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Clinical Neurophysiology 118 (2007) 669–675

Event-related potentials in idiopathic rapid eye movementssleep behaviour disorder

Alberto Raggi a,b,*, Mauro Manconi c, Monica Consonni a,b, Cristina Martinelli b,c,Marco Zucconi c, Stefano F. Cappa a,b, Luigi Ferini-Strambi c

a Department of Neurology and Neurorehabilitation, San Raffaele Turro Hospital, Via Stamira d’Ancona 20, 20127 Milan, Italyb Department of Psychology and Neuroscience, Vita-Salute San Raffaele University, Milan, Italy

c Center of Sleep Medicine, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy

Accepted 19 November 2006

Abstract

Objective: To assess psychophysiological parameters in idiopathic rapid eye movements sleep behaviour disorder (RBD), in order toidentify possible markers for pre or sub-clinical cognitive abnormalities.Methods: Sixteen consecutive unmedicated patients with idiopathic RBD and 16 age- and sex-matched controls performed active andpassive auditory oddball paradigms and an attentional test.Results: There were no significant between-group latency and amplitude differences. The two groups showed a difference in the inter-peak interval between N100 and P200 in the active condition. A significant correlation between attentional matrices scores and N100amplitude at Fz and Cz to standard stimuli in the passive condition was found in controls but not in patients.Conclusions: In RBD there are minimal event-related potentials (ERPs) abnormalities involving the early stages of informationprocessing.Significance: ERPs are not sensitive to pre or sub-clinical cognitive abnormalities in RBD. In alternative, these findings might supportthe existence of a truly idiopathic RBD syndrome.� 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Rapid eye movements sleep behaviour disorder; Oddball P300; Mismatch negativity

1. Introduction

Rapid eye movements (REM) sleep behaviour disorder(RBD) is a parasomnia associated to REM sleep that wasfirst described by Schenck et al. (1986) as a distinct clinicalcondition. The loss of the normal muscle atonia, excessivephasic electromyographic (EMG) twitches, and abnormalmotor and vocal behaviour emerging from REM sleep rep-resent the main features of this disorder. Both the patientand the bed partner may report injuries as a consequenceof violent behaviour, which usually correlates with anaggressive dream content (Mahowald and Schenck, 1994;

1388-2457/$32.00 � 2006 International Federation of Clinical Neurophysiolo

doi:10.1016/j.clinph.2006.11.011

* Corresponding author. Tel.: +39 02 26433305; fax: +39 02 26433394.E-mail address: raggi.alberto@hsr.it (A. Raggi).

Ferini-Strambi and Zucconi, 2000). RBD is a male-predom-inant disorder, typically appearing around the age of 60years. Findings from the animal model of RBD suggest adysfunction in descending brainstem neurons involved inmotor inhibition during REM sleep (Hendricks et al., 1982).

According to the association with neurodegenerativediseases, brainstem lesions, other sleep disorders or otherneurological pathologies, RBD can be classified in idio-pathic or secondary form. In particular, RBD has beendocumented to co-occur with neurodegenerative disorderswith a pathological intracellular deposit of a-synucleineprotein, such as Parkinson’s disease (PD), multiple-systematrophy (MSA) and dementia with Lewy bodies (DLB)(Boeve et al., 1998, 2001; Comella et al., 1993; Fermanet al., 1999; Perry et al., 1990; Turner et al., 1997). In these

gy. Published by Elsevier Ireland Ltd. All rights reserved.

670 A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675

neurodegenerative conditions, RBD may represent one ofthe first symptoms, preceding the diagnosis as long as 10years. A recent prospective study showed that around65% of patients developed a Parkinsonian syndrome within13.3 years from the RBD onset (Schenck et al., 2003).Additional evidence confirms the development of clinicalsigns typical of neurodegenerative disorders after differenttime intervals ranging between 5 and 20 years (Fantiniet al., 2001; Zucconi et al., 2003; Iranzo et al., 2006; Plazziet al., 1997). On the other side, Comella et al. (1998) esti-mated the prevalence of RBD within a group of 61 PDpatients to be about 15%.

The existence of a truly idiopathic form of RBD is stilldebated. Compared to normal subjects, patients with idio-pathic RBD present selective neuropsychological deficits,but only limited evidence is available (Cox et al., 1990;Ferini-Strambi et al., 2004).

The current challenge in clinical research is to discover amarker able to quantify the risk progression to neurode-generative diseases in patients with idiopathic RBD.Assessment of neuropsychological, motor (finger tappingtest) and olfactory functions may partially solve this impor-tant issue (Postuma et al., 2006).

