- Email: [email protected]
Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia
Accepted Manuscript Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia Oya Öztürk, Ayşegül Gündüz, Meral E. Kızıltan PII: DOI: Reference:
S1388-2457(16)30530-2 http://dx.doi.org/10.1016/j.clinph.2016.09.013 CLINPH 2007939
To appear in:
Clinical Neurophysiology
Accepted Date:
7 September 2016
Please cite this article as: Öztürk, O., Gündüz, A., Kızıltan, M.E., Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia, Clinical Neurophysiology (2016), doi: http://dx.doi.org/10.1016/j.clinph. 2016.09.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia† Oya Öztürk*, Ayşegül Gündüz**, Meral E. Kızıltan**
* Bakırköy Prof. Dr. Mazhar Osman Mental Health and Neurological Diseases Training and Research Hospital, Department of Neurology, Turkey ** Department of Neurology, Cerrahpaşa School of Medicine, Istanbul University, Turkey
Correspondence to: Ayşegül Gündüz Istanbul University, Cerrahpaşa School of Medicine, Department of Neurology, Turkey Tel.: +902124143165 Fax: +902126330176 E-mail: [email protected]
†
The abstract has been presented in the 20th International Congress of Parkinson's Disease and
Movement Disorders (2016).
1
ABSTRACT Objective: We analyzed prepulse inhibition (PPI) of the blink reflex (BR) in patients with cervical dystonia (CD) to examine the sensory modulation of the motor system. Methods: This study enrolled 22 consecutive patients with idiopathic CD and 25 ageand gender-matched healthy subjects. Prepulse inhibition of the BR was recorded after stimulating the median nerve at the wrist using an electrical stimulus twice at a perception threshold 100 ms before a test stimulus to the supraorbital nerve. Results: The R2 area and amplitude were significantly reduced and the R2 latency delayed after the conditioned stimulus in patients with CD. The R1 latency and amplitude did not differ between trials in patients with CD. In healthy subjects, the R1 amplitude was higher, whereas the R2 latency was delayed and the R2 amplitude and area were reduced after the conditioned stimulus. However, there was significantly less R2 and R2c area suppression in patients compared with healthy subjects. ANOVA showed that reduction of R2 area conditioned stimulus (F=6.620, p=0.003) and conditioned R2 area/test R2 area (F=5.217, p=0.009) were lower in patients with and without sensory tricks compared with healthy subjects, whereas the reduction in PPI was pronounced in patients without a sensory trick compared with healthy subjects. Conclusions: Patients with CD show significantly less prepulse R2 inhibition than healthy subjects, but this occurred without R1 facilitation. The absence of a sensory trick leads to the more pronounced reduction of PPI. Significance: The modulatory effects of sensory inputs are lost in patients with CD without sensory tricks.
2
Highlights 1. Patients with cervical dystonia have less prepulse R2 inhibition than healthy subjects. 2. The absence of a sensory trick leads to the more pronounced reduction of prepulse R2 inhibition. 3. The modulatory effects of sensory inputs are lost in the absence of a sensory trick.
Keywords: Prepulse inhibition; blink reflex; cervical dystonia; sensory trick.
Abbreviations: Blink reflex (BR); cervical dystonia (CD); interstimulus interval (ISI); magnetic resonance imaging (MRI); pedunculopontine tegmental nucleus (PPTN); prepulse inhibition (PPI); subthalamic nucleus (STN); Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).
3
1. Introduction Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both (Albanese et al., 2013). Cervical dystonia (CD) is a focal dystonia that affects the muscles of the neck and, sometimes, the shoulders. It typically starts in adulthood and may be accompanied by jerky movements of the head and neck. Electrophysiological studies have suggested that decreased inhibition, sensory dysfunction, and abnormal plasticity play roles in the pathophysiology of dystonia (Quartarone and Hallett, 2013). Patients with craniocervical dystonia
showed abnormalities of the interneurons mediating
exteroceptive reflexes, and these changes were outside the systems controlling the muscles with dystonia (Carella et al., 1994). The probability and magnitude of the auditory
startle
response
were
reduced
in
CD,
although
the
prolonged
electromyographic activity after the proper startle response suggested brainstem dysfunction (Müller et al., 2003). A typical finding of CD is the “sensory trick,” which is a reduction in involuntary contraction to a light touch (Albanese et al., 2013; Kagi et al., 2013). Disinhibition of the somatosensory cortex has also been demonstrated in CD (Siggelkow et al., 2002; Kanovský et al., 2003). Therefore, CD is now considered a disorder of sensorimotor gating that probably causes input–output mismatch in specific motor programs (Abbruzzese and Berardelli, 2003; Hallett, 1995; Stamelou et al., 2012). Prepulse inhibition (PPI) is a neurophysiological method defined as the inhibition of a reflex response caused by applying a subthreshold stimulus before the test stimulus (Graham, 1975; Hoffman and Ison, 1980; Valls-Sole et al., 1999). Prepulse
4
inhibition of the blink reflex (BR) leads to inhibition of the R2 magnitude, whereas a short interstimulus interval (ISI) increases the magnitude of R1 (prepulse facilitation) (Boelhouwer et al., 1991; Ison et al., 1990; Rossi and Scarpini, 1992). The neural correlates of PPI are theorized to be a network between the basal ganglia and brainstem reticular formation, probably including the pedunculopontine tegmental nucleus (PPTN) (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The PPI has been studied in patients with blepharospasm in whom the PPI was reduced particularly in patients without sensory tricks (Gómez-Wong et al., 1998). We analyzed the PPI of the BR in a group of patients with CD, because CD is a disorder of sensorimotor integration and PPI is an electrophysiological method used to determine the sensory modulation of motor systems.
