-traumatic Stress Disorder (Aurora er al. 2010); however, it could not explain our findings with decreased REM ratio, 1» 2010 The Authors. Journal of Ineleetual Disability Research © 2010 Blackwell Publishing Lid29 Journal of Intllecrual Disability Research ‘voUUME 55 nas 3 saReH 2011 FF Gombos eal. + Sleep architecture and EEG spectra in Williams syndrome Tablet Seep architecture fn paens with Wiliams syndrome and epially developing (TD) partipanss Williams syndrome ‘TD participants (n=9) =) . Sloop te (nin) 4392113 5302+ 669) oor Sloop efficiency (8) 802+ 168 94427 00233" WASO (in) 686» 522 64297 004 Seep latency (min) 289392 M43=93 02973 NREM (%) eos 43 T4243 0007 Stage 1%) 22*16 1308 o1si2 Stage 2%) 53872 567=33 02649 SWS (%) 24895 44245 00a REM (%) Is2=43 27643 0007 REM laconcy (ris) 1380 + 786 asi =275 00753 Lthour 234 120 M45= 98 oo1s7 PLM index 18223 1531 o7is7 [Number of sleep eyles 40217 52211 0073 ‘Average REM period (mis) 22790 244s oun Average sleep cycle (rin) 980+ 367 962=59) 09969 SWS; show wave sleep; WASO, wake tine ae ep onset; LM, lg movements; PLA inde, pid leg movements pet hou; NREM, non-api eye movements REM, apd ee movement z = z [Get Avg. Sleep Cycle Duration (min) 2 1D Williams Figure2 Average (Avg) sleep eye duration inde ypicaly Aeseloping (TD) (r= 9) and in he Willams syndrome (WS) (= 9) soups because the REM sleep ratio of the clonidine treated patient was above the mean REM sleep ratio in the WS group. There is a possibility that decreased sleep efficiency and decreased REM ratio might be improved by treatment, which, in turn, might improve daytime behavior (e.g. attention, learning capacity). Arens et al. (1998) treated WS children with clonazepam, and found fewer and shorter awakenings and less iritability during the day. Periodic limb movement disorder has been found in WS (Arens et al. 1998) and in Asperger's syn- drome (Godbout et al. 2000) in previous studies. However, we have not observed periodic limb movement disorder. Sleep maintenance was dis- turbed only by aspecific, non-periodic movement activity Williams syndrome participants experience sig- nificantly more cognitive overload and fatigue during the day because of their ID, and the df culty to adapt to their surroundings. It has been shown that fatigue increases the percentage of sws ‘The interpretation of the spectral results is fairly difficult because of the lack of quantitative sleep EEG studies in WS, We found increased delta activ- ity, increased SWA, and decreased alpha and sigma activity in the spectral analysis of the EEG channels in WS participants as compared with TD partici- pants. Delta activity and SWA are dominant in ‘SWS, and their increased presence in the power spectra might be related to the increased ratio of 1» 2010 The Authors. Journal of Ineleetual Disability Research © 2010 Blackwell Publishing Lid260 Journal of Intllecrual Disability Research F. Gombos eal. + Sleep archi ‘voUUME 55 nas 3 saReH 2011 ture and EEG spectra in Willams syndrome NREM FEG spectra Front P= 00s Right side REM EEG spectra Front Left side Abie Dan inane} ‘A: Absolute SWA # A: Relative SWA 4 or nae Aaj Retaive Sigma | Figure 3 Significant diferences inthe elesoencephalogram (EEG) spectra [sages 2 syndrome (WS) (n= 9) and ypclly developing (TD) (r= 9) parcpans Lf pan:sigifiane ferences in + and rapid eye movement (REM)] of Wakiams ‘movement (NREM) EEG spectra, Rg pune sgfcant diferences inthe REM EEG spec. Channel labeled with black led ater and wiangle indicate increased absolute dea and sow wate atv (SWA) and channels labeled with empry asterisk and wang indicate increased relative deka and SWWA in WS parcpant ax compared with TD parcpans, Channels Ibe with solid cic indicate ‘ecetsed ela alpha activity and chants Iabled with dashed cies inate decreased relative sigma acy in WS paripans 2+ ‘SWS in WS. Sleep spindling and spindle frequency activity were shown to be negative correlates of sleep intensity (delta power), decreasing consider- ably after periods of extended wakefulness (Dik 1995). Hence the decrease in sigma activity (cover ing the usual frequencies of sleep spindling) of our WS participants is coherent with their increased SWS and delta power, providing further potential cues for deeper sleep andor a homeostatic chal- lenge of the sleep regulation process. The increased delta (in both NREM and REM sleep) as well as the decreased relative NREM sigma activity in the patient group is reminiscent of the effeets of sleep deprivation on the EG and may suggest an elevated sleep propensity in WS (Diik etal. 19935 Jenni et al. 20055 Marzano et al. 2010). However, alpha power has been shown to covariate with delta and SWA in healthy participants’ NREM sleep (Borbaly et al. 1981, Marzano et al. 2010). There- fore, the region-independent decrease of the alpha power in our WS sample is not consistent with overall deeper sleep in WS. Ics also known that SWS percentage and delta EEG power in NREM sleep decrease in typical brain maturation (Feinberg & Campbell 2010), Increased SWS percentage and frontal delta as well as SWA power might be due to either fatigue or delayed brain maturation in WS. The frontopolar localisation of the increased delta power spectra may be related to the increases of grey matter in the frontal lobes (Campbell etal. 2009). Alternatively, the decreased sigma frequency EEG activity might be a neurophysiologic signature of impaired learning in WS. Sleep spindling has been shown to be involved in the consolidation of various types of memories, including the visuomotor domain (Tamaki eal 2008), and a decreased activ- ity might indicate consolidation deficiencies. Similar alterations in NREM and REM EEG spectra might indicate a more general feature in WS. It might well be that increased SWA and decreased alpha and sigma activity are present in the awake EEG spectra Conclusion We found atypical sleep architecture and altered sleep EEG spectra in WS. Some of these alterations © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Lid261 Journal of Intellectual Disability Research VOLUME 55 PART 3 atancat 203 F Gombor o al » Sleep architecture and EEG spectra in Williams syndrome hhave also been reported in other developmental dis orders, Sleep disruption, increased SWS, decreased REM sleep, specificities in the EEG spectra of sleep and leg movements altogether are characteristic features of sleep in WS. Further studies unraveling the relationship between these sleep alterations and daytime symptomatology and learning disabilities in WS are of special interest Acknowledgement ‘This study was supported by the Hungarian National Science Found (OTKA-NF60806 to LK.) 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