Cognitive performance in RBD has never been evaluat-ed by event-related potentials (ERPs). They are voltagefluctuations that are associated in time with some physicalor mental occurrence. These potentials can be recordedfrom the human scalp and extracted from the ongoing elec-troencephalogram (EEG) by means of filtering and signalaveraging. ERPs allow the study of the physiologicalsource of psychological processes in their dynamics (Prit-chard, 1981). The most studied paradigm is the Oddball

P300, which elicits negative (N100 and N200) and positivecomponents (P200 and P300) related to stimulus codifica-tion-identification-characterization, and therefore to infor-mation processing (Sutton et al., 1965; Pritchard, 1981).Normal peak latencies of N100 and P200 with longerP300 latencies have been reported in cortical dementias,while longer N100, P200, P300 latencies occur in sub-corti-cal dementias, such as PD plus dementia (Goodin andAminoff, 1986). Mismatch negativity (MMN) is an ERPcomponent elicited in the auditory oddball paradigm bylow probability deviant stimuli embedded in a sequenceof high probability standard stimuli. Since MMN is betterevident when subjects ignore the auditory stimuli or per-form a distracting task, it is supposed to be an index of pre-attentive processing (Naatanen, 1990). According toNaatanen (1992), MMN is automatically generated when-ever there is a mismatch between the neuronal model of thephysical features of the standard stimulus and the deviantstimulus. Findings in PD are not conclusive, but they sug-gest deteriorated automatic change detection (Pekkonenet al., 1995; Pekkonen, 2000).

The aim of the present study was to assess psychophys-iological parameters in idiopathic RBD, in order to identifypossible markers for pre or sub-clinical cognitiveabnormalities.

2. Methods

2.1. Subjects

A sample of consecutive and unmedicated idiopathicRBD patients, as well as a group of age- and sex-matchedcontrols, was prospective enrolled from the Sleep DisordersCenter of San Raffaele Institute of Milan over one year.RBD diagnosis was established by the recently revisedstandard criteria (American Academy of Sleep Medicine,2005). Sixteen patients (13 males and 3 females, mean age66.37 ± 6.14) and 16 controls (13 males and 3 females,mean age 67.56 ± 5.25) were included. RBD was excludedin the control group by means of history and polysomno-graphic data, while in the patient group the clinical RBDonset preceded of 41.2 ± 30.94 months in mean (range 6–120 months) our evaluation.

Both patients and controls underwent a standard ence-phalic MRI. Subjects with a history of other neurologicaldiseases, psychiatric disorders, head trauma, alcohol orpsychotropic drug use, hearing disturbance, a Mini MentalState Examination (Folstein et al., 1975) score lower than24, a unified Parkinson disease rating scale (Fahn andElton, 1987) score greater than 5, and with brainstem/dien-cephalic/hemispheric lesions on MRI scans were excluded.Other sleep disorders, such as narcolepsy and sleep apnoeasyndrome (clinical history, or polysomnographic assessedapnoea/hypo-apnoea index >5), and a shift work schedulewere also considered as exclusion criteria. Informed con-sent was obtained from all subjects, and the local EthicalCommittee approved the investigation.

2.2. Clinical and neuropsychological assessment

All subjects underwent a structured clinical interviewand a neurological examination, including the UnifiedParkinson’s Disease Rating Scale (UPDRS, Parts I–III)(Fahn et al., 1987). Handedness was measured by theEdinburgh Handedness Inventory (Oldfield, 1971).

The cognitive status was evaluated by means of the MiniMental State Examination – MMSE. In order to evaluateselective attention, all subjects were submitted to the Atten-tional Matrices test (Spinnler and Tognoni, 1987). In thistest, the subjects were required to cancel as many targetdigits as possible from 3 printed sheets containing num-bers, within a time of 45 s per sheet. The score is the num-ber of digits correctly crossed out (0–60).