2. Subjects and methods 2.1 Subjects The study enrolled 22 consecutive patients who were seen in our movement disorders outpatient clinic with a diagnosis of idiopathic CD and because the influence of age and gender on PPI of the BR is known, 25 age- and gender-matched healthy subjects (Kofler et al., 2013). Secondary causes of dystonia were excluded in all patients based on history, laboratory investigations, and cranial magnetic resonance imaging (MRI). All patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Electrophysiological assessments were performed in drug-naïve patients or at least 3 months after the last botulinum toxin administration when the complaints reached a maximum level. The study excluded patients who had involuntary
5
contractions of the facial muscles and those who had their facial muscles treated with botulinum toxin. The study was approved by the Institutional Review Board, and all participants provided informed consent. 2.2 Methods The electrophysiological recordings were performed using Ag-AgCl surface electromyography recording electrodes (Neuropack Σ-MEB-5504K, Nihon Kohden Corporation, Tokyo, Japan), according to standard techniques. 2.2.1 Blink reflex: The active electrode was placed on the lower eyelid, the reference electrode was placed on the lateral orbital margin, and the ground electrode was placed on the forehead. The supraorbital nerve was stimulated at the supraorbital margin percutaneously. The duration of the electrical stimulus was 0.2 ms, and its intensity was three times the perception threshold (8–14 mA). Five responses were recorded at random intervals of at least 20 seconds. The reflex response was defined as time-locked deflection with an amplitude of at least 50 µV compared with baseline. The analysis time was 20–30 ms/div, and the sensitivity was 50–200 μV. The filter settings were 3 kHz high-cut and 20 Hz low-cut. 2.2.2 Prepulse inhibition: The median nerve was stimulated using an electrical stimulus of 0.2 ms in duration at two to three times the intensity of the perception threshold; this occurred 100 ms before the test stimulus to the supraorbital nerve. The electrode positioning, filter settings, and sensitivity were the same as for the standard BR investigation. The analysis time was 20–30 ms/div for the investigations. Six trials were performed with at least 10 seconds between two consecutive stimuli.
6
2.3. Statistical analysis Following supraorbital nerve stimulation (test stimulus) and preceding median nerve stimulation/supraorbital nerve stimulation (conditioned stimulus), the onset latencies and peak-to-peak amplitudes of the R1 and R2 responses were measured using cursors. For the PPI analysis, six responses were averaged and rectified. Cursors were placed from the onset to the end of the response, and the R2 area was calculated automatically. The percentage change in the R2 area was calculated as the [R2 area at ISI 100 ms (conditioned stimulus)]/[R2 area at baseline (test stimulus)] × 100. The data were analyzed using the SPSS 15 statistical package (SPSS, Chicago, IL, USA). Age, gender, and prepulse stimulus intensity were compared between patients and healthy subjects using the independent-samples t-test for quantitative data and the chi-square test for qualitative data with the Bonferroni correction. The TWSTRS score was presented as the mean ± SD, whereas use of botulinum toxin and presence of a sensory trick were presented as the percentage of patients. The R1/R2 latencies and amplitudes and R2 areas obtained after the test stimuli and the percentage of suppression after the conditioned stimuli were compared between patients with CD and healthy subjects using the Mann–Whitney U-test. The correlation between the TWSTRS scores and conditioned/test R2 area was analyzed using Pearson correlation analysis. The R1/R2 latencies and amplitudes and R2 areas at baseline and ISI of 100 ms were compared separately within groups of patients with CD and healthy subjects using the Wilcoxon test. The same analysis was repeated by dichotomizing the patient group
7
based on the presence of a sensory trick: patients with and without a sensory trick. We used presence and absence of sensory trick as a grouping factor. The followings were compared among the two groups and healthy subjects using analysis of variance (ANOVA): TWSTRS scores, test R2 area, and conditioned R2 area/test R2 area. Posthoc analysis was performed using Tukey’s test. A p-value ≤ 0.05 was considered significant.
3. Results The mean ages of the patient group and healthy subjects were 38.1±9.4 and 37.3±10.6 years, respectively (p=0.783). The male/female ratios were 5/17 (22.7%/77.3%) and 12/13 (48%/52%), respectively (p=0.072). The mean TWSTRS score was 32.6±10.9. There were 14 (63.6%) patients who experienced sensory tricks, and 11 (50%) patients were botulinum toxin-naïve (Table 1). Three of the 8 patients who did not have sensory tricks were botulinum toxin-naïve, whereas the 8 of the 14 patients with sensory tricks were botulinum toxin-naïve. The prepulse stimulus intensities were 2.8±0.6 mA vs. 2.6±0.9 mA in the patient group and healthy subjects, respectively (p=0.412). The characteristics of the test BR were similar between patients and healthy subjects. Comparisons in patients with CD demonstrated a significantly reduced R2 area and amplitude and a delayed R2 latency after a conditioned stimulus compared with after the test stimuli (Table 2). Figures 1A and 1B show representative examples of the BR after test and conditioned stimuli in a patient with CD. The R1 latency and amplitude did not differ between trials. In healthy subjects, the R1 amplitude was
8
higher, whereas the R2 latency was delayed and the R2 amplitude and area were reduced after the conditioned stimulus (Figure 1C and 1D, Table 2). However, there was significantly less R2 area suppression in patients with CD than in healthy subjects (30.8±33.4% vs. 73.6±76.3%, p=0.007). There was no correlation between TWSTRS scores and conditioned/test R2 area (p=0.937, correlation factor=0.018). The mean TWSTRS scores were similar between the patients with and without sensory trick and between botulinum toxin-naïve patients (p=0.318) and patients who were previously treated with the toxin (p=0.465). Analysis using t-test for dependent groups demonstrated that the R2 area decreased significantly after the conditioned stimuli compared with trials after the test stimuli in patients with sensory tricks (p=0.026), whereas there was no significant change in the R2 area in patients without sensory tricks (p=0.484). ANOVA using presence or absence of sensory trick as grouping factor showed that reduction of R2 area conditioned stimulus (F=6.620, p=0.003) and conditioned R2 area/test R2 area (F=5.217, p=0.009) were lower in patients with and without sensory tricks compared with the healthy subjects; however, the reduction in conditioned R2 area/test R2 area was more prominent in patients without a sensory trick compared with healthy subjects. There was no difference in the baseline R2 area among groups. 4. Discussion The main finding of our study is the abnormally reduced PPI in CD and the consequently reduced inhibitory drives affecting the BR circuit in CD; this was particularly evident in CD patients who did not exhibit a sensory trick. PPI has been studied in various neurological and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, narcolepsy, schizophrenia, and fibromyalgia
