Normal Intracortical Excitability in Developmental Stuttering

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1 826 M. SOMMER ET AL. netic link between these two conditions should be further investigated. Acknowledgments: This study was supported in part by Telethon (E 0722), the University of Genova (to F.A.), and the Ministero della Sanità (to P.M.). REFERENCES 1. Pahwa R, Koller C. Is there a relationship between Parkinson s disease and essential tremor? Clin Neuropharmacol 1993;16: Tan EK, Matsuura T, Nagamitsu S, Khajavi M, Jankovic J, Ashizawa T. Polymorphism of NACP-Rep1 in Parkinson s disease: an etiologic link with essential tremor? Neurology 2000;54: Kruger R, Vieira SA, Kuhn W, et al. Increased susceptibility to sporadic Parkinson s disease by a certain combined alphasynuclein/apolipoprotein E genotype. Ann Neurol 1999;45: Farrer M, Maraganore DM, Lockhart P, et al. -synuclein gene haplotypes are associated with Parkinson s disease. Hum Mol Genet 2001;10: Khan N, Graham E, Dixon P, et al. Parkinson s disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype. Ann Neurol 2001;49: Findley LJ, Koller WC. Definition and behavioral classification. In: Findley LJ, Koller WC, editors. Handbook of tremor disorders. New York, NY: Marcel Dekker, Inc; p Pigullo S, Di Maria E, Marchese R, et al. No evidence of association between CAG expansions and essential tremor in a large cohort of Italian patients. J Neural Transm 2001;108: Abbruzzese G, Pigullo S, Di Maria E, et al. Clinical and genetic study of essential tremor in the Italian population. Neurol Sci 2002;22: Sham P, Curtis D. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet 1995;59: Sham PC, Cherny SS, Purcell S, Hewitt JK. Power of linkage versus association analysis of quantitative traits, by use of variance-components models, for sibship data. Am J Hum Genet 2000;66: Brin MF, Koller W. Epidemiology and genetics of essential tremor. Mov Disord 1998;13(Suppl.): Chiba-Falek O, Nussbaum RL. Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. Hum Mol Genet 2001;10: Schrag A, Munchau A, Bhatia KP, Quinn NP, Marsden CD. Essential tremor: an overdiagnosed condition? J Neurol 2000;247: Findley LJ. Epidemiology and genetics of essential tremor. Neurology 2000;54(Suppl.):S8 S Illarioshkin SN, Ivanova-Smolenskaya IA, Rahmonov RA, Markova ED, Stevanin G, Brice A. Clinical and genetic study of familial essential tremor in an isolate of Northern Tajikistan. Mov Disord 2000;15: Raethjen J, Lindemann M, Schmaljohann H, Wenzelburger R, Pfister PG, Deuschl G. Multiple oscillators are causing Parkinsonian and essential tremor. Mov Disord 2000;15: Farrer M, Gwinn-Hardy K, Muenter M, et al. A chromosome 4p haplotype segregating with Parkinson s disease and postural tremor. Hum Mol Genet 1999;8: Normal Intracortical Excitability in Developmental Stuttering Martin Sommer, MD,* Stephan Wischer, MD, Frithjof Tergau, MD, and Walter Paulus, MD Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany Abstract: Persistent developmental stuttering (PDS) shares clinical features with task-specific dystonias. In these dystonias, intracortical inhibition is abnormally weak. We therefore sought to determine intracortical inhibition and intracortical facilitation in PDS. In 18 subjects with PDS since childhood (mean age, 39.4 [SD 13.0] years) and 18 speech-fluent controls (43.6 [14.3] years), we investigated resting and active motor thresholds as well as intracortical inhibition and facilitation of the optimal representation of the abductor digiti minimi of the dominant hand using transcranial magnetic stimulation. In PDS, the resting and active motor thresholds were increased, whereas intracortical inhibition and facilitation were normal. Normal intracortical excitability makes a pathophysiological analogy between focal dystonia and PDS less likely. The enhanced motor threshold suggests reduced motor cortical neuronal membrane excitability in PDS Movement Disorder Society Key words: persistent developmental stuttering; transcranial magnetic stimulation; intracortical excitability Persistent developmental stuttering (PDS) is characterized by intermittent dysfluencies of speech acquired in childhood that are persistent after puberty. The core symptoms are repetitions and prolongations of syllables or sounds, and transient cessation of speech due to a freezing of muscles of respiration, phonation, and articulation. 