2.3. Polysomnographic evaluation

At least eight hours of nocturnal video-polysomnogra-phy (PSG) was carried out in all patients and controls afteran adaptation night in a standard sound-attenuated (noiselevel to a maximum of 30 dB nHL) sleep laboratory.Subjects were not allowed caffeinated beverages the after-noon preceding the recordings and were allowed to sleepin until their spontaneous awakening in the morning. The

A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675 671

following parameters were recorded: EEG (at least 6 chan-nels, including CZ, C3 or C4 and O1 or O2, referred to thecontra lateral mastoid); electro-oculogram (electrodesplaced 1 cm above the right outer cantus and 1 cm belowthe left outer cantus and referred to left mastoid), EMGof the submentalis muscle, EMG of the right and left tibi-alis anterior muscles, oral and nasal airflow thermistorsand/or nasal pressure cannula, thoracic and abdominalrespiratory effort strain gauge and oxygen saturation(pulse-oximetry). Sleep signals were sampled at 200 Hzand stored on hard disk. Sleep stages were scored accord-ing to the standard Rechtschaffen and Kales criteria on30-s epochs (1968). Periodic leg movements during sleep(PLMs) were scored according to the international criteria(Coleman, 1982). This included leg movements lasting 0.5–10 s,separated by intervals of 4–90 s and occurring in series of atleast four consecutive movements. PLMS index was calcu-lated as the number of leg movements per hour of sleep.

2.4. Event-related potentials (ERPs)

All recordings were made in a sound-attenuated room,with each subject lying down on a comfortable bedstead.Unipolar recordings referring to linked mastoids weremade between 32 electrodes according to the 10–10 system(Chatrian et al., 1988). Eye movement artefacts were mon-itored by vertical and horizontal electrooculogram. Aground electrode was positioned at FPz. Electrode imped-ances were less than 5 kX. All recordings were performed atten o’clock AM. The two paradigms were administered in arandom sequence.

2.4.1. Active oddball P300 paradigm

The subjects were informed that they would hear low-pitched tones interspersed occasionally with high-pitchedtones, and that they were required to silently count thehigh-pitched tones. They were told that at the end of thetrial they would be asked how many high tones they hadheard. Recordings were considered satisfactory if countingerror was less than 10%. Subjects were instructed to relaxand to keep as still as possible during the test. Standardstimuli were 80%, with a 1000 Hz frequency, a 100 msduration and a rise/fall of 10 ms. Target stimuli were20%, with a 2000 Hz frequency, a 100 ms duration and arise/fall of 10 ms. The stimuli were presented binaurallywith intensity of 75-dB sound pressure level throughintra-aura stimulators. Stimulus presentation was in a ran-dom order with a fixed interstimulus interval of 2 s. Bandpass was settled from 0.5 Hz (6 dB/oct) to 30 Hz (24 dB/oct) and EEG was continuously digitized at a rate of500 Hz/channel. EEG epochs of 1100 ms, beginning100 ms before each stimulus onset, were obtained off-lineby a computer and averaged separately for the standardand target tones. Trials exceeding ±80 lV were automati-cally excluded from the averages, as well as trials contain-ing excessive eye movements, blinks, bursts of muscleactivity, amplifier clipping, or other extra-cerebral arte-

facts. N100 was defined as the most positive peak in thelatency window 90–195 ms after stimulus onset at Fz todeviant and standard stimuli. P200 was defined as the mostpositive peak in the latency window 170–270 ms after stim-ulus onset at Cz to deviant stimuli. N200 was defined as themost negative peak in the latency window 225–410 ms atCz to deviant stimuli. P300 was defined as the most positivepeak in the latency window 300–500 ms at Pz to rarestimuli.

2.4.2. Mismatch (passive oddball) paradigm

The subjects were informed that they would hear asequence of tones and were instructed to ignore the stimu-lation and to concentrate on reading a self-selected book ormagazine. Standard stimuli were 92%, with a 1000 Hz fre-quency, a 50 ms duration and a rise/fall of 5 ms. Deviantstimuli were 8%, with a 1100 Hz frequency, a 50 ms dura-tion and a rise/fall of 5 ms. The stimuli were presented bin-aurally with intensity of 75-dB sound pressure levelthrough intra-aura stimulators. Stimulus presentation wasin a random order with a fixed interstimulus interval of500 ms. Band pass was settled from 0.5 Hz (6 dB/oct) to30 Hz (24 dB/oct) and EEG was continuously digitized ata rate of 500 Hz/channel. EEG epochs of 700 ms, begin-ning 100 ms before each stimulus onset, were obtainedoff-line by a computer and averaged separately for the stan-dard and deviant tones. Difference waveforms (in order todetect the MMN) were obtained by subtracting event-relat-ed potentials elicited by the deviant stimuli from event-re-lated potentials elicited by standard stimuli. Artefactswere excluded following the above-mentioned methods.N100 was defined as the most negative peak in the latencywindow 90–195 ms after stimulus onset at Fz to standardstimuli. MMN was defined as peak negativity at Fz, whereits amplitude is maximal, during the 140–260 ms latencyrange in the passive conditions difference (deviant-stan-dard) waveforms.