9
(Frauscher et al., 2012; Kofler and Halder, 2014; Valls-Solé et al., 2004). It is generally accepted to reflect the functional status of inhibitory brainstem interneurons and to be the electrophysiological counterpart of sensorimotor gating (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The only study of PPI in patients with dystonia was in blepharospasm, and the patients with blepharospasm showed an abnormally reduced PPI of the BR that was more frequent in patients who did not exhibit sensory tricks (Gómez-Wong et al., 1998). We observed a very similar effect in the group without dystonic involvement of the orbicular muscles, indicating a possible interaction of suprasegmental structures. The increased excitability of R2 has previously been shown in CD and other types of cranial dystonia and was attributed to the increased activity of dopaminergic pathways controlling the BR circuit (Carella et al., 1994). Loss of PPI suggests that the gating of sensory impulses is also abnormal in CD. The major anatomical structures that are responsible for PPI are located between the midbrain and the medulla, as PPI is observed in decerebrate animals (Li and Frost, 2000). The central structures are probably the connections between the PPTN and nucleus reticularis pontis caudalis (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The hippocampus, parahippocampal gyrus, basal ganglia (including parts of the putamen, globus pallidus, and nucleus accumbens), superior temporal gyrus, thalamus, and inferior frontal gyrus are all active in association with PPI and probably have modulatory effects (Kumari et al., 2005). Direct subthalamic nucleus (STN) stimulation simulates the effects of acoustic or somatosensory prepulses quite closely in humans undergoing functional neurosurgery for Parkinson’s disease (Costa et al., 2006). The observed effect was attributed to the pallidofugal fiber tracts running parallel to the STN on their way to the
10
PPTN or to the cholinergic fibers projecting from the PPTN to the thalamus that exert inhibitory actions on trigeminal afferents. In CD, the basal ganglia, thalamus, premotor– motor cortex, and cerebellum are very active (Galardi et al., 1996), and intraoperative recordings from the globus pallidus in dystonia suggested increased activity along the cortico–striato–external globus pallidus/internal globus pallidus pathways (Galardi et al., 1996). In summary, functional changes in the basal ganglia–thalamocortical loop seem to be important in the development of dystonic movements, and the reduced PPI is probably the result of functional changes in this pathway. Our study suggests that sensory tricks are probably the clinical counterparts of sensorimotor gating in physiology, which is probably one of the basic mechanisms by which the nervous system limits overactivity. In their study of blepharospasm, GómezWong et al. (1998) observed very similar PPI in patients with sensory tricks and suggested that the abnormalities of sensorimotor gating were consequences of dystonia and that continuous activity might cause loss of the modulatory effects of sensory inputs. Patients with sensory tricks exhibit increased metabolism of the superior and inferior parietal lobules ipsilateral to the involuntary contractions and decreased metabolism of contralateral supplementary motor and primary sensorimotor cortices (Naumann et al., 2000), indicating the key role of the multimodal association area, the parietal cortex (Kagi et al., 2013; Patel et al., 2014). However, patients who were incapable of using sensory tricks were hypothesized to have lost the cortical adaptive mechanisms to compensate for the basal ganglia dysfunction (Kagi et al., 2013). The preservation of PPI is probably the end result of the preservation of these adaptive mechanisms. There were no differences in the severity or duration of CD between the
11
patients with and without sensory tricks. Therefore, further studies are needed to understand the underlying cause. The main limitation of the study is the use of the median nerve at the wrist as a conditioning stimulus, as it may stimulate both motor and sensory pathways. The standard method is to stimulate the second or third finger. However, we know that the same volley of stimulation occurs with these two stimulations, and PPI may be triggered by stimulating other parts of the body, such as via tactile stimulation of the lower legs or via auditory stimulation (Leon-Sarmiento et al., 2015). In CD, we selected median nerve stimulation at the wrist because it was easier to fix in patients with vigorous contractions.
5. Conclusion In conclusion, there is loss of PPI in CD related to the absence of sensory tricks or to the use of the botulinum toxin. The association of PPI and sensory tricks suggests the preservation of cortical adaptive mechanisms and sensorimotor gating in that group of CD patients, whereas the modulatory effect of sensory inputs is lost in CD patients without sensory tricks.
Conflict of interest None.
Funding sources None.
12
References Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863-73. Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231-40. Boelhouwer AJW, Teurlings RJMA, Brunia CHM. The effect of an acoustic warning stimulus upon the electrically elicited blink reflex in humans. Psychophysiology 1991;28:133-9. Carella F, Ciano C, Musicco M, Scaioli V. Exteroceptive reflexes in dystonia: a study of the recovery cycle of the R2 component of the blink reflex and of the exteroceptive suppression of the contracting sternocleidomastoid muscle in blepharospasm and torticollis. Mov Disord 1994;9:183-187. Costa J, Valls-Solé J, Valldeoriola F, Pech C, Rumià J. Single subthalamic nucleus deep brain stimuli inhibit the blink reflex in Parkinson's disease patients. Brain 2006;129:1758-67. Frauscher B, Löscher WN, Ehrmann L, Gschliesser V, Brandauer E, Högl B, et al. Narcolepsy-cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement. J Sleep Res 2012;21:495-501. Galardi G, Perani D, Grassi F, Bressi S, Amadio S, Antoni M, et al. Basal ganglia and thalamo-cortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol Scand 1996;94:172-6.
