Effect of Bilateral Stimulation of the Subthalamic Nucleus on Parkinsonian Voice

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1 Brain and Language 78, (2001) doi: /brln , available online at on Effect of Bilateral Stimulation of the Subthalamic Nucleus on Parkinsonian Voice M. Gentil, P. Chauvin, S. Pinto, P. Pollak, and A. L. Benabid INSERM, Unité 318, Centre Hospitalier Universitaire de Grenoble, Grenoble, France Published online June 21, 2001 The purpose of this study was to assess several acoustic features of the voices of 26 parkinsonian patients under two conditions, with and without bilateral chronic stimulation of the subthalamic nucleus (STN) to estimate the effectiveness of this procedure on parkinsonian speech. When compared to unstimulated patients, stimulated patients showed longer duration of sustained vowels, shorter duration of sentences, nonsense words, and pauses, more variable fundamental frequency ( f 0) in sentences, and more stable f 0 during sustained vowels. Relative intensity was unchanged in both conditions. Further acoustic analyses are warranted to clarify the role of STN stimulation on parkinsonian speech Academic Press Key Words: Parkinson s disease; surgical treatment; subthalamic nucleus stimulation; dysarthria; voice; acoustic analysis. Voice abnormalities of patients with Parkinson s disease (PD) include breathy or rough voice quality (Darley, Aronson, & Brown, 1969; Hanson, Geratt, & Ward, 1984; Logemann et al., 1978), monotonous voice reduced in pitch and loudness variability (Aronson, 1990; Brin et al., 1992; Cummings et al., 1988), reduced loudness (Adams & Lang, 1992; Ramig, 1995), and short rushes of speech and long-duration silent hesitations (Illes, 1989; Netsell, Daniel, & Celesia, 1975). Given the frequency of occurrence of voice disorders among patients with PD, phonatory capabilities should be quantified for research objectives, mostly to provide baseline data from which to consider treatment-related changes. Levodopa therapy is an efficient treatment for PD, but long-term dopaminergic therapy is often complicated by motor fluctuations difficult to control. Advances in understanding the basal ganglia and its role in the pathogenesis of PD (Alexander et al., 1990; DeLong, 1990) coupled with refinements in imaging and surgical techniques have renewed interest in the surgical treatment of PD. In particular, since 1993, stimulation of the STN has been used to treat patients with disabling PD and severe motor fluctuations. Stimulation of the STN is effective for the main signs of parkinsonism bradykinesia, rigidity and tremor and greatly improves parkinsonian motor disability (Limousin et al., 1995, 1998; Krack et al., 1997). Although the effectiveness of this procedure on the articulatory organs is known (Gentil et al., 1999) the precise effect of STN stimulation on parkinsonian voice is not. It is important to evaluate this effect because we know that electrical stimulations of other targets, such as the ventral intermediate nucleus of the thalamus (VIM), have detrimental Address correspondence and reprint requests to Michèle Gentil, Centre Hospitalier Universitaire de Grenoble, Service Neurologie, BP 217, Grenoble cedex 9, France X/01 $35.00 Copyright 2001 by Academic Press All rights of reproduction in any form reserved.