2.5. Data analysis

Statistical analyses were performed using SPSS version12.0.1 software (SPSS, Chicago, IL). Independent Samplest-test was used to compare control and patient groups con-cerning age and years of education. Mann–Whitney testwas used to compare the two groups concerning EdinburghHandedness Inventory, MMSE, Attentional Matricesscores. N100 amplitude and latency were examined at Fz,Cz, F4, F3 to standard stimuli for both the active andthe passive conditions. P200 and N200 parameters wereexamined at Cz to deviant stimuli for the active condition.P300 amplitude and latency were calculated at Fz, FCz, Cz,CPz, Pz, F4, C4, P4, T8, F3, C3, P3, T7 to rare stimuli forthe active oddball paradigm. MMN was studied at Fz,FCz, Cz, F4, FC4, F3, FC3. The statistical analysis of theseresults was carried out by using the non-parametric Mann–Whitney test. Spearman’s test was used in the two groupsto assess the association of the attentional matrices scores

Table 1Polysomnographic characteristics in RBD patients and control subjects

Polysomnographic parameters Controls RBD patients p value

Sleep latency (min) 17.18 ± 9.5 26.50 ± 25.6 n.s.Sleep efficiency (%) 70.35 ± 4.0 68.99 ± 18.38 n.s.Stage 1 NREM (%) 7.84 ± 3.2 8.99 ± 4.48 n.s.Stage 2 NREM (%) 57.64 ± 6.1 49.34 ± 9.77 n.s.Stage 3–4 NREM (%) 15.24 ± 4.5 19.43 ± 9.79 n.s.REM sleep (%) 18.20 ± 6.7 22.25 ± 7.13 n.s.REM sleep latency (min) 100.89 ± 39.8 123.53 ± 83.23 n.s.PLMs index (n) 5.44 ± 4.5 33.94 ± 39.48 p = 0.008

Data are means ± SD; NREM, non-REM; PLMs, periodic leg movements during sleep.

672 A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675

with amplitude and latencies of some of the electrophysio-logical components. A p value lower than 0.05 was consid-ered significant.

3. Results

3.1. Clinical and neuropsychological findings

Patients and controls were not different for age(p = 0.561), years of education (mean = 11 ± 4.16 in con-trols vs 9.38 ± 4.79 in patients; p = 0.314.), EdinburghHandedness Inventory (mean = 22.88 ± 1.41 in controlsvs 21.13 ± 5.07 in patients; p = 0.466), Attentive Matrices(mean = 52.14 ± 7.91 in controls vs 50.19 ± 7.99 inpatients; p = 0.392) and MMSE (mean = 28.13 ± 1.45 incontrols vs 28.31 ± 1.66 in patients; p = 0.644) scores.

3.2. Polysomnographic findings

Results of polysomnographic study are summarized inTable 1. Except for the PLMS index, which was greater inthe patient group, no other significant differences wereobserved in sleep parameters between controls and patients.

3.3. Active oddball P300 paradigm findings

As shown in Tables 2 and 3, no significant differencesbetween controls and patients were observed in: N100

Table 2Comparison between latency and amplitude of N100 recorded at Fz and Cz, Prare (and frequent) stimuli in 16 controls and in 16 RBD patients in the activ

Mean latency (ms)

Controls RBD patients p valu

N100Fz 127 ± 17.53 117.13 ± 10.07 n.s.

(123.63 ± 9.72) (116.38 ± 9.27) (n.s.)Cz 127.38 ± 19.32 117.25 ± 10.12 n.s.

(124.12 ± 11.92) (116.50 ± 9.48) (n.s.)

P200Cz 216.63 ± 26.92 223 ± 23.47 n.s.

N200Fz 281.38 ±35.79 249.75 ± 51.21 n.s.Cz 280 ± 37.14 249.63 ± 50.81 n.s.Pz 279.88 ± 36.04 293.38 ± 52.77 n.s.

latency and amplitude to frequent and rare stimuli at Fzand Cz; P200 latency and amplitude to rare stimuli at Cz;N200 latency and amplitude to rare stimuli at Fz, Cz andPz; P300 latency and amplitude to rare stimuli at Fz;FCz, Cz, CPz, Pz, F4, C4, P4, T8, F3, C3 P3, T7 (Fig. 1.).