1 PDS is one of the most frequent speech disorders, affecting approximately 1% of the population. PDS affects males more often than females, at a ratio of about 3 to 4:1. 2,3 In contrast to neurogenic, late-onset stuttering, PDS is not linked to evident brain damage by trauma or stroke; morphological abnormalities are more subtle and comprise a disconnection of the left Rolandic operculum 4 and slight gyral abnormalities of the adjacent left prefrontal operculum. 5 Clinically, PDS shares features of task-specific dystonias. Both disorders are task-specific disorders of fine *Correspondence to: Martin Sommer, Department of Clinical Neurophysiology, University of Göttingen, Robert-Koch-Str. 40, D Göttingen, Germany. msommer@gwdg.de Received 24 April 2002; Revised 6 November 2002; Accepted 2 December 2002

2 INTRACORTICAL EXCITABILITY IN STUTTERING 827 motor control that present with an excessive activation of task-related and task-unrelated muscles. 6 Both PDS and focal dystonias are accentuated by emotional stress, are likely to have a genetic predisposition, and may occur during childhood or early adolescence. 2,7,8 These clinical similarities incited speculations as to whether PDS may be a task-specific dystonia. 9 PDS and dystonias differ in regard to the gender ratio, with males affected predominantly by PDS 2 and females by focal dystonias, and the age of onset, which is usually earlier in PDS than in focal dystonias. 2,8 A reduced intracortical inhibition in the focal dystonia of writer s cramp 10 has been demonstrated with a conditioning-test paired-pulse design of transcranial magnetic stimulation (TMS). 11,12 We extended that finding to the cortical representation of a hand muscle (abductor digiti minimi, ADM) of patients with the cranial dystonia of blepharospasm. 13 This suggests that in cranial dystonias the disturbed tuning between motor cortical inhibition of facilitation spreads to the cortical representation of clinically uninvolved hand muscles. Based on the clinical similarities of PDS and writer s cramp, we hypothesized that intracortical inhibition may be reduced in PDS. SUBJECTS AND METHODS We investigated 18 subjects with PDS (mean age SD, years). They were recruited from the Göttingen stuttering self-help group and by advertisement at the University campus. At the beginning of the study, they were asked to give a report of their current activities and of their history of speech dysfluencies. All subjects showed core symptoms of stuttering (repetitions and prolongations of sounds, and speech blocks) 1 in that interview. As healthy controls, we studied 18 subjects speech-fluent in a similar interview and with no personal history of stuttering (mean age, years). None of the subjects showed neurological or medical abnormality on routine examination; all had at least 8 of 10 points for right-handedness on the Oldfield handedness questionnaire. 14 None of the subjects were taking CNSactive drugs at the time of the study. The protocol was approved by the ethics committee of the University of Göttingen, and written informed consent was obtained from all participants. While the participants were sitting in a reclining chair, we delivered transcranial magnetic stimulation over the optimal representation of the ADM of the dominant hand. Stimuli were generated by two Magstim 200 stimulators connected via a bistimulation module to a figureof-eight coil in which each wing had an outer diameter of 7 cm (Magstim Company, Whitland, Dyfed, UK). The coil was held in the optimal position, i.e., tangentially to the skull with the handle pointing backwards at about 45 laterally. We recorded motor evoked potentials (MEPs) from the ADM using silver silver chloride electrodes in a belly tendon montage and a digital device at a sampling rate of 5 khz (Synamps; Neuroscan, Herndon, VA), recording 50 msec of prestimulus EMG to assess muscle relaxation. Data was filtered at 10 Hz and 2.5 khz. Reducing the stimulus intensity in steps of 1%, we defined the resting motor threshold (RMT) as the lowest intensity at which at least 5 of 10 consecutive MEPs were 50 V in amplitude while the investigated muscle was at rest. Audio-visual EMG feedback was provided to control for muscle relaxation. The lowest intensity at which 5 of 10 consecutive MEPs were 200 to 300 V in amplitude during voluntary abduction of the small finger was set as active motor threshold (AMT). 