Parkinsonism and Related Disorders 20 (2014) 297e302
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Sensorimotor gating deficits in multiple system atrophy: Comparison with Parkinson’s disease and idiopathic REM sleep behavior disorder Marielle Zoetmulder a, b, c, *, Heidi Bryde Biernat a, Miki Nikolic d, Lise Korbo a, Poul Jørgen Jennum b, c a
Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, Copenhagen, Denmark Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark d Department of Clinical Neurophysiology, Glostrup Hospital, Copenhagen, Denmark b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 January 2013 Received in revised form 22 October 2013 Accepted 30 November 2013
Background: Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism’s ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently associated with synucleinopathies. We investigated whether alterations in PPI were more pronounced in MSA compared with Parkinson’s disease (PD), idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy controls. Methods: 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy controls completed the study. A passive acoustic prepulse inhibition paradigm was applied with prepulses 5 dB and 15 dB above background noise at 30-, 60-, 120- and 300-ms intervals. Results: Non-parametric analyses showed that MSA patients had significantly lower prepulse inhibition, as measured with max-amplitude, than PD patients and iRBD patients on the 60 mse85 dB and 120 ms e85 dB inter-stimulus intervals. The same relation was found when using area under the curve. No differences were found between groups for the 30 mse85 dB and 300 mse85 dB. Furthermore, blink reflex characteristics such as habituation did not differ between patients and controls. Conclusions: The present study showed that sensorimotor gating, as measured with PPI, is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction, as well as the degeneration of other structures related to the PPI modulating pathways in MSA. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Prepulse inhibition Auditory blink reflex Idiopathic REM sleep behavior disorder Parkinson’s disease Multiple systems atrophy
1. Introduction Prepulse inhibition (PPI) is the attenuation of the startle reflex in response to a sudden stimuli (pulse), when preceded by a weaker sensory stimulus (prepulse). PPI is a well characterized and extensively studied model of sensorimotor gating that can be measured in vertebrates, rodents, nonhuman primates, and humans [1]. PPI is often disrupted in disorders with basal ganglia dysfunction [2]. Mice with a knockout of the dopamine-transporter exhibit PPI deficits [3], as do animals with lesions of the dorsal or ventral striatum [4,5]. The circuits of the startle response and * Corresponding author. Department of Neurology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. Tel.: þ45 35312845, þ45 22672707; fax: þ45 35313957. E-mail addresses: [email protected], marielle_ [email protected] (M. Zoetmulder). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.11.018
prepulse inhibition have been reviewed by Valls-Sole (2012). These circuits include projections from the basal ganglia output structures SNr/GPi to brainstem nuclei, such as the superior colliculus (SC) and pedunculopontine nucleus (PPN), although the exact mechanism is not fully understood [6]. The midbrain dopaminergic system seems to play an essential role in the regulation and modulation of PPI, although other neurotransmitters are known to affect PPI. Inverse correlations have been found between PPI levels and tyrosine hydroxylase immunoreactivity in the striatum of animals deficient of Nurr1 [7], a factor essential for the expression of the midbrain dopaminergic phenotype, and related to the presynaptic components of the striatal dopamine system. Reduced levels and genetic alterations of Nurr1 have been found in Parkinsonism [8,9]. 'Degeneration of the midbrain dopaminergic system is characteristic for the pathophysiological process of PD and MSA, particularly
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the gradual loss of dopamine secreting neurons in the substantia nigra and the dopamine transporters in the striatum [10]. This results in excessive inhibitory GABAergic basal ganglia projections to the thalamus and structures in the brainstem, such as the PPN. This dopaminergic denervation in the striatum can already be seen in patients with idiopathic REM sleep behavior disorder (iRBD), which is considered to be a potential preclinical stage for synucleinopathies like PD and MSA [10]. The neurodegenerative process of MSA is generally more severe than Parkinson’s disease, as MSA present with more a-synuclein accumulation in substantia nigra and dopaminergic dysfunction in striatum, more severe degeneration of the dopamine receptors, and more brainstem pathology [11,12]. We conducted a study, where we investigated PPI of the auditory blink reflex in patients with MSA, PD, iRBD, and healthy controls. As these patientgroups present with varying degrees of dysfunction involving the brainstem and basal ganglia, we hypothesized that 1) PPI may be a marker of disease evolution and severity, and 2) PPI may be more decreased in MSA than in PD. 2. Methods 2.1. Subjects The study included 12 patients with iRBD, 40 patients with PD, 10 patients with MSA (9 MSA patients with the parkinsonian variant, 1 MSA patient with the cerebellar variant), and 20 healthy controls. They were recruited from the Movement Disorder Clinic at Bispebjerg Hospital, the Danish Center for Sleep Medicine at Glostrup Hospital, and from Dansk Parkinsonforening, the patient support group in Denmark. iRBD was diagnosed according to the ICSD-2 criteria, PD according to the UK Parkinson Disease Society Brain Bank criteria, and MSA according to the second consensus statement on the diagnosis of multiple system atrophy [11]. Patients and healthy controls were put through a research battery consisting of PPI, neurological examination, routine blood analysis, polysomnography, and a hearing test. Patients and healthy controls were between 45 years and 75 years old, apart from 2 iRBD patients who were younger than 45. The PD and MSA patients received optimal treatment with Parkinson medications, but did not take acetylcholinesterase inhibitors. Exclusion criteria were: MMSE 40 dB(A) at 1000 Hz) and head trauma. Furthermore, patients were excluded when they had: an apneaehypopnea index (AHI) > 10 per hour of total sleep, an AHI > 10 per hour of REM sleep on polysomnography, a history suggestive of a clinically