Inter-peak intervals between N100 and P200 (N1–P2),P200 and N200 (P2–N2), and between N200 and P300(N2–P3) were calculated to rare stimuli at Cz for bothgroups. No significant differences were found betweenpatients and controls in: mean P2–N2 (63.38 ms ± 25.96vs. 71 ms ± 42.47); mean N2–P3 (113.38 ms ± 41.63 vs.106.38 ms ± 38.93). Mean N1–P2 was longer in patients(106.38 ms ± 24.53) compared to controls(89.25 ms ± 22.91), but this difference did not reach a sta-tistical significance (p = 0.054).

A correlation (Spearman’s test) between N1–P2 andN100 and P200 latencies at Cz was calculated in order todefine which of the two components was prevalent in deter-mining the N1–P2 length. There was a significant correla-tion between N1–P2 and P200 latency both for controls(r = 0.713; p = 0.002) and for patients (r = 0.896;p < 0.001).

3.4. Mismatch (passive oddball) paradigm findings

No significant difference between controls and patientswas observed in N100 latency and amplitude to standardstimuli at Fz (127 ms ± 17.62 vs 128.8 ms ± 23.39,

200 recorded at Cz, and N200 recorded at Fz, Cz, Pz leads, evoked by thee oddball paradigm

Mean amplitude (lV)

e Controls RBD patients p value

�9.33 ± 3.82 �9.87 ± 4.05 n.s.(�9.28 ± 3.70) (�9.90 ± 3.41) (n.s.)�8.096 ± 3.55 �7.88 ± 3.95 n.s.(�7.96 ± 3.58) (�8.03 ± 3.79) (n.s.)

4.85 ± 4.05 4.69 ± 1.53 n.s.

1.05 ± 3.09 �0.05 ± 2.89 n.s.0.53 ± 3.61 �0.05 ± 2.55 n.s.0.53 ± 2.71 0.10 ± 2.57 n.s.

Table 3Comparison between P300 latency and amplitude, recorded from 13 scalp locations in 16 controls and in 16 RBD patients, evoked by the rare stimuli inthe oddball paradigm

Mean latency (ms) Mean amplitude (lV)

Controls RBD patients p value Controls RBD patients p value

Fz 392.00 ± 43.94 393.50 ± 46.56 n.s. 7.88 ± 4.86 8.21 ± 4.85 n.s.FCz 395.00 ± 44.82 394.75 ± 44.85 n.s. 7.50 ± 3.77 8.06 ± 4.72 n.s.Cz 393.37 ± 46.47 401.00 ± 46.04 n.s. 8.17 ± 3.85 8.14 ± 4.38 n.s.CPz 398.38 ± 45.49 400.87 ± 46.84 n.s. 8.29 ± 3.18 8.37 ± 4.10 n.s.Pz 398.88 ± 43.51 401.25 ± 46.70 n.s. 8.07 ± 2.97 7.99 ± 4.06 n.s.F4 381.38 ± 49.77 393.00 ± 46.93 n.s. 6.97 ± 4.78 7.41 ± 4.24 n.s.C4 390.81 ± 51.36 396.75 ± 42.63 n.s. 7.77 ± 2.91 7.69 ± 3.74 n.s.P4 404.50 ± 43.31 407.33 ± 33.10 n.s. 6.96 ± 2.31 6.57 ± 2.90 n.s.T8 367.88 ± 51.62 382.63 ± 53.43 n.s. 4.28 ± 2.20 3.50 ± 2.19 n.s.F3 382.75 ± 49.05 398.50 ± 43.67 n.s. 7.61 ± 5.09 7.11 ± 4.12 n.s.C3 386.13 ± 51.79 398.88 ± 40.62 n.s. 7.55 ± 3.11 6.84 ± 3.50 n.s.P3 396.63 ± 52.02 401.00 ± 37.18 n.s. 7.10 ± 3.02 6.18 ± 2.86 n.s.T7 366.25 ± 60.32 386.40 ± 53.38 n.s. 4.67 ± 2.95 3.37 ± 1.70 n.s.

A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675 673

p = n.s. – mean amplitude = �1.45 lV ± 1.65 vs �1.59lV ± 1.58, p = n.s.) (Fig. 1.) and Cz (mean latency128.29 ± 18.56 vs 129.20 ms ± 23.59, p = n.s. – meanamplitude �1.47 lV ± 1.65 vs �1.47 lV ± 1.51, p = n.s.).

Table 4 illustrates MMN latency and amplitude to rarestimuli at Fz, FCz, Cz, F4, FC4, F3, FC3, in controls andin RBD patients. There were not significant between-groupdifferences.

A correlation analysis (Spearman’s test) was performedfor both groups between attentional matrices scores andN100 latencies and amplitudes at Fz and Cz for standardstimuli. A significant correlation was found only in the con-trol group for amplitudes either at Fz (r = �0.593;p = 0.042) or Cz (r = �0.617; p = 0.033).