15 For intracortical excitability, we delivered conditioning-test paired TMS pulses that consisted of a subthreshold conditioning stimulus (90% AMT) followed by a test pulse yielding MEPs of 1 mv after an interval of 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, or 30 msec, each interval being tested at least 10 times in random order. The MEPs elicited by the paired stimuli were expressed as a percentage of the MEP induced by the intermixed single test pulses. Trials with imperfect muscle relaxation in the prestimulus recording were rejected. To test whether the higher conditioning pulse intensity in the stuttering group distorted the results, we also studied intracortical excitability in 3 stuttering subjects (2 men, 1 woman; mean age, 51.3 years) using conditioning stimulus intensities of 70, 80, and 90% AMT, test pulses yielding MEPs of 1 mv, and conditioning-test intervals of 1, 2, 3, 4 and 10 msec, each interval being tested at least 10 times in random order. Data analysis was identical to the principal experiment. For correlation analysis, we calculated Pearson s correlation coefficient. All results are indicated as mean value SD, and the level of significance was set at P RESULTS In 2 subjects with PDS not included in the analysis, motor thresholds were too high to evoke reliable MEPs. In the remaining 16 subjects with PDS, mean motor thresholds were significantly higher than in controls (unpaired, two-tailed t test; RMT, P 0.04; AMT, P 0.02; Fig. 1). Consequently, the mean conditioning pulse of the paired-pulse paradigm was higher in subjects with PDS ( % of stimulator output) than in controls ( % unpaired, two-tailed t test, P 0.02), as

3 828 M. SOMMER ET AL. FIG. 1. Transcranial magnetic stimulation motor threshold for evoking motor evoked potentials in the resting or voluntarily activated abductor digiti minimi muscle of the dominant hand (mean SD). *Significant between-group difference (two-tailed, unpaired t tests, P 0.04). Note that motor thresholds are higher in the subjects with PDS. was the test pulse ( vs % unpaired, two-tailed t test, P 0.19). The intracortical inhibition was similar in subjects with PDS and controls. There was no significant difference at any interstimulus interval (two-tailed, unpaired t tests, P 0.1), or for the pool of inhibitory intervals (unpaired, two-tailed t test of intervals 1 4 msec, P 0.28; Fig. 2). The control experiment showed that reduced conditioning pulse intensities are less effective (Fig. 3). Hence, adjusting the conditioning pulse to the increased AMT in the stuttering group is necessary to detect the maximum intracortical excitability present in that group. The resting and active motor thresholds were not correlated strongly with age either in subjects with PDS or in controls; correlation coefficients were between 0.25 and DISCUSSION To our knowledge, this was the first assessment of motor thresholds and intracortical excitability in PDS. Our results for intracortical excitability were within normal ranges and did not match the reduced intracortical inhibition reported for writer s cramp 10 and for blepharospasm. 13 Apparently, the pathophysiology of PDS is distinct from that of focal dystonias. This conclusion was supported further by the threshold elevation we found in PDS, because motor thresholds have been reported as unchanged in focal dystonias. 10,13,16 The intracortical inhibition is likely mediated by inhibitory motor cortical interneurons. 17 Its reduction in focal dystonia suggests that these interneurons are under direct or indirect control of the basal ganglia output neurons. 10 The reduced inhibition is rather unspecific, because it has been reported in a variety of neurological and psychiatric disorders. 