relevant sleep disorder, or a history of bruxism. Healthy controls and patients with iRBD did not have current or past use of any central nervous system (CNS) active medication or melatonin. Demographic information and medication status of the groups are presented in Table 1. The patients gave oral and written consent, according to the Declaration of Helsinki. The study was approved by the local ethical committee (reference code: H-A-2007-0120). 2.2. Auditory blink reflex measurement A commercially available human startle response system (EMG SR-HLAB, San Diego Instruments, San Diego, CA, USA) was used to examine the eye blink component of the acoustic startle response. Two miniature silver/silver chloride electrodes were placed over the right orbicularis oculi muscle and a ground electrode behind the right ear over the mastoid. Acoustic stimuli were administered binaurally through Sony MDR-V6 headphones. Subjects sat upright and were instructed to relax, stay awake and look at a fixating point straight ahead. Pulses consisted of 40 ms, 115 dB white noise bursts, and prepulses consisted of 20 ms, 75 dB and 85 dB white noise bursts over 70 dB background noise. Three acoustic blink reflexeliciting stimuli against a background of 70 dB broadband white noise were administered before each session, to evaluate the quality of the signal and adjust the amplifier level. Band-pass filters were set between low (30 Hz) and high (1000 Hz). The recording period began with a 3-min acclimatisation period of 70 dB broadband white noise, which continued throughout the entire session as background noise. The trials began with four blink reflexeliciting stimuli of 115 dB white noise for 40 ms (pulse-alone) followed by six blocks of 11 trials. Each block consisted of three pulsealone stimuli, and eight prepulse-pulse trials. Four prepulse-pulse intervals (onset to onset) were used (30, 60, 120 and 300 ms), both 5 and 15 dB above the 70 dB background noise (see Fig. 1). For each interval there were six trials with the 75 dB prepulse and six trials with the 85 dB prepulse. The mean inter-trial interval was 15 s. The session ended with four pulse-alone trials. None of the subjects had more than three (out of six) trials per trial type discarded in any single session. A scoring program was written in MATLAB, to analyze the EMG-responses visually and manually. This program corrected for differences in amplification. Measures consisted of the percent PPI measured with max amplitude, percentage PPI measured with area under the curve, and habituation (the relative reduction in mean blink reflex magnitude from the first four and the last four pulse-alone trials). Mean scores for these measures were calculated from the six responses of each prepulse/pulse lead interval. Mean blink reflex
Table 1 Baseline characteristics of the patients, mean SD. Demographic and clinical data
iRBD
PD
MSA
Controls
P-value
Gender M/F Age (years) Age at disease onset (years) UPDRS H&Y MMSE ACE LED-levodopa (mg) LED-dopamine agonists (mg) LED-levodopa þ dopamine agonists (mg) Total LED-levodopa þ dopamine agonist þ other (mg) Patients using antidepressants
9/3 56.25 12.97 55.75 13.18 0.8 1.31 0 28.45 1.69 89.18 7.38 e e e e 1.00
20/20 62.72 6.58 57.46 7.56 22.63 8.65 1.96 0.78 28.64 1.63 91.43 4.82 351.26 383.41 138.86 112.22 490.13 418.85 546.89 432.22 8.00
3/7 63.40 6.73 61.40 6.18 48.42 11.14 4.05 0.96 27.80 1.61 86.87 5.86 732.5 249.35 126.30 95.13 793.50 281.90 889.48 239.64 1.00
10/10 56.40 9.99 NS 0.76 1.16 0 29.35 0.786 95.43 2.33 e e e e 0.00
NS * NS **,***,y,yy,yyy **,***,y,yy,yyy NS *,y,z,x x NS NS x
IRBD: Idiopathic rapid eye movement sleep behavior disorder; PD: Parkinson’s disease; MSA: multiple system atrophy; UPDRS: Unified Parkinson’s disease rating scale; H&Y: Hoehn & Yahr score; MMSE: Mini mental state examination; ACE: Addenbrooke’s cognitive examination; LED: levodopa equivalent dose. *PD vs. controls, P 0.05; **PD vs. controls, P 0.0005; ***PD vs. iRBD, P 0.0005; yMSA vs. controls, P 0.0005; yyMSA vs. PD, P 0.0005; yyyMSA vs. iRBD, P 0.0005; ziRBD vs. controls, P 0.05; xMSA vs. PD, P 0.05.
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3. Results 3.1. Demographic characteristics
Fig. 1. This figure explains the relation of the magnitude between the pulse-alone trial and the prepulseepulse trial. The inter-stimulus-interval between the prepulse and pulse is defined by X in the figure and varies between 30, 60, 120, and 300 ms from onset prepulse to onset pulse. The acoustic blink reflex represents the muscular contraction of the orbicularis oculi muscle.
magnitude was calculated by averaging responses for the initial four pulse-alone trials. PPI (%) was calculated by the formula: 100 (mean magnitude on prepulse trials/mean magnitude on pulse-alone trials) 100. Trials with excessive baseline activity 100 ms before the expected response were excluded to minimize confounding of possible spontaneous and voluntary eye blink activity upon the blink reflex. Blink reflex habituation was assessed by comparing averaged results of the first four blink reflexes (blink reflex magnitude) in the beginning of the session, with the four blink reflexes at the end of the session. Patients were excluded from the analysis if their blink reflex magnitude was zero in at least 50% of the first four pulse-alone trials or if more than three of the six prepulseepulse trials were discarded. 2.3. Polysomnography All subjects had one night of PSG recording in accordance with American Academy of Sleep Medicine 2007 criteria. Recordings included at least 6 electroencephalography leads (F3-A2, F4-A1, C3A2, C4-A1, O1-A2, O2-A1), surface electromyography of the submental muscle, and the left and right anterior tibialis muscle, electrocardiography, electrooculography (EOG), nasal and oral air flow, thoracic and abdominal respiratory effort, oxygen saturation, and microphone and digitally synchronized videography. Impedances were kept below 10 kU. Sleep stages were analyzed and scored according to American Academy of Sleep Medicine (AASM) criteria with allowance to score REM sleep despite excessive EMG activity in the mentalis muscle channel. RBD was diagnosed according to ICSD-2 criteria. A clinical interview was performed to assess the presence of RBD symptoms, and patients filled in the Stiasny-Kolster RBD scale questionnaire. 2.4. Statistical analysis KruskaleWallis non-parametric analysis of variance was performed to detect any group effects on demographic variables, the percentage PPI (%PPI) and UPDRS-scores, followed up by post hoc analyses (ManneWhitney test) when appropriate. Furthermore, the Wilcoxon-test was performed to analyze habituation-effects within groups. Correlation analysis was performed with Kendall’s tau. Statistical analyses were done using SPSS version 17 (SPSS Inc., Chicago, IL, USA). A 5% significance level was adopted.