Fig. 1. Grand averages of the responses obtained from Pz for the active paradparadigm ( deviant minus standard stimuli, deviant stimuli, standa

4. Discussion

There is evidence that idiopathic RBD may progressto a Parkinsonian syndrome with dementia (Schencket al., 1996, 2003; Iranzo et al., 2006). An importantissue is to identify markers for possible pre or sub-clini-cal cognitive and extrapyramidal abnormalities in idio-pathic RBD (Ferini-Strambi et al., 2004; Postumaet al., 2006). Psychophysiology may be useful for thispurpose. Starting from the notion that N100, but notN200 and P300, latency prolongation distinguisheddemented Parkinsonian patients from patients withAlzheimer’s disease (Goodin and Aminoff, 1986, 1987),we assessed an oddball P300 paradigm in idiopathic

igm ( target stimuli, standard stimuli) and from Fz for the passiverd stimuli).

Table 4MMN latency and amplitude, recorded from 9 scalp locations in controls and in RBD patients, in the deviant – standard condition

Mean latency (ms) Mean amplitude (lV)

Controls RBD patients p value Controls RBD patients p value

Fz 193.20 ± 29.56 192.93 ± 25.87 n.s. �2.46 ± 1.15 �2.77 ± 1.21 n.s.FCz 192.53 ± 33.96 192.93 ± 25.58 n.s. �2.52 ± 0.79 �2.61 ± 1.23 n.s.Cz 192.53 ± 34.10 192.40 ± 25.61 n.s. �2.18 ± 0.81 �2.21 ± 0.93 n.s.F4 195.14 ± 32.34 197.20 ± 30.00 n.s. �2.85 ± 0.98 �2.81 ± 1.26 n.s.FC4 195.79 ± 32.89 198.13 ± 31.91 n.s. �2.79 ± 0.89 �2.68 ± 1.11 n.s.F3 191.33 ± 35.86 189.20 ± 21.98 n.s. �2.23 ± 1.92 �2.65 ± 1.22 n.s.FC3 189.60 ± 36.47 194.80 ± 26.14 n.s. �2.35 ± 1.37 �2.31 ± 1.02 n.s.

674 A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675

RBD. The N100, P200, N200, P300 latencies were notdifferent in comparison to normal subjects.

However, a number of studies employing the oddballtask have indicated a probable correlation between thelatency of ERP components and changes in informationprocessing in some neurodegenerative diseases (Syndulkoet al., 1982; Pfefferbaum et al., 1984; Gordon et al.,1986), and, moreover, almost all of these reports have eval-uated the single-peak latency of a single ERP component,without considering the interaction among several suchcomponents, while each inter-peak latency may show apassing speed towards a step within the cognitive process(Sumi et al., 2000). Despite its marginal significance(p = 0.054), an interesting finding was that the two groupsshowed a difference in the inter-peak interval betweenN100 and P200 (N1–P2). In order to define which of thetwo components was prevalent in determining the N1–P2length, correlation between N1–P2 interval and bothN100 and P200 latencies at Cz was assessed in both con-trols and patients. The N1–P2 inter-peak length is positive-ly correlated to the P200 latency, while no correlation wasfound between N1–P2 interval and N100 latency. There-fore, we assumed that the inter-peak prolongation is deter-mined by an increase of P200 latency, rather than an earlyoccurrence of N100 component. Since N1–P2 was longer inRBD patients than in controls, the difference may becaused by a more prolonged latency of P200, despite thelack of between-group difference in P200 latencies. Thefinding may thus reflect a possible impairment of the earlystages of information processing in idiopathic RBD.

To assess the earliest stages at which information pro-cessing could be impaired in RBD patients, we adminis-tered also a mismatch (passive oddball) paradigm. IndeedMMN stands for an automatic, preattentive stage of audi-tory information processing (Naatanen, 1990). There werenot significant between-group differences in MMN ampli-tude and latency. Only in the control group, N100 ampli-tude at Fz and Cz for standard stimuli in the passivecondition correlated to the score in the attentional matricestest. N100 is a measure of the early stages of attention pro-cessing and attentional matrices investigate the capabilityto detect a stimulus. Therefore we can infer that controlsseem to have a better functioning concerning the early stag-es of attention selectivity. An impairment of sensory filter-

ing in DLB has been described in a recent study (Perriolet al., 2005). Moreover, DLB has been reported to differfrom Alzheimer’s disease (AD) because of the greaterimpairment of attention (Hansen et al., 1990; Salmonet al., 1996).