18 Intracortical inhibition is altered by drugs affecting dopaminergic, GABAergic, or glutamatergic transmission (see Ziemann et al. 18 for overview). Our results suggested that synaptic transmission by these transmitters is unaffected in the motor cortex of subjects with PDS. Motor thresholds show some interindividual variability, 19 possibly related to the positioning of motor neurons and their afferent interneurons within the motor cortex, or to the density of corticospinal connections. 18,20 Clinical studies demonstrated normal motor thresholds in focal dystonia. 10,13,16 The motor threshold is decreased after transient 21 or permanent deafferentation, 22 but increased after lesions of the corticospinal tract, as in the course of amyotrophic lateral sclerosis 23,24 or after stroke. 25,26 We conclude that corticospinal motor tract excitability is abnormally high in PDS. The pattern of increased motor threshold and normal intracortical inhibition is reminiscent of the effect of the sodium channel blockers in controls. 27 An artifact of increased arousal in the PDS group is unlikely, because 1) prestimulus recordings of the recordings accepted for analysis did not show increased voluntary muscle activity; and 2) increased arousal would be expected to lower the motor thresholds rather than increase them. 28 One may object that the abductor digiti minimi is not a suitable muscle for studying PDS, and that a facial or FIG. 2. Intracortical excitability from a conditioning-test paired-pulse transcranial magnetic stimulation paradigm in 16 subjects with PDS and 18 age-matched controls. Conditioned motor evoked potentials are expressed in percent of the unconditioned response (dashed line). Note that the groups yield virtually identical results for inhibition (interstimulus intervals, 1 5 msec) and for facilitation (6 20 msec). All symbols represent the mean SD.

4 INTRACORTICAL EXCITABILITY IN STUTTERING 829 FIG. 3. Control experiment testing the intracortical excitability in 3 stuttering subjects at three different levels of conditioning pulse intensity. As in Figure 2, conditioned motor evoked potentials are expressed in percent of the unconditioned response (dashed line). The findings indicate that conditioning pulse intensities that are too low yield artificially low levels of intracortical inhibition. Hence, in the principal experiment it was necessary to adjust the conditioning pulse to the higher AMT of the stuttering subjects. All symbols represent the mean SD. laryngeal muscle may have been more appropriate. The main argument for choosing the ADM was a technical one. In our experience, noninvasive surface EMG traces from facial muscles are contaminated usually by considerable background noise, making reliable assessment of intracortical excitability very difficult. Two other arguments supported the choice of a small hand muscle. First, speech muscle representations are linked closely to and reflect the excitability of hand muscle representations, as has been shown in a study of hand muscle MEP facilitation during speech. 29 Second, reduced intracortical inhibition in dystonia is not limited to the representation of the body part affected clinically, but is much more widespread, involving hand muscle representations in cranial dystonia 13 and even contralateral hand muscle representations in unilateral writer s cramp. 10 Hence, if there was a reduced intracortical inhibition in a face or speech muscle representation, there is good reason to expect that it would be present in hand muscle representations as well. In summary, our results make a pathophysiological analogy between focal dystonias and PDS less likely. Acknowledgments: This study has been supported by a grant from the Bundesministerium für Bildung und Forschung of the Federal Republic of Germany ( C-1059). Part of this work was presented previously in abstract form. 30 REFERENCES 1. Bloodstein O. A handbook on stuttering, Fifth ed. San Diego: Singular Publishing Group; Yairi E, Ambrose NG. Early childhood stuttering I: persistency and recovery rates. J Speech Lang Hear Res 1999;42: Natke U. Stottern: Erkenntnisse, Theorien, Behandlungsmethoden. Bern, Göttingen, Toronto, Seattle: Hans Huber Verlag; Sommer M, Koch MA, Paulus W, Weiller C, Büchel C. Disconnection of speech-relevant brain areas in developmental stuttering. Lancet 2002;360: Foundas AL, Bollich AM, Corey DM, Hurley M, Heilman KM. Anomalous anatomy