Demographic and clinical data for the four groups are presented in Table 1. Group comparisons with one-way ANOVA showed that PD patients were significantly older than healthy controls (U ¼ 248.00, Z ¼ 2.39, P ¼ 0.017). Furthermore, UPDRS scores were significantly different between groups, as expected (P < 0.001). Post-hoc analysis showed that MSA patients had significantly higher UPDRS scores than PD patients (U ¼ 15, Z ¼ 3.54, P < 0.001), iRBD (U ¼ 0, Z ¼ 3.50, P < 0.001) and healthy controls (U ¼ 0, Z ¼ 3.70, P < 0.001). PD patients had significantly higher UPDRS scores than iRBD patients (U ¼ 0, Z ¼ 4.74, P < 0.001) and healthy controls (U ¼ 0, Z ¼ 5.23, P < 0.001). No differences were found between iRBD patients and healthy controls on the UPDRS (P > 0.05). Furthermore, MSA patients scored significantly lower on Addenbrooke’s cognitive examination (ACE) than PD patients (U ¼ 93, Z ¼ 2.06, P ¼ 0.040), and healthy controls (U ¼ 8.50, Z ¼ 3.63, P < 0.001), but not compared with patients with iRBD (U ¼ 39, Z ¼ 0.80, P ¼ 0.424). None of the patients received acetylcholinesterase inhibitor. Exclusion of the patients taking antidepressants did not affect the PPI results, and therefore they were included in the study. 3.2. PPI differences between groups KruskaleWallis non-parametric analysis of variance revealed no significant group differences regarding mean blink reflex amplitude, the blink reflex habituation, and PPI on the four PPI prepulse/ pulse intervals in the 75 dB background condition (P > 0.05). Therefore the following results represent data associated with the 85 dB background condition. We found significant group effects on PPI at the 60 ms and 120 ms prepulse/pulse interval (P ¼ 0.004 and P ¼ 0.018, respectively), while no significant group effects were found on the 30 ms and 300 ms intervals. A post-hoc analysis performed with the ManneWhitney U test showed that MSA had significantly lower PPI at the 60 ms prepulse/pulse interval than PD (U ¼ 70, Z ¼ 2.77, P ¼ 0.006), iRBD (U ¼ 9, Z ¼ 2.93, P ¼ 0.003) and healthy controls (U ¼ 24, Z ¼ 3.03, P ¼ 0.002), and a significantly lower PPI at the 120 ms prepulse/pulse interval than PD (U ¼ 41, Z ¼ 2.54, P ¼ 0.011), iRBD (U ¼ 7, Z ¼ 2.19, P ¼ 0.028) and healthy controls (U ¼ 19, Z ¼ 2.14, P ¼ 0.033), see Fig. 2. In addition, MSA showed a significantly higher area under the curve at the 60 ms prepulse/ pulse interval than PD (U ¼ 85, Z ¼ 2.80, P ¼ 0.005), iRBD (U ¼ 13, Z ¼ 3.10, P ¼ 0.002) and healthy controls (U ¼ 28, Z ¼ 3.20, P ¼ 0.002), and a significantly higher area under the curve at the 120 ms prepulse/pulse interval than PD (U ¼ 43, Z ¼ 3.82, P ¼ 0.000), iRBD (U ¼ 23, Z ¼ 2.44, P ¼ 0.015) and healthy controls (U ¼ 37, Z ¼ 2.77, P ¼ 0.006). No group effects were found at the 30 ms and 300 ms prepulse/pulse intervals. When plotting the mean PPI for each group as a function of the four prepulse/pulse intervals, PD patients, iRBD patients and healthy controls all showed the usually seen U-shaped pattern of highest inhibition at the 120 ms interval, with lesser inhibition at both shorter and longer intervals. However, patients with MSA showed a reversed pattern with least inhibition at 60 ms interval and highest at 300 ms, data shown in Fig. 3. 3.3. Dopaminergic medication and PPI As dopamine function may alter the level of PPI, we analyzed if dopaminergic medication exerted an influence on the 60 ms and 120 ms prepulse/pulse interval in PD and MSA. In the PD group we
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Fig. 2. The graphs show prepulse inhibition of the auditory blink reflex in a healthy subject (A) and a patient with MSA (B). P ¼ pulse, referring to the acoustic blink reflex stimulus; PP ¼ prepulse. The inter-stimuli intervals are 60 ms (2) or 120 ms (3).
habituation reached significance in MSA (Z ¼ 2.80, P ¼ 0.005), PD (Z ¼ 5.51, P ¼ 0.000), iRBD (Z ¼ 3.06, P ¼ 0.002), and healthy controls (Z ¼ 3.92, P ¼ 0.000). Mean area under the curve following the last 4 blink reflex stimuli was reduced compared with the first 4 blink reflex stimuli in MSA (Z ¼ 2.805.51, P ¼ 0.005), PD (Z ¼ 5.51, P < 0.0005), iRBD (Z ¼ 3.06, P ¼ 0.002) and healthy controls (Z ¼ 3.92, P < 0.0005). A between-group analysis of area under the curve did not show any significant group differences.
4. Discussion
Fig. 3. Mean percentage PPI of the patient groups as a function of the prepulse/pulse interval (ms). HC: healthy controls; iRBD: idiopathic rapid eye movement sleep behavior disorder; PD: Parkinson’s disease; MSA: multiple system atrophy; PPI: prepulse inhibition.
found significant positive correlations between PPI at the 120 ms prepulse/pulse interval and levodopa (R ¼ 0.184, P ¼ 0.125), dopamine agonist (R ¼ 0.307, P ¼ 0.009), levodopa þ dopamine agonist (R ¼ 0.286, P ¼ 0.013), and total LED (R ¼ 0.223, P ¼ 0.056), while the correlation for the PPI at the 60 ms prepulse/pulse interval was non-significant. In addition, we found significant inverse correlations between UPDRS motor score and PPI at the 60 ms prepulse/pulse interval (R ¼ 0.264, P ¼ 0.042) and the 120 ms prepulse/pulse interval (R ¼ 0.273, P ¼ 0.035), indicating a possible relation between PPI and motor function in PD. In the MSA group the correlations between the 60 ms and 120 ms prepulse/ pulse interval and dopaminergic medication were all nonsignificant.