2 234 GENTIL ET AL. effects on speech (Benabid et al., 1996; Gentil et al., 2000). To estimate the effectiveness of bilateral STN stimulation on parkinsonian voice, analysis of the acoustic parameters of duration, fundamental frequency, and relative intensity in various speech tasks was performed in PD patients without medication under two conditions: with bilateral stimulation and without stimulation. Subjects METHODS Twenty-six idiopathic PD patients (13 males and 13 females) participated in this study. They underwent bilateral stereotaxic electrode implantation into the STN for chronic high stimulation. The main steps of this surgical procedure were the following. The target (subthalamic nucleus) was located using imaging (ventriculography and magnetic resonance imaging) and electrophysiology. The electrode was implanted in stereotaxic conditions under local anesthesia, so the effect of electrical stimulation on parkinsonian features could be assessed. Subsequently, the electrode was connected to a pulse generator implanted in the subclavicular area. The electrode for chronic stimulation includes four contacts and one was selected as a cathode. The voltage, the frequency, and the pulse width delivered by the pulse generator were adjusted (Benabid et al., 1998; Caparros-Lefebvre et al., 1999). At the time of surgery the mean (standard deviation) age of the patients was 55 (7) years and the mean duration of symptoms was 14 (4) years. Acoustical evaluations were performed within a period of 3 months to 3 years after surgery. The selection criteria were the patients consent and their speech impairment evaluated without medication and without stimulation as moderate by a neurologist, with the item 18, speech, in part 3 of the Unified Parkinsons s disease rating scale (UPDRS), a qualitative scale (Fahn et al., 1987), as well as judged by our own perception. No patient had been under voice therapy. This study was approved by the Grenoble University Hospital ethics committee. Speech Sample and Rationale Subjects were required to (1) sustain the vowels /a/ and /i/ for as long and as steadily as possible on a single deep breath (three times); (2) repeat a same phrase Le petit chat joue avec la balle without stopping for 30 s; (3) produce short sentences C est bas. Qu en pensez-vous? at a conversational speaking rate (three times); (4) produce three words, pas, passe, passe-temps, at a conversational speaking rate; and (5) repeat the nonsense words /epapap/ and /pataka/ at a conversational speaking rate and as fast as possible, respectively (five times). Four measures were obtained from the sustained vowels: mean fundamental frequency ( f 0) and standard deviation (SD) indicating variability of f 0, mean relative intensity and SD, maximum duration. In particular, these last two variables assessed rigidity in respiratory musculature and reduced inspiratory and expiratory volumes (King et al., 1994). During the repetition of a same phrase for 30 s, the number and duration of pauses associated with inspiratory and expiratory volumes were measured as well as the relative intensity associated with vocal fold adduction. Affirmative and interrogative phrases were used to measure the variability of f 0 in relation to rigidity in laryngeal muscles, especially in the cricothyroid muscles responsible for controlling pitch changes (Aronson, 1990), and incomplete closure of vocal cords. In total, 78 phrases had a statement intonation and 78 phrases had a question intonation. Production of the one- to three-syllable words was included for the purpose of determining if patients with PD adjusted syllable duration to the number of syllables in the word. For normal speakers, it is known that the base word duration decreases as the number of syllables increases from one to three (Lehiste, 1972). Nonsense words were chosen to determine overall speech duration, at various speaking rates. Data Collection and Analysis Voice recordings were obtained with each patient seated in a Faraday cage and fitted with an ATM 71 head-worn microphone (Audio Technica, Stow, OH, U.S.A.). Sound was recorded at a sampling frequency of 16 khz using the software program Phonedit (SQ Lab, Aix en Provence, France). The purpose of this study was to yield quantitatively based conclusions regarding the change in acoustic parameters of phonation for PD patients treated with stimulation of STN. Consequently, the patients were evaluated in the morning after a period of at least 10 h without medication under two conditions: during bilateral STN stimulation and 30 min after stopping STN stimulation.