13
Gómez-Wong E, Martí MJ, Tolosa E, Valls-Solé J. Sensory modulation of the blink reflex in patients with blepharospasm. Arch Neurol 1998;55:1233-1237. Graham FK. Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psycophysiology 1975;12:238-48. Hallett M. Is dystonia a sensory disorder? Ann Neurol 1995;38:139-40. Hoffman HS, Ison JR. Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system process sensory input. Psychol Rev 1980;87:175-89. Ison JR, Sanes JN, Foss JA. Facilitation and inhibition of the human startle blink reflex by stimulus anticipation. Behav Neurosci 1990;104:418-29. Kagi G, Katschnig P, Fioro M, Tinazzi M, Ruge D, Rothwell J, et al. Sensory tricks in primary cervical dystonia depend on visuotactile temporal discrimination. Mov Disord 2013;28:356-61. Kanovský P, Bares M, Streitová H, Klajblová H, Daniel P, Rektor I. Abnormalities of cortical excitability and cortical inhibition in cervical dystonia Evidence from somatosensory evoked potentials and paired transcranial magnetic stimulation recordings. J Neurol 2003;250:42-50. Koch M, Kungel M, Herbert H. Cholinergic neurons in the pedunculopontin tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat. Exp Brain Res 1993;97:71-82. Kofler M, Kumru H, Schaller J, Saltuari L. Blink reflex prepulse inhibition and excitability recovery: influence of age and sex. Clin Neurophysiol 2013;124:126-35. 14
Kofler M, Halder W. Alterations in excitatory and inhibitory brainstem interneuronal circuits in fibromyalgia: evidence of brainstem dysfunction. Clin Neurophysiol 2014;125:593-601. Kumari V, Antonova E, Zachariah E, Galea A, Aasen I, Ettinger U, et al. Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans. Neuroimage 2005;26:1052-8. Leon-Sarmiento FE, Peckham E, Leon-Ariza DS, Bara-Jimenez W, Hallett M. Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology. J Clin Neurophysiol 2015;32:369-74. Li L, Frost BJ. Azimuthal directional sensitivity of prepulse inhibition of the pinna startle reflex in decerebrate rats. Brain Res Bull 2000;51:95-100. Müller J, Kofler M, Wenning GK, Seppi K, Valls-Solé J, Poewe W. Auditory startle response in cervical dystonia. Mov Disord 2003;18:1522-6. Naumann M, Magyar-Lehmann S, Reiners K, Erbguth F, Leenders KL. Sensory tricks in cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor programming. Ann Neurol 2000;47:322-8. Nishibayashi H, Ogura M, Kakishita K, Tanaka S, Tachibana Y, Nambu A, Kita H, Itakura T, et al. Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery. Mov Disord 2011;26:469-76. Patel N, Hanfelt J, Marsh L, Jankovic J; members of the Dystonia Coalition. Alleviating manoeuvres (sensory tricks) in cervical dystonia. J Neurol Neurosurg Psychiatry 2014;85:882-4.
15
Quartarone A, Hallett M. Emerging concepts in the physiological basis of dystonia. Mov Disord 2013;28:958-67. Rossi A, Scarpini C. Gating of trigemino-facial reflex from low-threshold trigeminal and extratrigeminal cutaneous fibres in humans. J Neurol Neurosurg Psychiatry 1992;55:774-80. Saitoh K, Tilson HA, Shaw S, Dyer RS. Possible role of the brainstem in the mediation of prepulse inhibition in the rat. Neurosci Lett 1987;75:216-22. Siggelkow S, Kossev A, Moll C, Däuper J, Dengler R, Rollnik JD. Impaired sensorimotor integration in cervical dystonia: a study using transcranial magnetic stimulation and muscle vibration. J Clin Neurophysiol 2002;19:232-9. Stamelou M, Edwards MJ, Hallett M, Bhatia KP. The non-motor syndrome of primary
dystonia:
clinical
and
pathophysiological
implications.
Brain
2012;135:1668-81. Swerdlow NR, Geyer MA. Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine tegmental nucleus. Behav Neurosci 1993;107:104-17. Valls-Solé J, Muñoz 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;115:1527-36. Valls-Sole J, Valldeoriola F, Molinuevo JL, Cossu G, Nobbe F. Prepulse modulation of the startle reaction and the blink reflex in normal human subjects. Exp Brain Res 1999;129:49-56.
16
Table 1. Comparisons of demographical and clinical of patients and healthy subjects. CD Patients
Healthy subjects
P
n=22
n=25
Age (years)
38.1±9.4
37.3±10.6
0.783
Gender M/F n (%)
5/17 (22.7/77.3)
12/13 (48/52)
0.072
Sensory trick n (%)
14 (63.6)
-
-
Botulinum toxin n (%)
11 (50)
-
-
TWSTRS score
32.6±10.9
-
-
CD, cervical dystonia; PPI, prepulse inhibition; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale. All comparisons were done using independent samples t-test or chi square test.
17
Table 2. Comparison of findings after test stimulus and prepulse inhibition in patients and healthy subjects. Patients
Healthy subjects
Test
PPI
p
Test
PPI
p
R1 latency (ms)
10.8±1.3
10.7±1.3
0.393
10.2±1.2
10.2±1.3
0.962
R1 amplitude (µV)
339.7±218.9
338.8±240.3
0.924
373.3±262.2
461.0±261.9
0.003**
R2 latency (ms)
31.9±3.7
34.5±4.4
0.011*
33.9±4.3
35.5±4.0
0.040*
R2 amplitude (µV)
316.4±132.9
187.1±108.3
0.000**
283.1±184.0
145.6±158.9
0.002**
R2 area (ms mV)
4.4±2.5
2.8±2.6
0.020*
3.6±2.2
1.0±1.1
0.000**
PPI, prepulse inhibition All comparisons were done using Wilcoxon test. *p<0.050; **p<0.010
18
Figure Legend
Figure 1. A. Raw and rectified images of the blink reflex after a test stimulus in a 48year-old woman with CD. B. Raw and rectified images of the blink reflex after a conditioned stimulus in the same patient. A higher R2 amplitude and larger R2 area can be seen after the conditioned stimulus. C. Raw and rectified images of the blink reflex after a test stimulus in a healthy 35-year-old woman. D. Raw and rectified images of the blink reflex after a conditioned stimulus in the same healthy subject.