3.4. Habituation of the acoustic blink reflex Comparing the mean max amplitude of the first four blink reflexes of the PPI-session with the last four blink reflexes,
The present study demonstrated that MSA patients have significant PPI deficits of the acoustic blink reflex. These patients showed particular reduced PPI for 60 ms, and 120 ms interstimulus-intervals compared with PD patients, iRBD patients and healthy controls. This suggests that the prepulse circuit in MSA is not sufficiently activated to enable premotoneuronal inhibition of incoming excitatory inputs, resulting in motoneuronal facilitation. The marked decrease of PPI in MSA is in agreement with a study from Perriol et al., who found PPI deficits in dementia with Lewy bodies (DLB), another atypical parkinsonian disorder belonging to the group of a-synucleinopathies and associated with marked pathology in striatum and brainstem [13]. These authors also reported PPI deficits in PD with dementia, although to a lesser degree. The significant difference in PPI between MSA and PD might be explained by the neuropathological characteristics of the disorders. In MSA, degeneration of the brainstem nuclei, nigrostriatal pathway, and cerebellum is frequent and often severe [11]. The parkinsonian variant of MSA (MSA-P) differs significantly from PD in terms of decreased a-synuclein accumulation in substantia nigra, putaminal volume, glucose metabolism, and postsynaptic D2 receptor density [12], the latter being normal or even upregulated in the early stages of PD. Histological and autoradiographical studies have shown that levodopa-resistance, which is a key feature of MSA, is associated with neuronal loss, gliosis, and loss of postsynaptic D2-dopamine receptors [14]. Pharmacological treatment with dopamine downstream of the striatum will therefore not be
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effective in alleviating Parkinsonism. The same might apply to PPI in this disorder. Lesions of the PPN attenuate PPI of the startle reflex [15,16] and may potentiate the startle response [16], although the latter has not been found in all studies [15,17]. This could partly explain the PPI deficits seen in MSA patients, as neuropathological studies in these patients have shown brainstem atrophy with marked loss of the PPN [18] and a high density of oligodendroglial cytoplasmic inclusions (GCI) within the pontine reticular formation [11]. In PD, there is a predominantly presynaptic dysfunction with decreases in striatal dopamine synthesis, storage, release and transporter binding. Dopaminergic treatment is known to alleviate the motor-symptoms of PD [19], and seems to reduce reflex abnormalities in these patients [20]. Dopaminergic treatment reduces the excessive GABAergic projections from the basal ganglia output structures SNr/GPi, which include the SC and PPN in the brainstem. As the SC and PPN are involved in PPI, optimizing neural transmission in these pathways would result in increased PPI in PD. The PD patients in the present study were optimally treated. According to Basso et al. (1996), dysfunction of the basal ganglia may disrupt the blink reflex by a circuit involving the superior colliculus (SC) and raphe magnus (RM). According to these authors excessive GABAergic output from the basal ganglia over-inhibits the SC, as is the case in Parkinson’s disease. In turn, the SC does not excite tonically active RM neurons sufficiently to inhibit spinal trigeminal neurons, which would result in increased blink reflexes [21]. This is the case when supraorbital stimuli are applied. However, previous studies have also found that lesions of the SC may disrupt auditory PPI, without altering the auditory startle response [22]. In addition, animals with unilateral lesions of the substantia nigra pars compacta present with normal excitable acoustic reflex blinks [23]. This could suggest that excessive GABAergic basal ganglia output, via a circuit involving the SC, may be associated with deficient auditory prepulse inhibition in the presence of normal acoustic blink reflexes. The MSA patients in the present study had normal acoustic blink reflexes as compared to healthy controls. This in line with a previous study conducted by Valldeoriola et al. (1997), who found normal acoustic blink reflexes and, like us, investigated their patients in the sitting position [24]. However, Kofler et al. (2003) investigated the acoustic startle response in MSA patients while in the supine position, and found increased auditory blink reflexes compared to healthy controls. In addition, these authors found exaggerated startle responses in muscles, which are associated with postural control. Therefore, posture might play a role in reflex excitability [25]. It is not known whether the level of PPI depends on posture as well. The finding of PPI deficits in the presence of an unaltered auditory blink reflex, is not in line with the hypothesis that PPI depends on the blink reflex excitability, as suggested by Schicatano et al. (2000). These authors found, in 6-OHDA-lesioned rats with hyperexcitable trigeminal blink reflexes, that an acoustic prepulse facilitated the trigeminal blink reflex, while this same prepulse inhibited a normal acoustic blink reflex. In their study, the prepulse modification correlated with trigeminal reflex blink excitability [23]. Similar results were found in a study by Valls-Sole et al. (2004) where 14 of 20 PD patients presented with hyperexcitable trigeminal blink reflexes. These authors found a significant inverse correlation between trigeminal blink reflex excitability and PPI [26]. However, PPI and the paired-pulse test (assessing blink reflex excitability), are not correlated in every disorder [26,27], and therefore probably measure two independent systems. In addition, lesions to the PPN abolish PPI without consistently affecting the startle response itself, whereas lesions to the dorsolateral pontine tegmentum or the medial medulla disinhibit the
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startle response without affecting PPI [28]. This may indicate that prepulse inhibition does not depend on the startle response excitability in every instance, as has been suggested previously by Schicatano et al. (2000). Although not investigated in this study, future studies could include both measurements with PPI and the paired pulse test. The temporal range around 60 ms for detecting PPI deficits has been shown to be most sensitive in other neuropsychiatric disorders, with similar prepulseepulse characteristics [1]. In addition, striatal cells seem to respond to auditory information and display inhibitory gating, with a gating peak at 60 ms post-stimulation by sensory input [29]. Habituation of the blink reflex did not differ between groups measured with max amplitude and area under the curve, which is in accordance with previous studies showing a similar habituation pattern in PD, Lewy body dementia and healthy controls [30]. A study by Kofler et al. (2003) found decreased acoustic startle probability in 14% of MSA-P patients compared to 34% in healthy controls when all muscles investigated were combined, and significant habituation in MSA-P was seen only in extremity muscles. These results may point to a reduced habituation of the acoustic startle response in MSA patients. However, the assessment of the acoustic startle response may be influenced by posture [25]. As our patients were investigated in the sitting position, whereas the patients in the study by Kofler et al. (2003) were assessed in the supine position, we cannot compare results. To our knowledge, this is the first study to report decreased PPI in MSA patients compared with PD. The marked difference in PPI between MSA and PD is of interest, because clinical separation of these disorders has often proven to be difficult in the early disease stages, despite their distinct histological appearances and pathological entities. An accurate diagnosis is important because prognosis, and response to therapy vary according to the underlying pathology. A non-invasive neurophysiological measure such as PPI may add additional information in the differential diagnosis between PD and the atypical parkinsonian disorder MSA while patients receive optimal treatment.
Acknowledgment This study was funded by the Lundbeck Foundation, the National Foundation for Parkinson’s Disease, and the Toyota Foundation.