A possible limitation of the study could be the small sizeof the sample that required the use of non-parametric tests.A larger sample would have allowed us to employ paramet-ric tests, with a higher probability to detect between-groupdifferences in ERP parameters.

In conclusion, cognitive evoked potentials are not sensi-tive to pre or sub-clinical cognitive abnormalities in idio-pathic RBD, at least during middle-early stages of diseasecourse. However, ERPs might be sensitive only inadvanced stages of the disease. Only a longer psychophys-iological follow-up will provide an answer to this question.In alternative, these findings might support the existence ofa truly idiopathic RBD syndrome.

Acknowledgements

The Study was supported in part by Fondazione Pierfr-anco e Luisa Mariani – ONLUS – Neurologia Infantile –Milan.

References

American Academy of Sleep Medicine. International Classification ofSleep Disorders. 2nd ed. Westchester, (IL): American Academy ofSleep Medicine; 2005.

Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorderand degenerative dementia: an association likely reflecting Lewy bodydisease. Neurology 1998;51:363–70.

Boeve BF, Silber MH, Ferman TJ, Lucas JA, Parisi JE. Associationof REM sleep behavior disorder and neurodegenerative diseasemay reflect an underlying synucleinopathy. Mov Disord2001;16:622–30.

Chatrian GE, Lettich E, Nelson PL. Modified nomenclature forthe ‘‘10%’’ electrode system. J Clin Neurophysiol1988;5:183–6.

Coleman RM. Periodic movements in sleep (nocturnal myoclonus) andrestless legs syndrome. In: Guilleminaut C, editor. Sleeping andWaking Disorders: Indications and Techniques. Menlo Park: Addi-son Wesley; 1982. p. 265–85.

Comella C, Tanner C, Ristanovic R. Polysomnographic sleep measures inParkinson’s disease patients with treatment-induced hallucinations.Ann Neurol 1993;34:710–4.

A. Raggi et al. / Clinical Neurophysiology 118 (2007) 669–675 675

Comella C, Nardine T, Diederich N, Stebbins G. Sleep-related violence,injury, and REM sleep behavior disorder in Parkinson’s disease.Neurology 1998;51:526–9.

Cox S, Risse G, Hawkins J, Shenck C, Mahowald M. Neuropsychologicaldata in 34 patients with REM sleep behavior disorder (RBD). SleepRes 1990;19:206.

Fantini L, Filipini D, Montplaisir J. Idiopathic REM behavior disorder: alongitudinal study. Mov Disord 2001;16(Suppl. 1):S58–82.

Ferini-Strambi L, Zucconi M. REM sleep behavior disorder. ClinNeurophysiol 2000;111(Supp l):S136–40.

Ferini-Strambi L, Di Gioia MR, Castronovo V, et al. Neuropsycho-logical assessment in idiopathic REM sleep behaviour disorder(RBD). Does the idiopathic form of RBD really exist? Neurology2004;62:41–5.

Ferman T, Boeve B, Smith G, et al. REM sleep behavior disorder anddementia: cognitive differences when compared with AD. Neurology1999;52:951–7.

Fahn S, Elton RL. Members of the UPDRS development committee. In:Fahn S, Marsden CD, Calne DB, Goldstein M , editors. RecentDevelopments in Parkinson’s Disease. Florham Park, NJ: MacmillanHealth Care Information; 1987. p. 153–64.

Folstein MF, Folstein SE, McHugh PR. ‘‘Mini-mental state’’ – a practicalmethod for grading the cognitive state of patients for the clinician. JPsychiatr Res 1975;12:189–98.

Goodin DS, Aminoff MJ. Electrophysiological differences between sub-types of dementia. Brain 1986;109:1103–13.

Goodin DS, Aminoff MJ. Electrophysiological differences betweendemented and nondemented patients with Parkinson’s disease. AnnNeurol 1987;21:90–4.

Gordon E, Krauhin C, Harris A, Meares R, Howson A. The differentialdiagnosis of dementia using P300 latency. Biol Psychiatry1986;21:1123–32.

Hansen LA, Salmon D, Galasko D, et al. The Lewy body variant ofAlzheimer’s disease: a clinical and pathological entity. Neurology1990;40:1–8.

Hendricks JC, Morrison AR, Mann GL. Different behaviors duringparadoxical sleep without atonia depend on pontine lesion site. BrainRes 1982;239:81–105.