19
20
S1388-2457(16)30530-2 http://dx.doi.org/10.1016/j.clinph.2016.09.013 CLINPH 2007939
To appear in:
Clinical Neurophysiology
Accepted Date:
7 September 2016
Please cite this article as: Öztürk, O., Gündüz, A., Kızıltan, M.E., Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia, Clinical Neurophysiology (2016), doi: http://dx.doi.org/10.1016/j.clinph. 2016.09.013
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Deficient median nerve prepulse inhibition of the blink reflex in cervical dystonia† Oya Öztürk*, Ayşegül Gündüz**, Meral E. Kızıltan**
* Bakırköy Prof. Dr. Mazhar Osman Mental Health and Neurological Diseases Training and Research Hospital, Department of Neurology, Turkey ** Department of Neurology, Cerrahpaşa School of Medicine, Istanbul University, Turkey
Correspondence to: Ayşegül Gündüz Istanbul University, Cerrahpaşa School of Medicine, Department of Neurology, Turkey Tel.: +902124143165 Fax: +902126330176 E-mail: [email protected]
†
The abstract has been presented in the 20th International Congress of Parkinson's Disease and
Movement Disorders (2016).
1
ABSTRACT Objective: We analyzed prepulse inhibition (PPI) of the blink reflex (BR) in patients with cervical dystonia (CD) to examine the sensory modulation of the motor system. Methods: This study enrolled 22 consecutive patients with idiopathic CD and 25 ageand gender-matched healthy subjects. Prepulse inhibition of the BR was recorded after stimulating the median nerve at the wrist using an electrical stimulus twice at a perception threshold 100 ms before a test stimulus to the supraorbital nerve. Results: The R2 area and amplitude were significantly reduced and the R2 latency delayed after the conditioned stimulus in patients with CD. The R1 latency and amplitude did not differ between trials in patients with CD. In healthy subjects, the R1 amplitude was higher, whereas the R2 latency was delayed and the R2 amplitude and area were reduced after the conditioned stimulus. However, there was significantly less R2 and R2c area suppression in patients compared with healthy subjects. ANOVA showed that reduction of R2 area conditioned stimulus (F=6.620, p=0.003) and conditioned R2 area/test R2 area (F=5.217, p=0.009) were lower in patients with and without sensory tricks compared with healthy subjects, whereas the reduction in PPI was pronounced in patients without a sensory trick compared with healthy subjects. Conclusions: Patients with CD show significantly less prepulse R2 inhibition than healthy subjects, but this occurred without R1 facilitation. The absence of a sensory trick leads to the more pronounced reduction of PPI. Significance: The modulatory effects of sensory inputs are lost in patients with CD without sensory tricks.
2
Highlights 1. Patients with cervical dystonia have less prepulse R2 inhibition than healthy subjects. 2. The absence of a sensory trick leads to the more pronounced reduction of prepulse R2 inhibition. 3. The modulatory effects of sensory inputs are lost in the absence of a sensory trick.
Keywords: Prepulse inhibition; blink reflex; cervical dystonia; sensory trick.
Abbreviations: Blink reflex (BR); cervical dystonia (CD); interstimulus interval (ISI); magnetic resonance imaging (MRI); pedunculopontine tegmental nucleus (PPTN); prepulse inhibition (PPI); subthalamic nucleus (STN); Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS).
3
1. Introduction Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both (Albanese et al., 2013). Cervical dystonia (CD) is a focal dystonia that affects the muscles of the neck and, sometimes, the shoulders. It typically starts in adulthood and may be accompanied by jerky movements of the head and neck. Electrophysiological studies have suggested that decreased inhibition, sensory dysfunction, and abnormal plasticity play roles in the pathophysiology of dystonia (Quartarone and Hallett, 2013). Patients with craniocervical dystonia
showed abnormalities of the interneurons mediating
exteroceptive reflexes, and these changes were outside the systems controlling the muscles with dystonia (Carella et al., 1994). The probability and magnitude of the auditory
startle
response
were
reduced
in
CD,
although
the
prolonged
electromyographic activity after the proper startle response suggested brainstem dysfunction (Müller et al., 2003). A typical finding of CD is the “sensory trick,” which is a reduction in involuntary contraction to a light touch (Albanese et al., 2013; Kagi et al., 2013). Disinhibition of the somatosensory cortex has also been demonstrated in CD (Siggelkow et al., 2002; Kanovský et al., 2003). Therefore, CD is now considered a disorder of sensorimotor gating that probably causes input–output mismatch in specific motor programs (Abbruzzese and Berardelli, 2003; Hallett, 1995; Stamelou et al., 2012). Prepulse inhibition (PPI) is a neurophysiological method defined as the inhibition of a reflex response caused by applying a subthreshold stimulus before the test stimulus (Graham, 1975; Hoffman and Ison, 1980; Valls-Sole et al., 1999). Prepulse
4
inhibition of the blink reflex (BR) leads to inhibition of the R2 magnitude, whereas a short interstimulus interval (ISI) increases the magnitude of R1 (prepulse facilitation) (Boelhouwer et al., 1991; Ison et al., 1990; Rossi and Scarpini, 1992). The neural correlates of PPI are theorized to be a network between the basal ganglia and brainstem reticular formation, probably including the pedunculopontine tegmental nucleus (PPTN) (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The PPI has been studied in patients with blepharospasm in whom the PPI was reduced particularly in patients without sensory tricks (Gómez-Wong et al., 1998). We analyzed the PPI of the BR in a group of patients with CD, because CD is a disorder of sensorimotor integration and PPI is an electrophysiological method used to determine the sensory modulation of motor systems.