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[19] Huot P, Parent A. Dopaminergic neurons intrinsic to the striatum. J Neurochem 2007;101:1441e7. [20] Klawans Jr HL, Goodwin JA. Reversal of the glabellar reflex in parkinsonism by L-dopa. J Neurol Neurosurg Psychiatry 1969;32:423e7. [21] Basso MA, Evinger C. An explanation for reflex blink hyperexcitability in Parkinson’s disease. II. Nucleus raphe magnus. J Neurosci 1996;16:7318e30. [22] Fendt M, Koch M, Schnitzler HU. Sensorimotor gating deficit after lesions of the superior colliculus. Neuroreport 1994;5:1725e8. [23] Schicatano EJ, Peshori KR, Gopalaswamy R, Sahay E, Evinger C. Reflex excitability regulates prepulse inhibition. J Neurosci 2000;20:4240e7. [24] Valldeoriola F, Valls-Sole J, Tolosa E, Nobbe FA, Munoz JE, Marti J. The acoustic startle response is normal in patients with multiple system atrophy. Mov Disord 1997;12:697e700. [25] Kofler M, Muller J, Seppi K, Wenning GK. Exaggerated auditory startle responses in multiple system atrophy: a comparative study of Parkinson and cerebellar subtypes. Clin Neurophysiol 2003;114:541e7. [26] Valls-Sole J, Munoz JE, Valldeoriola F. Abnormalities of prepulse inhibition do not depend on blink reflex excitability: a study in Parkinson’s disease and Huntington’s disease. Clin Neurophysiol 2004;115:1527e36. [27] Frauscher B, Loscher WN, Ehrmann L, Gschliesser V, Brandauer E, Hogl B, et al. Narcolepsy-cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement. J Sleep Res 2012;21:495e501. [28] Wu MF, Siegel JM, Shouse MN, Schenkel E. Lesions producing REM sleep without atonia disinhibit the acoustic startle reflex without affecting prepulse inhibition. Brain Res 1990;528:330e4. [29] Cromwell HC, Klein A, Mears RP. Single unit and population responses during inhibitory gating of striatal activity in freely moving rats. Neuroscience 2007;146:69e85. [30] Kofler M, Muller J, Wenning GK, Reggiani L, Hollosi P, Bosch S, et al. The auditory startle reaction in parkinsonian disorders. Mov Disord 2001;16: 62e71.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Sensorimotor gating deficits in multiple system atrophy: Comparison with Parkinson’s disease and idiopathic REM sleep behavior disorder Marielle Zoetmulder a, b, c, *, Heidi Bryde Biernat a, Miki Nikolic d, Lise Korbo a, Poul Jørgen Jennum b, c a
Department of Neurology, Bispebjerg Hospital, Copenhagen, Denmark Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, Copenhagen, Denmark Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark d Department of Clinical Neurophysiology, Glostrup Hospital, Copenhagen, Denmark b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 January 2013 Received in revised form 22 October 2013 Accepted 30 November 2013
Background: Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism’s ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently associated with synucleinopathies. We investigated whether alterations in PPI were more pronounced in MSA compared with Parkinson’s disease (PD), idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy controls. Methods: 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy controls completed the study. A passive acoustic prepulse inhibition paradigm was applied with prepulses 5 dB and 15 dB above background noise at 30-, 60-, 120- and 300-ms intervals. Results: Non-parametric analyses showed that MSA patients had significantly lower prepulse inhibition, as measured with max-amplitude, than PD patients and iRBD patients on the 60 mse85 dB and 120 ms e85 dB inter-stimulus intervals. The same relation was found when using area under the curve. No differences were found between groups for the 30 mse85 dB and 300 mse85 dB. Furthermore, blink reflex characteristics such as habituation did not differ between patients and controls. Conclusions: The present study showed that sensorimotor gating, as measured with PPI, is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction, as well as the degeneration of other structures related to the PPI modulating pathways in MSA. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Prepulse inhibition Auditory blink reflex Idiopathic REM sleep behavior disorder Parkinson’s disease Multiple systems atrophy
1. Introduction Prepulse inhibition (PPI) is the attenuation of the startle reflex in response to a sudden stimuli (pulse), when preceded by a weaker sensory stimulus (prepulse). PPI is a well characterized and extensively studied model of sensorimotor gating that can be measured in vertebrates, rodents, nonhuman primates, and humans [1]. PPI is often disrupted in disorders with basal ganglia dysfunction [2]. Mice with a knockout of the dopamine-transporter exhibit PPI deficits [3], as do animals with lesions of the dorsal or ventral striatum [4,5]. The circuits of the startle response and * Corresponding author. Department of Neurology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. Tel.: þ45 35312845, þ45 22672707; fax: þ45 35313957. E-mail addresses: [email protected], marielle_ [email protected] (M. Zoetmulder). 1353-8020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.parkreldis.2013.11.018
prepulse inhibition have been reviewed by Valls-Sole (2012). These circuits include projections from the basal ganglia output structures SNr/GPi to brainstem nuclei, such as the superior colliculus (SC) and pedunculopontine nucleus (PPN), although the exact mechanism is not fully understood [6]. The midbrain dopaminergic system seems to play an essential role in the regulation and modulation of PPI, although other neurotransmitters are known to affect PPI. Inverse correlations have been found between PPI levels and tyrosine hydroxylase immunoreactivity in the striatum of animals deficient of Nurr1 [7], a factor essential for the expression of the midbrain dopaminergic phenotype, and related to the presynaptic components of the striatal dopamine system. Reduced levels and genetic alterations of Nurr1 have been found in Parkinsonism [8,9]. 'Degeneration of the midbrain dopaminergic system is characteristic for the pathophysiological process of PD and MSA, particularly
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the gradual loss of dopamine secreting neurons in the substantia nigra and the dopamine transporters in the striatum [10]. This results in excessive inhibitory GABAergic basal ganglia projections to the thalamus and structures in the brainstem, such as the PPN. This dopaminergic denervation in the striatum can already be seen in patients with idiopathic REM sleep behavior disorder (iRBD), which is considered to be a potential preclinical stage for synucleinopathies like PD and MSA [10]. The neurodegenerative process of MSA is generally more severe than Parkinson’s disease, as MSA present with more a-synuclein accumulation in substantia nigra and dopaminergic dysfunction in striatum, more severe degeneration of the dopamine receptors, and more brainstem pathology [11,12]. We conducted a study, where we investigated PPI of the auditory blink reflex in patients with MSA, PD, iRBD, and healthy controls. As these patientgroups present with varying degrees of dysfunction involving the brainstem and basal ganglia, we hypothesized that 1) PPI may be a marker of disease evolution and severity, and 2) PPI may be more decreased in MSA than in PD. 2. Methods 2.1. Subjects The study included 12 patients with iRBD, 40 patients with PD, 10 patients with MSA (9 MSA patients with the parkinsonian variant, 1 MSA patient with the cerebellar variant), and 20 healthy controls. They were recruited from the Movement Disorder Clinic at Bispebjerg Hospital, the Danish Center for Sleep Medicine at Glostrup Hospital, and from Dansk Parkinsonforening, the patient support group in Denmark. iRBD was diagnosed according to the ICSD-2 criteria, PD according to the UK Parkinson Disease Society Brain Bank criteria, and MSA according to the second consensus statement on the diagnosis of multiple system atrophy [11]. Patients and healthy controls were put through a research battery consisting of PPI, neurological examination, routine blood analysis, polysomnography, and a hearing test. Patients and healthy controls were between 45 years and 75 years old, apart from 2 iRBD patients who were younger than 45. The PD and MSA patients received optimal treatment with Parkinson medications, but did not take acetylcholinesterase inhibitors. Exclusion criteria were: MMSE 40 dB(A) at 1000 Hz) and head trauma. Furthermore, patients were excluded when they had: an apneaehypopnea index (AHI) > 10 per hour of total sleep, an AHI > 10 per hour of REM sleep on polysomnography, a history suggestive of a clinically