3 STN STIMULATION EFFECT ON VOICE IN PD 235 In addition, the motor disability of the patients was assessed in each condition by means of Part 3 of the UPDRS using a 0 (no impairment) to 4 (severe impairment) scale, maximum score, 108). In particular, speech was evaluated with item 18 of the UPDRS: 0 normal; 1 slight loss of expression, diction, and/or volume; 2 monotone, slurred but understandable, moderately impaired; 3 marked impairment, difficult to understand; 4 unintelligible. The voice analysis program Phonedit of SQ Lab was used. The fundamental frequency referring to the first harmonic of the voice was computed using a method of temporal detection called AMDF (average magnitude difference function). First, the acoustic signal was filtered, and then one window of the signal was moved until it met a similar zone of the signal, thus allowing us to determine f 0 (Ross et al., 1974). Intensity was computed using a temporal method, rms (root mean square), that is, the mean amplitude of a signal during integration time (10 ms). For measurement of duration each phonation was displayed, and cursors were placed to mark the onset and offset of each segment to measure. The results for males and females are presented separately and without comparison between them because the physiology of males and females being different, the values of certain variables, especially f 0, vary according to sex. The statistical analysis used Minitab (State College, PA, U.S.A.) and included t tests to estimate significant differences (p.05) between patients with and without stimulation. RESULTS UPDRS Score The motor disability of all the patients, assessed by means of the UPDRS, was improved with bilateral stimulation of the subthalamic nuclei. The percentage of improvement was 57% for males and 59% for females. Speech impairment (item 18 of the UPDRS) was also improved. For males as well as females the median speech score before STN stimulation was 2 and after STN stimulation it was 1. Duration When compared to patients with stimulation, patients without stimulation showed a shorter maximal phonation time of sustained vowels /a/ and /i/ (Table 1) and a longer duration of the nonsense word /pataka/ repeated five times at a fast speaking rate, with a significant difference between both conditions of examination for the males (Fig. 1). Duration of the phrases C est bas. Qu en pensez-vous? at a conversational speaking rate was barely longer in patients without stimulation than in patients with stimulation and no significant difference was noted between both conditions. For males, these durations were 1.41 s without stimulation and 1.39 s with stimulation; for females, they were 1.56 and 1.54 s, respectively. Production of the three words pas, passe, passe-temps indicated that parkinsonian patients without or with stimulation adjusted the base word duration to the number of syllables in the word. Thus, concerning stimulated patients the average duration of base word in twosyllable words was 78% (for males) and 75% (for females) of the average duration in the one-syllable word. The base word duration in three-syllable words was 38% TABLE 1 Maximal Phonation Time [and (SD)] in Seconds for the Sustained Vowels /a/ and /i/ in Males and Females, with and without Stimulation Males Females With stimulation Without stimulation With stimulation Without stimulation /a/ (5.2) 7.53 (3.9)* 8.16 (4.0) 7.25 (4.6) /i/ (5.1) 8.24 (4.8) 8.95 (4.3) 6.62 (3.5) * p.05.

4 236 GENTIL ET AL. FIG. 1. Mean and standard deviation of the overall duration of the nonsense word /pataka/ at a fast speaking rate for males and females. (for males and females) of that for a single-syllable word. The unstimulated patients showed a quite similar reduction of syllable duration. Pause Detections When compared to stimulated patients, unstimulated patients reported a larger duration of pauses, mostly in males. The ratio pause duration divided by overall duration was 19% in stimulated patients versus 26% in unstimulated for the males and 9% in stimulated patients versus 11.4% in unstimulated for the females. Fundamental Frequency Analysis of fundamental frequency during sustained vowels indicated that the mean f 0 was higher in patients without stimulation than in patients with stimulation. For example, for sustained /a/ in males a significant difference (p.05) was noted between conditions; the mean f 0 was 129 Hz in unstimulated patients and 105 Hz in stimulated patients. In addition, during sustained vowels the mean value of standard deviation of f 0 was significantly larger in patients without stimulation, indicating a larger variability of f 0. This observation was available for males and females. Figure 2 shows the f 0 signal of the sustained vowel /a/, for female patient 6, mean f Hz with stimulation (top) and 197 Hz without stimulation (bottom). Analysis of f 0 during production of the phrases C est bas. Qu en pensez-vous? revealed a larger variability of f 0 between the beginning and end of each phrase for stimulated patients than for unstimulated patients. Figure 3 shows this variability in males for the C est bas and Qu en pensez-vous? difference between /ε/ in c est and /a/ in bas, that is, 18 Hz for stimulated patients versus 13 Hz for unstimulated patients; the difference between /ã/ in qu en and /u/ in vous, that is, 9 Hz for stimulated patients versus 4 Hz for unstimulated patients.