2. Subjects and methods 2.1 Subjects The study enrolled 22 consecutive patients who were seen in our movement disorders outpatient clinic with a diagnosis of idiopathic CD and because the influence of age and gender on PPI of the BR is known, 25 age- and gender-matched healthy subjects (Kofler et al., 2013). Secondary causes of dystonia were excluded in all patients based on history, laboratory investigations, and cranial magnetic resonance imaging (MRI). All patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Electrophysiological assessments were performed in drug-naïve patients or at least 3 months after the last botulinum toxin administration when the complaints reached a maximum level. The study excluded patients who had involuntary
5
contractions of the facial muscles and those who had their facial muscles treated with botulinum toxin. The study was approved by the Institutional Review Board, and all participants provided informed consent. 2.2 Methods The electrophysiological recordings were performed using Ag-AgCl surface electromyography recording electrodes (Neuropack Σ-MEB-5504K, Nihon Kohden Corporation, Tokyo, Japan), according to standard techniques. 2.2.1 Blink reflex: The active electrode was placed on the lower eyelid, the reference electrode was placed on the lateral orbital margin, and the ground electrode was placed on the forehead. The supraorbital nerve was stimulated at the supraorbital margin percutaneously. The duration of the electrical stimulus was 0.2 ms, and its intensity was three times the perception threshold (8–14 mA). Five responses were recorded at random intervals of at least 20 seconds. The reflex response was defined as time-locked deflection with an amplitude of at least 50 µV compared with baseline. The analysis time was 20–30 ms/div, and the sensitivity was 50–200 μV. The filter settings were 3 kHz high-cut and 20 Hz low-cut. 2.2.2 Prepulse inhibition: The median nerve was stimulated using an electrical stimulus of 0.2 ms in duration at two to three times the intensity of the perception threshold; this occurred 100 ms before the test stimulus to the supraorbital nerve. The electrode positioning, filter settings, and sensitivity were the same as for the standard BR investigation. The analysis time was 20–30 ms/div for the investigations. Six trials were performed with at least 10 seconds between two consecutive stimuli.
6
2.3. Statistical analysis Following supraorbital nerve stimulation (test stimulus) and preceding median nerve stimulation/supraorbital nerve stimulation (conditioned stimulus), the onset latencies and peak-to-peak amplitudes of the R1 and R2 responses were measured using cursors. For the PPI analysis, six responses were averaged and rectified. Cursors were placed from the onset to the end of the response, and the R2 area was calculated automatically. The percentage change in the R2 area was calculated as the [R2 area at ISI 100 ms (conditioned stimulus)]/[R2 area at baseline (test stimulus)] × 100. The data were analyzed using the SPSS 15 statistical package (SPSS, Chicago, IL, USA). Age, gender, and prepulse stimulus intensity were compared between patients and healthy subjects using the independent-samples t-test for quantitative data and the chi-square test for qualitative data with the Bonferroni correction. The TWSTRS score was presented as the mean ± SD, whereas use of botulinum toxin and presence of a sensory trick were presented as the percentage of patients. The R1/R2 latencies and amplitudes and R2 areas obtained after the test stimuli and the percentage of suppression after the conditioned stimuli were compared between patients with CD and healthy subjects using the Mann–Whitney U-test. The correlation between the TWSTRS scores and conditioned/test R2 area was analyzed using Pearson correlation analysis. The R1/R2 latencies and amplitudes and R2 areas at baseline and ISI of 100 ms were compared separately within groups of patients with CD and healthy subjects using the Wilcoxon test. The same analysis was repeated by dichotomizing the patient group
7
based on the presence of a sensory trick: patients with and without a sensory trick. We used presence and absence of sensory trick as a grouping factor. The followings were compared among the two groups and healthy subjects using analysis of variance (ANOVA): TWSTRS scores, test R2 area, and conditioned R2 area/test R2 area. Posthoc analysis was performed using Tukey’s test. A p-value ≤ 0.05 was considered significant.
3. Results The mean ages of the patient group and healthy subjects were 38.1±9.4 and 37.3±10.6 years, respectively (p=0.783). The male/female ratios were 5/17 (22.7%/77.3%) and 12/13 (48%/52%), respectively (p=0.072). The mean TWSTRS score was 32.6±10.9. There were 14 (63.6%) patients who experienced sensory tricks, and 11 (50%) patients were botulinum toxin-naïve (Table 1). Three of the 8 patients who did not have sensory tricks were botulinum toxin-naïve, whereas the 8 of the 14 patients with sensory tricks were botulinum toxin-naïve. The prepulse stimulus intensities were 2.8±0.6 mA vs. 2.6±0.9 mA in the patient group and healthy subjects, respectively (p=0.412). The characteristics of the test BR were similar between patients and healthy subjects. Comparisons in patients with CD demonstrated a significantly reduced R2 area and amplitude and a delayed R2 latency after a conditioned stimulus compared with after the test stimuli (Table 2). Figures 1A and 1B show representative examples of the BR after test and conditioned stimuli in a patient with CD. The R1 latency and amplitude did not differ between trials. In healthy subjects, the R1 amplitude was
8
higher, whereas the R2 latency was delayed and the R2 amplitude and area were reduced after the conditioned stimulus (Figure 1C and 1D, Table 2). However, there was significantly less R2 area suppression in patients with CD than in healthy subjects (30.8±33.4% vs. 73.6±76.3%, p=0.007). There was no correlation between TWSTRS scores and conditioned/test R2 area (p=0.937, correlation factor=0.018). The mean TWSTRS scores were similar between the patients with and without sensory trick and between botulinum toxin-naïve patients (p=0.318) and patients who were previously treated with the toxin (p=0.465). Analysis using t-test for dependent groups demonstrated that the R2 area decreased significantly after the conditioned stimuli compared with trials after the test stimuli in patients with sensory tricks (p=0.026), whereas there was no significant change in the R2 area in patients without sensory tricks (p=0.484). ANOVA using presence or absence of sensory trick as grouping factor showed that reduction of R2 area conditioned stimulus (F=6.620, p=0.003) and conditioned R2 area/test R2 area (F=5.217, p=0.009) were lower in patients with and without sensory tricks compared with the healthy subjects; however, the reduction in conditioned R2 area/test R2 area was more prominent in patients without a sensory trick compared with healthy subjects. There was no difference in the baseline R2 area among groups. 4. Discussion The main finding of our study is the abnormally reduced PPI in CD and the consequently reduced inhibitory drives affecting the BR circuit in CD; this was particularly evident in CD patients who did not exhibit a sensory trick. PPI has been studied in various neurological and psychiatric disorders, such as Parkinson’s disease, Huntington’s disease, narcolepsy, schizophrenia, and fibromyalgia