of speech-language areas in adults with persistent developmental stuttering. Neurology 2001;57: Berardelli A, Rothwell JC, Hallett M, Thompson PD, Manfredi M, Marsden CD. The pathophysiology of primary dystonia. Brain 1998;121: Paden EP, Yairi E, Ambrose NG. Early childhood stuttering II: initial status of phonological abilities. J Speech Lang Hear Res 1999;42: Müller F, Dichgans J, Jankovic J. Dyskinesias. In: Brandt T, Caplan L, Dichgans J, Diener HC, Kennard C, editors. Neurological disorders: course and treatment. New York: Academic Press; Kiziltan G, Akalin MA. Stuttering may be a type of action dystonia. Mov Disord 1996;11: Ridding MC, Sheean G, Rothwell JC, Inzelberg R, Kujirai T. Changes in the balance between motor cortical excitation and inhibition in focal, task specific dystonia. J Neurol Neurosurg Psychiatry 1995;59: Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P, Marsden CD. Corticocortical inhibition in human motor cortex. J Physiol 1993;471: Ziemann U, Rothwell JC, Ridding MC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol 1996;496: Sommer M, Ruge D, Tergau F, Beuche W, Altenmüller E, Paulus W. Intracortical excitability in the hand motor representation in hand dystonia and blepharospasm. Mov Disord 2002;5: Oldfield RC. The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 1971;9: Rothwell JC, Hallett M, Berardelli A, Eisen A, Rossini P, Paulus W. Magnetic stimulation: motor evoked potentials. In: Deuschl G, Eisen A, editors. Recommendations for the practice of clinical neurophysiology: guidelines of the international federation of clinical neurophysiology. Amsterdam: Elsevier Science BV; p Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition in writer s cramp during voluntary muscle activation. Neurology 1997;49: Hallett M. Transcranial magnetic stimulation and the human brain. Nature 2000;406: Ziemann U, Hallett M. Basic neurophysiological studies with TMS. In: George MS, Belmaker RH, editors. Transcranial magnetic stimulation in neuropsychiatry. Washington, DC: American Psychiatric Press; p Sommer M, Wu T, Tergau F, Paulus W. Intra- and interindividual variability of motor responses to repetitive transcranial magnetic stimulation. Clin Neurophysiol 2002;113: Chen R, Tam A, Butefisch C, Corwell B, Ziemann U, Rothwell JC, Cohen LG. Intracortical inhibition and facilitation in different representations of the human motor cortex. J Neurophysiol 1998; 80: Sommer M, Canelo M, Tergau F, Paulus W. Periphere Eis-Applikation bei Morbus Parkinson lindert den Tremor und disinhibiert kortikospinale motorische Bahnen. Klinische Neurophysiologie 2000;31:185.

5 830 M. SOMMER ET AL. 22. Chen R, Corwell B, Yaseen Z, Hallett M, Cohen LG. Mechanisms of cortical reorganization in lower-limb amputees. J Neurosci 1998;18: Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 1997;49: Sommer M, Tergau F, Wischer S, Reimers CD, Beuche W, Paulus W. Riluzole does not have an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral sclerosis. J Neurol 1999;246(Suppl.): Traversa R, Cicinelli P, Oliveri M, Giuseppina Palmieri M, Filippi MM, Pasqualetti P, Rossini PM. Neurophysiological follow-up of motor cortical output in stroke patients. Clin Neurophysiol 2000; 111: Byrnes ML, Thickbroom GW, Phillips BA, Mastaglia FL. Longterm changes in motor cortical organisation after recovery from subcortical stroke. Brain Res 2001;889: Ziemann U, Lonnecker S, Steinhoff BJ, Paulus W. Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study. Ann Neurol 1996;40: Ridding MC, Taylor JL, Rothwell JC. The effect of voluntary contraction on cortico-cortical inhibition in human motor cortex. J Physiol (Lond) 1995;487: Tokimura H, Tokimura Y, Oliviero A, Asakura T, Rothwell JC. Speech-induced changes in corticospinal excitability. Ann Neurol 1996;40: Sommer M, Wischer S, Tergau F, Paulus W. Intracortical excitability in developmental stuttering. J Neurol 2001;248(Suppl.):47.

Riluzole does not have an acute effect on motor thresholds and the intracortical excitability in amyotrophic lateral sclerosis

J Neurol (1999) 246 [Suppl 3]: III/22 III/26 Steinkopff Verlag 1999 Martin Sommer Frithjof Tergau Stephan Wischer Carl-D. Reimers Wolfgang Beuche Walter Paulus Riluzole does not have an acute effect on