Iranzo A, Molinuevo JL, Santamaria J, et al. Rapid-eye-movement sleepbehavior disorder a san early marker for a neurodegenerative disorder:a descriptive study. Lancet Neurol 2006;5:572–7.

Mahowald MW, Schenck CH. REM sleep behavior disorder. In: KrygerMH, Roth T, Dement WC, editors. Principles and Practice of SleepMedicine. Philadelphia: Saunders; 1994. p. 574–88.

Naatanen R. The role of attention in auditory information processing asrevealed by event-related-potentials and other brain measures ofcognitive function. Behav Brain Sci 1990;13:201–88.

Naatanen R. Attention and Brain Function. Lawrence Erlbraum Asso-ciates Publisher; 1992.

Oldfield R. The assessment and analysis of handedness: the Edinburghinventory. Neuropsychologia 1971;1:97–113.

Pekkonen E, Jousmaki V, Reinikainen K, Partanen J. Automatic auditorydiscrimination is impaired in Parkinson’s disease. ElectroencephalogrClin Neurophysiol 1995;95:47–52.

Pekkonen E. Mismatch negativity in aging and in Alzheimer’s andParkinson’s disease. Audiol Neurootol 2000;5:216–24.

Perriol MP, Dujardin K, Derambure P, et al. Disturbance of sensoryfiltering in dementia with Lewy bodies: comparison with Parkinson’sdisease dementia and Alzheimer’s disease. J Neurol NeurosurgPsychiatry 2005;76:106–8.

Perry R, Irving D, Blessed G, Fairbairn A, Perry EK. Senile dementia ofLewy body disease. A clinically and neuropathologically distinct formof Lewy body dementia in the elderly. J Neurol Sci 1990;95:119–39.

Pfefferbaum A, Wenegrat BG, Ford JM, Roth WT, Kopell BS. Clinicalapplication of the P3 component of event-related potentials. Dementia,depression and schizophrenia. Electroencephalogr Clin Neurophysiol1984;59:104–24.

Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders inmultiple system atrophy. Neurology 1997;48:1094–7.

Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J. Potentialearly markers of Parkinson disease in idiopathic REM sleep behaviordisorder. Neurology 2006;66:845–51.

Pritchard WS. Psychophysiology of P300. Psychol Bull 1981;89:506–40.Rechtschaffen A, Kales A. A manual of standardized terminology,

techniques and scoring for sleep stages in human subjects. LosAngeles: Brain Information Service, Brain Research Institute, UCLA,1968.

Salmon DP, Galasko D, Hansen LA, et al. Neuropsychological deficitsassociated with diffuse Lewy body disease. Brain Cogn 1996;31:166–75.

Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronicbehavioural disorders of human REM sleep: a new category ofparasomnia. Sleep 1986;9:293–308.

Schenck C, Bundlie S, Mahowald M. Delayed emergence of a Parkinso-nian disorder in 38% of 29 older men initially diagnosed withidiopathic rapid eye movement sleep behavior disorder. Neurology1996;46:388–93.

Schenck CH, Bundlie SR, Mahowald MW. REM behavior disorder (RBD):delayed emergence of Parkinsonism and/or dementia in 65% of oldermen initially diagnosed with idiopathic RBD, and analysis of theminimum and maximum tonic and/or phasic electromyographic abnor-malities found during REM sleep. Sleep 2003;26(abstract suppl):A316.

Spinnler H, Tognoni G. Standardizzazione e taratura italiana di testneuropsicologici. Ital J Neurol Sci 1987;6(Suppl. 8):27–38.

Sumi N, Nan’no H, Fujimoto O, Ohta Y, Takeda M. Interpeak latency ofauditory event-related potentials (P300) in senile depression and dementiaof the Alzheimer type. Psychiatry Clin Neurosci 2000;54:679–84.

Sutton S, Baren M, Zubin J, John ER. Evoked potential correlates ofstimulus uncertainty. Science 1965;150:1187–8.

Syndulko K, Hansch EC, Cohen SN, et al. Long-latency event-relatedpotentials in normal aging and dementia. In: Courjon J, Maugiere F,Revol M, editors. Clinical Applications of Evoked Potentials inNeurology. New York: Raven Press; 1982. p. 279–85.

Turner R, Chervin R, Frey K, Minoshima S, Kuhl D. Probable diffuseLewy body disease presenting as REM sleep behavior disorder.Neurology 1997;49:523–7.

Zucconi M, Di Gioia MR, Baietto C, et al. REM sleep behavior disorder(RBD): clinical and polysomnographic evaluation of 100 consecutivepatients. Sleep 2003;26:A317.