9
(Frauscher et al., 2012; Kofler and Halder, 2014; Valls-Solé et al., 2004). It is generally accepted to reflect the functional status of inhibitory brainstem interneurons and to be the electrophysiological counterpart of sensorimotor gating (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The only study of PPI in patients with dystonia was in blepharospasm, and the patients with blepharospasm showed an abnormally reduced PPI of the BR that was more frequent in patients who did not exhibit sensory tricks (Gómez-Wong et al., 1998). We observed a very similar effect in the group without dystonic involvement of the orbicular muscles, indicating a possible interaction of suprasegmental structures. The increased excitability of R2 has previously been shown in CD and other types of cranial dystonia and was attributed to the increased activity of dopaminergic pathways controlling the BR circuit (Carella et al., 1994). Loss of PPI suggests that the gating of sensory impulses is also abnormal in CD. The major anatomical structures that are responsible for PPI are located between the midbrain and the medulla, as PPI is observed in decerebrate animals (Li and Frost, 2000). The central structures are probably the connections between the PPTN and nucleus reticularis pontis caudalis (Koch et al., 1993; Saitoh et al., 1987; Swerdlow and Geyer, 1993). The hippocampus, parahippocampal gyrus, basal ganglia (including parts of the putamen, globus pallidus, and nucleus accumbens), superior temporal gyrus, thalamus, and inferior frontal gyrus are all active in association with PPI and probably have modulatory effects (Kumari et al., 2005). Direct subthalamic nucleus (STN) stimulation simulates the effects of acoustic or somatosensory prepulses quite closely in humans undergoing functional neurosurgery for Parkinson’s disease (Costa et al., 2006). The observed effect was attributed to the pallidofugal fiber tracts running parallel to the STN on their way to the
10
PPTN or to the cholinergic fibers projecting from the PPTN to the thalamus that exert inhibitory actions on trigeminal afferents. In CD, the basal ganglia, thalamus, premotor– motor cortex, and cerebellum are very active (Galardi et al., 1996), and intraoperative recordings from the globus pallidus in dystonia suggested increased activity along the cortico–striato–external globus pallidus/internal globus pallidus pathways (Galardi et al., 1996). In summary, functional changes in the basal ganglia–thalamocortical loop seem to be important in the development of dystonic movements, and the reduced PPI is probably the result of functional changes in this pathway. Our study suggests that sensory tricks are probably the clinical counterparts of sensorimotor gating in physiology, which is probably one of the basic mechanisms by which the nervous system limits overactivity. In their study of blepharospasm, GómezWong et al. (1998) observed very similar PPI in patients with sensory tricks and suggested that the abnormalities of sensorimotor gating were consequences of dystonia and that continuous activity might cause loss of the modulatory effects of sensory inputs. Patients with sensory tricks exhibit increased metabolism of the superior and inferior parietal lobules ipsilateral to the involuntary contractions and decreased metabolism of contralateral supplementary motor and primary sensorimotor cortices (Naumann et al., 2000), indicating the key role of the multimodal association area, the parietal cortex (Kagi et al., 2013; Patel et al., 2014). However, patients who were incapable of using sensory tricks were hypothesized to have lost the cortical adaptive mechanisms to compensate for the basal ganglia dysfunction (Kagi et al., 2013). The preservation of PPI is probably the end result of the preservation of these adaptive mechanisms. There were no differences in the severity or duration of CD between the
11
patients with and without sensory tricks. Therefore, further studies are needed to understand the underlying cause. The main limitation of the study is the use of the median nerve at the wrist as a conditioning stimulus, as it may stimulate both motor and sensory pathways. The standard method is to stimulate the second or third finger. However, we know that the same volley of stimulation occurs with these two stimulations, and PPI may be triggered by stimulating other parts of the body, such as via tactile stimulation of the lower legs or via auditory stimulation (Leon-Sarmiento et al., 2015). In CD, we selected median nerve stimulation at the wrist because it was easier to fix in patients with vigorous contractions.
5. Conclusion In conclusion, there is loss of PPI in CD related to the absence of sensory tricks or to the use of the botulinum toxin. The association of PPI and sensory tricks suggests the preservation of cortical adaptive mechanisms and sensorimotor gating in that group of CD patients, whereas the modulatory effect of sensory inputs is lost in CD patients without sensory tricks.
Conflict of interest None.
Funding sources None.
12
References Albanese A, Bhatia K, Bressman SB, Delong MR, Fahn S, Fung VS, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013;28:863-73. Abbruzzese G, Berardelli A. Sensorimotor integration in movement disorders. Mov Disord 2003;18:231-40. Boelhouwer AJW, Teurlings RJMA, Brunia CHM. The effect of an acoustic warning stimulus upon the electrically elicited blink reflex in humans. Psychophysiology 1991;28:133-9. Carella F, Ciano C, Musicco M, Scaioli V. Exteroceptive reflexes in dystonia: a study of the recovery cycle of the R2 component of the blink reflex and of the exteroceptive suppression of the contracting sternocleidomastoid muscle in blepharospasm and torticollis. Mov Disord 1994;9:183-187. Costa J, Valls-Solé J, Valldeoriola F, Pech C, Rumià J. Single subthalamic nucleus deep brain stimuli inhibit the blink reflex in Parkinson's disease patients. Brain 2006;129:1758-67. Frauscher B, Löscher WN, Ehrmann L, Gschliesser V, Brandauer E, Högl B, et al. Narcolepsy-cataplexy: deficient prepulse inhibition of blink reflex suggests pedunculopontine involvement. J Sleep Res 2012;21:495-501. Galardi G, Perani D, Grassi F, Bressi S, Amadio S, Antoni M, et al. Basal ganglia and thalamo-cortical hypermetabolism in patients with spasmodic torticollis. Acta Neurol Scand 1996;94:172-6.