5 STN STIMULATION EFFECT ON VOICE IN PD 237 FIG. 2. The f 0 signal of the sustained vowel /a/, female patient 6, mean f Hz with stimulation (top) and 197 Hz without stimulation (bottom). Vocal Intensity Concerning mean values of relative intensity during sustained vowels, no difference was noted between conditions of examination. These values were slightly larger for males than for females; that is, they were increased by 4 to 5 db. In addition, the standard deviation was not significantly different between the stimulated and unstimulated patients in males and females. Relating to the repetitions of the phrase le petit chat joue avec la balle for 30 s, no significant difference was observed between conditions (with stimulation and without stimulation) for the relative intensity of the vowel /a/ in /ʃa/ of the FIG. 3. Variability of the f 0 in the phrases C est bas. Qu en pensez-vous? with and without stimulation, for males.

6 238 GENTIL ET AL. first repetition as well as for the relative intensity of the vowel /a/ in /ʃa/ of the last repetition. This observation was available for males and females. DISCUSSION In this study, selected patients were characterized by analogous speech impairment without medication and without stimulation and similar duration of symptoms. This criterion was important from our point of view, given the progressive deterioration of phonatory capabilities in PD patients voices during the evolution of the disease (King et al., 1994). Cautious interpretation of the results is necessary. These are typical of the selected patients whose speech impairment was generally assessed as moderate (without medication and without stimulation). They could be different for other parkinsonian patients with severe dysarthria. Motor control improvement by the bilateral stimulation of the STN reflects the good sensitivity of the parkinsonian syndrome to STN stimulation. The item dysarthria of the UPDRS was also improved. However, the use of a qualitative five-point scale to precisely estimate speech disorders is inadequate and measurements of the acoustical signal turned out to be necessary to confirm perceptual assessment, in particular with regard to the voice. Stimulation favorably influenced the patients voices. In stimulated patients we noted a longer maximal phonation time of sustained vowels as well as a reduction of the pauses in phrase repetitions for 30 s. These results provide information regarding the effect of STN stimulation on patients respiratory and laryngeal conditions. The underlying physiological changes could involve increased vocal fold adduction and increased inspiratory and expiratory volumes. In addition, sustained vowels provided a test to examine phonatory stability avoiding interference from speech prosody and articulation (Barken & Orlikoff, 1992). Fewer irregular changes of the f 0 contours of isolated vowels were found in stimulated patients, as indicated by standard deviation. Finally, the higher f 0 of sustained vowels in unstimulated patients compared to stimulated patients called to mind some observations relative to the measurement of f 0. Thus, Canter (1963) showed that male PD patients had a mean f 0 of 129 Hz, higher than the f 0 in the control group (106 Hz), and Metter and Hanson (1986) observed that the mean f 0 increased with increased clinical disability evaluated using the Webster scale. The variability of f 0 in phrases reflects frequency variation associated with intonation. The lack of variability in the f 0 contours of phrases corresponded to a reduced efficiency of the laryngeal muscles, confirming a muscular rigidity often found in PD (Weismer, 1984), especially in the cricothyroid muscles responsible for controlling pitch change (Aronson, 1990). Variation in f 0 was more restricted in the sentences produced by unstimulated patients and suggested a larger laryngeal rigidity. Indeed, with STN stimulation, parkinsonian patients varied intonation contour more easily and their speech sounded more normal and natural. The parkinsonian patients with and without stimulation made, as healthy subjects (Gentil, 1990), normal adjustments of the syllable duration of the base word as the number of syllables in the word was increased. Syllable reduction requires a flexible and responsive capacity for sequencing complex motor instructions. Whereas the behavioral deficits concerning the execution of sequential motor tasks in PD are known (Benecke et al., 1987; Harrington & Haaland, 1991) the capability of controlling an appropriate reduction of the base syllable indicated that patients with PD can compute the general program of an action that takes into account extrinsic properties of the final target. Similar observations were reported for motor acts of limbs in PD (Gentilucci & Negrotti, 1999).