relevant sleep disorder, or a history of bruxism. Healthy controls and patients with iRBD did not have current or past use of any central nervous system (CNS) active medication or melatonin. Demographic information and medication status of the groups are presented in Table 1. The patients gave oral and written consent, according to the Declaration of Helsinki. The study was approved by the local ethical committee (reference code: H-A-2007-0120). 2.2. Auditory blink reflex measurement A commercially available human startle response system (EMG SR-HLAB, San Diego Instruments, San Diego, CA, USA) was used to examine the eye blink component of the acoustic startle response. Two miniature silver/silver chloride electrodes were placed over the right orbicularis oculi muscle and a ground electrode behind the right ear over the mastoid. Acoustic stimuli were administered binaurally through Sony MDR-V6 headphones. Subjects sat upright and were instructed to relax, stay awake and look at a fixating point straight ahead. Pulses consisted of 40 ms, 115 dB white noise bursts, and prepulses consisted of 20 ms, 75 dB and 85 dB white noise bursts over 70 dB background noise. Three acoustic blink reflexeliciting stimuli against a background of 70 dB broadband white noise were administered before each session, to evaluate the quality of the signal and adjust the amplifier level. Band-pass filters were set between low (30 Hz) and high (1000 Hz). The recording period began with a 3-min acclimatisation period of 70 dB broadband white noise, which continued throughout the entire session as background noise. The trials began with four blink reflexeliciting stimuli of 115 dB white noise for 40 ms (pulse-alone) followed by six blocks of 11 trials. Each block consisted of three pulsealone stimuli, and eight prepulse-pulse trials. Four prepulse-pulse intervals (onset to onset) were used (30, 60, 120 and 300 ms), both 5 and 15 dB above the 70 dB background noise (see Fig. 1). For each interval there were six trials with the 75 dB prepulse and six trials with the 85 dB prepulse. The mean inter-trial interval was 15 s. The session ended with four pulse-alone trials. None of the subjects had more than three (out of six) trials per trial type discarded in any single session. A scoring program was written in MATLAB, to analyze the EMG-responses visually and manually. This program corrected for differences in amplification. Measures consisted of the percent PPI measured with max amplitude, percentage PPI measured with area under the curve, and habituation (the relative reduction in mean blink reflex magnitude from the first four and the last four pulse-alone trials). Mean scores for these measures were calculated from the six responses of each prepulse/pulse lead interval. Mean blink reflex
Table 1 Baseline characteristics of the patients, mean SD. Demographic and clinical data
iRBD
PD
MSA
Controls
P-value
Gender M/F Age (years) Age at disease onset (years) UPDRS H&Y MMSE ACE LED-levodopa (mg) LED-dopamine agonists (mg) LED-levodopa þ dopamine agonists (mg) Total LED-levodopa þ dopamine agonist þ other (mg) Patients using antidepressants
9/3 56.25 12.97 55.75 13.18 0.8 1.31 0 28.45 1.69 89.18 7.38 e e e e 1.00
20/20 62.72 6.58 57.46 7.56 22.63 8.65 1.96 0.78 28.64 1.63 91.43 4.82 351.26 383.41 138.86 112.22 490.13 418.85 546.89 432.22 8.00
3/7 63.40 6.73 61.40 6.18 48.42 11.14 4.05 0.96 27.80 1.61 86.87 5.86 732.5 249.35 126.30 95.13 793.50 281.90 889.48 239.64 1.00
10/10 56.40 9.99 NS 0.76 1.16 0 29.35 0.786 95.43 2.33 e e e e 0.00
NS * NS **,***,y,yy,yyy **,***,y,yy,yyy NS *,y,z,x x NS NS x
IRBD: Idiopathic rapid eye movement sleep behavior disorder; PD: Parkinson’s disease; MSA: multiple system atrophy; UPDRS: Unified Parkinson’s disease rating scale; H&Y: Hoehn & Yahr score; MMSE: Mini mental state examination; ACE: Addenbrooke’s cognitive examination; LED: levodopa equivalent dose. *PD vs. controls, P 0.05; **PD vs. controls, P 0.0005; ***PD vs. iRBD, P 0.0005; yMSA vs. controls, P 0.0005; yyMSA vs. PD, P 0.0005; yyyMSA vs. iRBD, P 0.0005; ziRBD vs. controls, P 0.05; xMSA vs. PD, P 0.05.
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3. Results 3.1. Demographic characteristics
Fig. 1. This figure explains the relation of the magnitude between the pulse-alone trial and the prepulseepulse trial. The inter-stimulus-interval between the prepulse and pulse is defined by X in the figure and varies between 30, 60, 120, and 300 ms from onset prepulse to onset pulse. The acoustic blink reflex represents the muscular contraction of the orbicularis oculi muscle.
magnitude was calculated by averaging responses for the initial four pulse-alone trials. PPI (%) was calculated by the formula: 100 (mean magnitude on prepulse trials/mean magnitude on pulse-alone trials) 100. Trials with excessive baseline activity 100 ms before the expected response were excluded to minimize confounding of possible spontaneous and voluntary eye blink activity upon the blink reflex. Blink reflex habituation was assessed by comparing averaged results of the first four blink reflexes (blink reflex magnitude) in the beginning of the session, with the four blink reflexes at the end of the session. Patients were excluded from the analysis if their blink reflex magnitude was zero in at least 50% of the first four pulse-alone trials or if more than three of the six prepulseepulse trials were discarded. 2.3. Polysomnography All subjects had one night of PSG recording in accordance with American Academy of Sleep Medicine 2007 criteria. Recordings included at least 6 electroencephalography leads (F3-A2, F4-A1, C3A2, C4-A1, O1-A2, O2-A1), surface electromyography of the submental muscle, and the left and right anterior tibialis muscle, electrocardiography, electrooculography (EOG), nasal and oral air flow, thoracic and abdominal respiratory effort, oxygen saturation, and microphone and digitally synchronized videography. Impedances were kept below 10 kU. Sleep stages were analyzed and scored according to American Academy of Sleep Medicine (AASM) criteria with allowance to score REM sleep despite excessive EMG activity in the mentalis muscle channel. RBD was diagnosed according to ICSD-2 criteria. A clinical interview was performed to assess the presence of RBD symptoms, and patients filled in the Stiasny-Kolster RBD scale questionnaire. 2.4. Statistical analysis KruskaleWallis non-parametric analysis of variance was performed to detect any group effects on demographic variables, the percentage PPI (%PPI) and UPDRS-scores, followed up by post hoc analyses (ManneWhitney test) when appropriate. Furthermore, the Wilcoxon-test was performed to analyze habituation-effects within groups. Correlation analysis was performed with Kendall’s tau. Statistical analyses were done using SPSS version 17 (SPSS Inc., Chicago, IL, USA). A 5% significance level was adopted.