13
Gómez-Wong E, Martí MJ, Tolosa E, Valls-Solé J. Sensory modulation of the blink reflex in patients with blepharospasm. Arch Neurol 1998;55:1233-1237. Graham FK. Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psycophysiology 1975;12:238-48. Hallett M. Is dystonia a sensory disorder? Ann Neurol 1995;38:139-40. Hoffman HS, Ison JR. Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system process sensory input. Psychol Rev 1980;87:175-89. Ison JR, Sanes JN, Foss JA. Facilitation and inhibition of the human startle blink reflex by stimulus anticipation. Behav Neurosci 1990;104:418-29. Kagi G, Katschnig P, Fioro M, Tinazzi M, Ruge D, Rothwell J, et al. Sensory tricks in primary cervical dystonia depend on visuotactile temporal discrimination. Mov Disord 2013;28:356-61. Kanovský P, Bares M, Streitová H, Klajblová H, Daniel P, Rektor I. Abnormalities of cortical excitability and cortical inhibition in cervical dystonia Evidence from somatosensory evoked potentials and paired transcranial magnetic stimulation recordings. J Neurol 2003;250:42-50. Koch M, Kungel M, Herbert H. Cholinergic neurons in the pedunculopontin tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat. Exp Brain Res 1993;97:71-82. Kofler M, Kumru H, Schaller J, Saltuari L. Blink reflex prepulse inhibition and excitability recovery: influence of age and sex. Clin Neurophysiol 2013;124:126-35. 14
Kofler M, Halder W. Alterations in excitatory and inhibitory brainstem interneuronal circuits in fibromyalgia: evidence of brainstem dysfunction. Clin Neurophysiol 2014;125:593-601. Kumari V, Antonova E, Zachariah E, Galea A, Aasen I, Ettinger U, et al. Structural brain correlates of prepulse inhibition of the acoustic startle response in healthy humans. Neuroimage 2005;26:1052-8. Leon-Sarmiento FE, Peckham E, Leon-Ariza DS, Bara-Jimenez W, Hallett M. Auditory and Lower Limb Tactile Prepulse Inhibition in Primary Restless Legs Syndrome: Clues to Its Pathophysiology. J Clin Neurophysiol 2015;32:369-74. Li L, Frost BJ. Azimuthal directional sensitivity of prepulse inhibition of the pinna startle reflex in decerebrate rats. Brain Res Bull 2000;51:95-100. Müller J, Kofler M, Wenning GK, Seppi K, Valls-Solé J, Poewe W. Auditory startle response in cervical dystonia. Mov Disord 2003;18:1522-6. Naumann M, Magyar-Lehmann S, Reiners K, Erbguth F, Leenders KL. Sensory tricks in cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor programming. Ann Neurol 2000;47:322-8. Nishibayashi H, Ogura M, Kakishita K, Tanaka S, Tachibana Y, Nambu A, Kita H, Itakura T, et al. Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery. Mov Disord 2011;26:469-76. Patel N, Hanfelt J, Marsh L, Jankovic J; members of the Dystonia Coalition. Alleviating manoeuvres (sensory tricks) in cervical dystonia. J Neurol Neurosurg Psychiatry 2014;85:882-4.
15
Quartarone A, Hallett M. Emerging concepts in the physiological basis of dystonia. Mov Disord 2013;28:958-67. Rossi A, Scarpini C. Gating of trigemino-facial reflex from low-threshold trigeminal and extratrigeminal cutaneous fibres in humans. J Neurol Neurosurg Psychiatry 1992;55:774-80. Saitoh K, Tilson HA, Shaw S, Dyer RS. Possible role of the brainstem in the mediation of prepulse inhibition in the rat. Neurosci Lett 1987;75:216-22. Siggelkow S, Kossev A, Moll C, Däuper J, Dengler R, Rollnik JD. Impaired sensorimotor integration in cervical dystonia: a study using transcranial magnetic stimulation and muscle vibration. J Clin Neurophysiol 2002;19:232-9. Stamelou M, Edwards MJ, Hallett M, Bhatia KP. The non-motor syndrome of primary
dystonia:
clinical
and
pathophysiological
implications.
Brain
2012;135:1668-81. Swerdlow NR, Geyer MA. Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine tegmental nucleus. Behav Neurosci 1993;107:104-17. Valls-Solé J, Muñoz 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;115:1527-36. Valls-Sole J, Valldeoriola F, Molinuevo JL, Cossu G, Nobbe F. Prepulse modulation of the startle reaction and the blink reflex in normal human subjects. Exp Brain Res 1999;129:49-56.
16
Table 1. Comparisons of demographical and clinical of patients and healthy subjects. CD Patients
Healthy subjects
P
n=22
n=25
Age (years)
38.1±9.4
37.3±10.6
0.783
Gender M/F n (%)
5/17 (22.7/77.3)
12/13 (48/52)
0.072
Sensory trick n (%)
14 (63.6)
-
-
Botulinum toxin n (%)
11 (50)
-
-
TWSTRS score
32.6±10.9
-
-
CD, cervical dystonia; PPI, prepulse inhibition; TWSTRS, Toronto Western Spasmodic Torticollis Rating Scale. All comparisons were done using independent samples t-test or chi square test.
17
Table 2. Comparison of findings after test stimulus and prepulse inhibition in patients and healthy subjects. Patients
Healthy subjects
Test
PPI
p
Test
PPI
p
R1 latency (ms)
10.8±1.3
10.7±1.3
0.393
10.2±1.2
10.2±1.3
0.962
R1 amplitude (µV)
339.7±218.9
338.8±240.3
0.924
373.3±262.2
461.0±261.9
0.003**
R2 latency (ms)
31.9±3.7
34.5±4.4
0.011*
33.9±4.3
35.5±4.0
0.040*
R2 amplitude (µV)
316.4±132.9
187.1±108.3
0.000**
283.1±184.0
145.6±158.9
0.002**
R2 area (ms mV)
4.4±2.5
2.8±2.6
0.020*
3.6±2.2
1.0±1.1
0.000**
PPI, prepulse inhibition All comparisons were done using Wilcoxon test. *p<0.050; **p<0.010
18
Figure Legend
Figure 1. A. Raw and rectified images of the blink reflex after a test stimulus in a 48year-old woman with CD. B. Raw and rectified images of the blink reflex after a conditioned stimulus in the same patient. A higher R2 amplitude and larger R2 area can be seen after the conditioned stimulus. C. Raw and rectified images of the blink reflex after a test stimulus in a healthy 35-year-old woman. D. Raw and rectified images of the blink reflex after a conditioned stimulus in the same healthy subject.
19
20