7 STN STIMULATION EFFECT ON VOICE IN PD 239 There is a certain amount of disagreement in the literature concerning the characteristic speaking rate of patients with PD. Patients ability to repeat syllables rapidly has been investigated. Canter (1965) reported that the PD patients were impaired in their ability to produce rapid articulatory movements. The duration of repetitions of /pataka/ at a fast speaking rate was longer in patients without stimulation. For these utterances we should point out that the intersubject variability was particularly high in females. On the contrary, the duration of the phrases at a conversational speaking rate was similar with and without stimulation. However, a shortening of pauses was remarked in utterance repetitions of the stimulated patients, indicating a more fluent and natural speech. Indeed, Metter et al. (1986) noted that one of the most variable features of hypokinetic dysarthria is speaking rate. The effects of STN stimulation on vocal intensity were less evident. The measures of relative intensity were not modulated consistently by STN stimulation treatment. These results deserve some comments. Overall vocal intensity level and range is highly variable depending on the severity of the disease (Ludlow & Bassich, 1984). Whereas the patients in this study had a generally moderate speech impairment, improvement in vocal intensity by STN stimulation could have been more sensible in patients suffering from severe dysarthria. In conclusion, bilateral STN stimulation influences speech. In a previous study (Gentil et al., 1999), we noted a significant improvement in the force of the articulatory organs and we showed in the present study a tendency for voice to improve. Further speech investigations, in a large number of parkinsonian patients suffering from more or less severe dysarthria, are necessary to clarify the impact of this surgical procedure on speech. REFERENCES Adams, S. G., & Lang, A. E. (1992). Can the Lombard effect be used to improve low voice intensity in Parkinson s disease? European Journal of Disorders of Communication, 27, Alexander, G. E., & Crutcher, M. D. (1990). Functional architecture of basal ganglia circuits: Neural substrates of parallel processing. Trends in Neuroscience, 13, Aronson, A. (1990). Clinical voice disorders. New York: Thième Stratton. Baken, R. J., & Orlikoff, R. F. (1992). Acoustic assessment of vocal function. In A. Blitzer, M. P. Brin, C. T. Sasaki, S. Fahn, & K. S. Harris (Eds.), Neurological disorders of the larynx. New York: Thième. Pp Benabid, A. L., Pollak, P., Gao, P., et al. (1996). Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. Journal of Neurosurgery, 11, Benabid, A. L., Benazzouz, A., Hoffmann, D., Limousin, P., Krack, P., & Pollak, P. (1998). Long-term electrical inhibition of deep brain targets in movement disorders. Movement Disorders, 13, Benecke, R., Rothwell, J. C., Dick, J. P. R., Day, B. L., & Marsden, C. D. (1987). Disturbance of sequential movements in patients with Parkinson s disease. Brain, 110, Brin, M. F., Fahn, S., Blitzer, A., Ramig, L. O., & Stewart, C. (1992). Movement disorders of the larynx. In A. Blitzer, M. F. Brin, C. T. Sasaki, S. Fahn, & K. S. Harris (Eds.), Neurological disorders of the larynx. New York: Thième. Pp Canter, G. J. (1963). Speech characteristics of patients with Parkinson s disease: I. Intensity, pitch and duration. Journal of Speech and Hearing Disorders, 28, Canter, G. J. (1965). Speech characteristics of patients with Parkinson s disease: III Articulation, diadochokinesia, and overall speech adequacy. Journal of Speech and Hearing Disorders, 30, Capparros-Lefebvre, D., Blond, S., N Guyen, J. P., Pollak, P., & Benabid, A. L. (1999). Chronic deep brain stimulation for movement disorders. In E. F. Cohadon (Ed.), Advances and technical standards in neurosurgery. Vienna: Springer-Verlag. Pp

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