Demographic and clinical data for the four groups are presented in Table 1. Group comparisons with one-way ANOVA showed that PD patients were significantly older than healthy controls (U ¼ 248.00, Z ¼ 2.39, P ¼ 0.017). Furthermore, UPDRS scores were significantly different between groups, as expected (P < 0.001). Post-hoc analysis showed that MSA patients had significantly higher UPDRS scores than PD patients (U ¼ 15, Z ¼ 3.54, P < 0.001), iRBD (U ¼ 0, Z ¼ 3.50, P < 0.001) and healthy controls (U ¼ 0, Z ¼ 3.70, P < 0.001). PD patients had significantly higher UPDRS scores than iRBD patients (U ¼ 0, Z ¼ 4.74, P < 0.001) and healthy controls (U ¼ 0, Z ¼ 5.23, P < 0.001). No differences were found between iRBD patients and healthy controls on the UPDRS (P > 0.05). Furthermore, MSA patients scored significantly lower on Addenbrooke’s cognitive examination (ACE) than PD patients (U ¼ 93, Z ¼ 2.06, P ¼ 0.040), and healthy controls (U ¼ 8.50, Z ¼ 3.63, P < 0.001), but not compared with patients with iRBD (U ¼ 39, Z ¼ 0.80, P ¼ 0.424). None of the patients received acetylcholinesterase inhibitor. Exclusion of the patients taking antidepressants did not affect the PPI results, and therefore they were included in the study. 3.2. PPI differences between groups KruskaleWallis non-parametric analysis of variance revealed no significant group differences regarding mean blink reflex amplitude, the blink reflex habituation, and PPI on the four PPI prepulse/ pulse intervals in the 75 dB background condition (P > 0.05). Therefore the following results represent data associated with the 85 dB background condition. We found significant group effects on PPI at the 60 ms and 120 ms prepulse/pulse interval (P ¼ 0.004 and P ¼ 0.018, respectively), while no significant group effects were found on the 30 ms and 300 ms intervals. A post-hoc analysis performed with the ManneWhitney U test showed that MSA had significantly lower PPI at the 60 ms prepulse/pulse interval than PD (U ¼ 70, Z ¼ 2.77, P ¼ 0.006), iRBD (U ¼ 9, Z ¼ 2.93, P ¼ 0.003) and healthy controls (U ¼ 24, Z ¼ 3.03, P ¼ 0.002), and a significantly lower PPI at the 120 ms prepulse/pulse interval than PD (U ¼ 41, Z ¼ 2.54, P ¼ 0.011), iRBD (U ¼ 7, Z ¼ 2.19, P ¼ 0.028) and healthy controls (U ¼ 19, Z ¼ 2.14, P ¼ 0.033), see Fig. 2. In addition, MSA showed a significantly higher area under the curve at the 60 ms prepulse/ pulse interval than PD (U ¼ 85, Z ¼ 2.80, P ¼ 0.005), iRBD (U ¼ 13, Z ¼ 3.10, P ¼ 0.002) and healthy controls (U ¼ 28, Z ¼ 3.20, P ¼ 0.002), and a significantly higher area under the curve at the 120 ms prepulse/pulse interval than PD (U ¼ 43, Z ¼ 3.82, P ¼ 0.000), iRBD (U ¼ 23, Z ¼ 2.44, P ¼ 0.015) and healthy controls (U ¼ 37, Z ¼ 2.77, P ¼ 0.006). No group effects were found at the 30 ms and 300 ms prepulse/pulse intervals. When plotting the mean PPI for each group as a function of the four prepulse/pulse intervals, PD patients, iRBD patients and healthy controls all showed the usually seen U-shaped pattern of highest inhibition at the 120 ms interval, with lesser inhibition at both shorter and longer intervals. However, patients with MSA showed a reversed pattern with least inhibition at 60 ms interval and highest at 300 ms, data shown in Fig. 3. 3.3. Dopaminergic medication and PPI As dopamine function may alter the level of PPI, we analyzed if dopaminergic medication exerted an influence on the 60 ms and 120 ms prepulse/pulse interval in PD and MSA. In the PD group we
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Fig. 2. The graphs show prepulse inhibition of the auditory blink reflex in a healthy subject (A) and a patient with MSA (B). P ¼ pulse, referring to the acoustic blink reflex stimulus; PP ¼ prepulse. The inter-stimuli intervals are 60 ms (2) or 120 ms (3).
habituation reached significance in MSA (Z ¼ 2.80, P ¼ 0.005), PD (Z ¼ 5.51, P ¼ 0.000), iRBD (Z ¼ 3.06, P ¼ 0.002), and healthy controls (Z ¼ 3.92, P ¼ 0.000). Mean area under the curve following the last 4 blink reflex stimuli was reduced compared with the first 4 blink reflex stimuli in MSA (Z ¼ 2.805.51, P ¼ 0.005), PD (Z ¼ 5.51, P < 0.0005), iRBD (Z ¼ 3.06, P ¼ 0.002) and healthy controls (Z ¼ 3.92, P < 0.0005). A between-group analysis of area under the curve did not show any significant group differences.
4. Discussion
Fig. 3. Mean percentage PPI of the patient groups as a function of the prepulse/pulse interval (ms). HC: healthy controls; iRBD: idiopathic rapid eye movement sleep behavior disorder; PD: Parkinson’s disease; MSA: multiple system atrophy; PPI: prepulse inhibition.
found significant positive correlations between PPI at the 120 ms prepulse/pulse interval and levodopa (R ¼ 0.184, P ¼ 0.125), dopamine agonist (R ¼ 0.307, P ¼ 0.009), levodopa þ dopamine agonist (R ¼ 0.286, P ¼ 0.013), and total LED (R ¼ 0.223, P ¼ 0.056), while the correlation for the PPI at the 60 ms prepulse/pulse interval was non-significant. In addition, we found significant inverse correlations between UPDRS motor score and PPI at the 60 ms prepulse/pulse interval (R ¼ 0.264, P ¼ 0.042) and the 120 ms prepulse/pulse interval (R ¼ 0.273, P ¼ 0.035), indicating a possible relation between PPI and motor function in PD. In the MSA group the correlations between the 60 ms and 120 ms prepulse/ pulse interval and dopaminergic medication were all nonsignificant.
3.4. Habituation of the acoustic blink reflex Comparing the mean max amplitude of the first four blink reflexes of the PPI-session with the last four blink reflexes,
The present study demonstrated that MSA patients have significant PPI deficits of the acoustic blink reflex. These patients showed particular reduced PPI for 60 ms, and 120 ms interstimulus-intervals compared with PD patients, iRBD patients and healthy controls. This suggests that the prepulse circuit in MSA is not sufficiently activated to enable premotoneuronal inhibition of incoming excitatory inputs, resulting in motoneuronal facilitation. The marked decrease of PPI in MSA is in agreement with a study from Perriol et al., who found PPI deficits in dementia with Lewy bodies (DLB), another atypical parkinsonian disorder belonging to the group of a-synucleinopathies and associated with marked pathology in striatum and brainstem [13]. These authors also reported PPI deficits in PD with dementia, although to a lesser degree. The significant difference in PPI between MSA and PD might be explained by the neuropathological characteristics of the disorders. In MSA, degeneration of the brainstem nuclei, nigrostriatal pathway, and cerebellum is frequent and often severe [11]. The parkinsonian variant of MSA (MSA-P) differs significantly from PD in terms of decreased a-synuclein accumulation in substantia nigra, putaminal volume, glucose metabolism, and postsynaptic D2 receptor density [12], the latter being normal or even upregulated in the early stages of PD. Histological and autoradiographical studies have shown that levodopa-resistance, which is a key feature of MSA, is associated with neuronal loss, gliosis, and loss of postsynaptic D2-dopamine receptors [14]. Pharmacological treatment with dopamine downstream of the striatum will therefore not be
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effective in alleviating Parkinsonism. The same might apply to PPI in this disorder. Lesions of the PPN attenuate PPI of the startle reflex [15,16] and may potentiate the startle response [16], although the latter has not been found in all studies [15,17]. This could partly explain the PPI deficits seen in MSA patients, as neuropathological studies in these patients have shown brainstem atrophy with marked loss of the PPN [18] and a high density of oligodendroglial cytoplasmic inclusions (GCI) within the pontine reticular formation [11]. In PD, there is a predominantly presynaptic dysfunction with decreases in striatal dopamine synthesis, storage, release and transporter binding. Dopaminergic treatment is known to alleviate the motor-symptoms of PD [19], and seems to reduce reflex abnormalities in these patients [20]. Dopaminergic treatment reduces the excessive GABAergic projections from the basal ganglia output structures SNr/GPi, which include the SC and PPN in the brainstem. As the SC and PPN are involved in PPI, optimizing neural transmission in these pathways would result in increased PPI in PD. The PD patients in the present study were optimally treated. According to Basso et al. (1996), dysfunction of the basal ganglia may disrupt the blink reflex by a circuit involving the superior colliculus (SC) and raphe magnus (RM). According to these authors excessive GABAergic output from the basal ganglia over-inhibits the SC, as is the case in Parkinson’s disease. In turn, the SC does not excite tonically active RM neurons sufficiently to inhibit spinal trigeminal neurons, which would result in increased blink reflexes [21]. This is the case when supraorbital stimuli are applied. However, previous studies have also found that lesions of the SC may disrupt auditory PPI, without altering the auditory startle response [22]. In addition, animals with unilateral lesions of the substantia nigra pars compacta present with normal excitable acoustic reflex blinks [23]. This could suggest that excessive GABAergic basal ganglia output, via a circuit involving the SC, may be associated with deficient auditory prepulse inhibition in the presence of normal acoustic blink reflexes. The MSA patients in the present study had normal acoustic blink reflexes as compared to healthy controls. This in line with a previous study conducted by Valldeoriola et al. (1997), who found normal acoustic blink reflexes and, like us, investigated their patients in the sitting position [24]. However, Kofler et al. (2003) investigated the acoustic startle response in MSA patients while in the supine position, and found increased auditory blink reflexes compared to healthy controls. In addition, these authors found exaggerated startle responses in muscles, which are associated with postural control. Therefore, posture might play a role in reflex excitability [25]. It is not known whether the level of PPI depends on posture as well. The finding of PPI deficits in the presence of an unaltered auditory blink reflex, is not in line with the hypothesis that PPI depends on the blink reflex excitability, as suggested by Schicatano et al. (2000). These authors found, in 6-OHDA-lesioned rats with hyperexcitable trigeminal blink reflexes, that an acoustic prepulse facilitated the trigeminal blink reflex, while this same prepulse inhibited a normal acoustic blink reflex. In their study, the prepulse modification correlated with trigeminal reflex blink excitability [23]. Similar results were found in a study by Valls-Sole et al. (2004) where 14 of 20 PD patients presented with hyperexcitable trigeminal blink reflexes. These authors found a significant inverse correlation between trigeminal blink reflex excitability and PPI [26]. However, PPI and the paired-pulse test (assessing blink reflex excitability), are not correlated in every disorder [26,27], and therefore probably measure two independent systems. In addition, lesions to the PPN abolish PPI without consistently affecting the startle response itself, whereas lesions to the dorsolateral pontine tegmentum or the medial medulla disinhibit the
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startle response without affecting PPI [28]. This may indicate that prepulse inhibition does not depend on the startle response excitability in every instance, as has been suggested previously by Schicatano et al. (2000). Although not investigated in this study, future studies could include both measurements with PPI and the paired pulse test. The temporal range around 60 ms for detecting PPI deficits has been shown to be most sensitive in other neuropsychiatric disorders, with similar prepulseepulse characteristics [1]. In addition, striatal cells seem to respond to auditory information and display inhibitory gating, with a gating peak at 60 ms post-stimulation by sensory input [29]. Habituation of the blink reflex did not differ between groups measured with max amplitude and area under the curve, which is in accordance with previous studies showing a similar habituation pattern in PD, Lewy body dementia and healthy controls [30]. A study by Kofler et al. (2003) found decreased acoustic startle probability in 14% of MSA-P patients compared to 34% in healthy controls when all muscles investigated were combined, and significant habituation in MSA-P was seen only in extremity muscles. These results may point to a reduced habituation of the acoustic startle response in MSA patients. However, the assessment of the acoustic startle response may be influenced by posture [25]. As our patients were investigated in the sitting position, whereas the patients in the study by Kofler et al. (2003) were assessed in the supine position, we cannot compare results. To our knowledge, this is the first study to report decreased PPI in MSA patients compared with PD. The marked difference in PPI between MSA and PD is of interest, because clinical separation of these disorders has often proven to be difficult in the early disease stages, despite their distinct histological appearances and pathological entities. An accurate diagnosis is important because prognosis, and response to therapy vary according to the underlying pathology. A non-invasive neurophysiological measure such as PPI may add additional information in the differential diagnosis between PD and the atypical parkinsonian disorder MSA while patients receive optimal treatment.
Acknowledgment This study was funded by the Lundbeck Foundation, the National Foundation for Parkinson’s Disease, and the Toyota Foundation.
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