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Decrease of middle cerebral artery blood flow velocity after low-frequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex
Clinical Neurophysiology 113 (2002) 951–955 www.elsevier.com/locate/clinph
Decrease of middle cerebral artery blood flow velocity after lowfrequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex Jens D. Rollnik a,*, Ariane Du¨sterho¨ft a, Jan Da¨uper a, Andon Kossev b, Karin Weissenborn a, Reinhard Dengler a a
Department of Neurology and Clinical Neurophysiology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30623, Hannover, Germany b Department of Biophysics, Bulgarian Academy of Sciences, Sofia, Bulgaria Accepted 2 March 2002
Abstract Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in a variety of neuropsychiatric disorders. Both, inhibition and activation of cortical areas may be achieved using different stimulation parameters. Using low-frequency rTMS (0.9 Hz), inhibition of cortical areas can be observed. Methods: In the present study, 38 right-handed, healthy, normotensive subjects (aged 21–50 years, mean 30.2 years, SD ¼ 4:9; 17 women) were enrolled. Twenty-five participants received active rTMS (5 min of 0.9 Hz rTMS, stimulus intensity 90% of motor threshold) of the right dorsolateral prefrontal cortex. Sham stimulation (n ¼ 13 subjects) occurred in the same manner as active rTMS, except that the angle of the coil was at 458 off the skull. Simultaneously, ipsilateral and contralateral maximal middle cerebral artery (MCA) flow velocity (and pulsatility index, PI) was monitored using transcranial Doppler sonography. Results: In the group with active rTMS, maximal MCA flow velocity decreased from a baseline (before rTMS) of 101.6 cm/s (SD ¼ 26:0) to a mean of 92.6 cm/s (SD ¼ 23:7) immediately after rTMS, T ¼ 5:06, P , 0:001. This equals a mean decrease of 9.0 cm/s (SD ¼ 8:3) or approximately 8.9% of baseline flow. Five and 10 min after rTMS, there was a return to baseline. PI significantly decreased 10 min after rTMS (mean difference 20.05, SD ¼ 0:05, T ¼ 2:29, P , 0:05). In the contralateral MCA, maximal flow velocity tended to increase 10 min after rTMS (mean difference 17.4 cm/s, SD ¼ 17:5; T ¼ 22:03, P ¼ 0:054). With sham rTMS, no significant changes occurred. Conclusions: The results from our study support the hypothesis that low-frequency rTMS may influence cerebral blood flow (CBF) over short periods of time, inducing a temporary decrease of maximal CBF in the ipsilateral MCA followed by an increase in the contralateral MCA. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Repetitive transcranial magnetic stimulation; Dorsolateral prefrontal cortex; Transcranial Doppler; Cerebral blood flow
1. Introduction Transcranial magnetic stimulation (TMS) allows a noninvasive stimulation of the cerebral cortex and an evaluation of cortical excitability (Kossev et al., 2001; Rollnik et al., 2000b; Schubert et al., 1998). Repetitive TMS (rTMS) may be used to activate or inhibit selected cortical areas, depending on the stimulation parameters. Low-frequency rTMS (0.9 Hz) of the motor cortex induces a decrease of cortical excitability (Chen et al., 1997). Higher stimulation frequencies (e.g. 5 Hz) may lead to an activation of cortical areas (Rollnik et al., 2000c, 2001). These effects have been used * Corresponding author. Tel.: 149-511-532-3578; fax: 149-511-5323115. E-mail address: [email protected] (J.D. Rollnik).
to treat several neuropsychiatric disorders. rTMS has been found to have therapeutic potential in disturbances associated with frontal hypometabolism, such as major depression or chronic schizophrenia with predominance of negative symptoms (Geller et al., 1997; George et al., 1997; Feinsod et al., 1998). The studies have demonstrated that both – high-frequency (activating) rTMS of the dominant hemisphere as well as low-frequency (inhibiting) rTMS of the contralateral dorsolateral prefrontal cortex (DLPFC) – have antidepressant effects. This effect could be explained by the finding that the left DLPFC shows a relative hypometabolism in major depression, while the contralateral DLPFC shows an increase of metabolic activity. Further, activating rTMS of the DLPFC (dominant hemisphere) has antipsychotic effects (Rollnik et al., 2000a). This finding
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(02)00063-9
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J.D. Rollnik et al. / Clinical Neurophysiology 113 (2002) 951–955
might be explained by an improvement of prefrontal cortical hypometabolism, leading to changes of neuronal excitability, cerebral blood flow (CBF), and glucose metabolism (Fox et al., 1997). Fox et al. (1997) stimulated the hand area of primary motor cortex (M1) in the left cerebral hemisphere with TMS while local and remote effects were recorded with positron emission tomography (PET). At the stimulated site, TMS increased blood flow (12–20%) in a highly focal manner, without an inhibitory surround (Fox et al., 1997). Transcranial Doppler ultrasonography (TCD) may detect changes of CBF, induced, e.g. by cognitive stimulation, activating rTMS, or ischemia (Aaslid et al., 1989; Caramia et al., 2000; Conrad and Klingelho¨ fer, 1989; Pecuch et al., 2000; Rossini et al., 1990; Sander et al., 1995, 1996; Schmidt et al., 1999; Stoll et al., 1999). Several studies suggest that there is a close coupling of neuronal activity, brain metabolism (mainly reflecting synaptic activity), and CBF (Kuschinsky, 1991; Sander et al., 1995; Wise et al., 1991). Sander et al. (1995) found a significant increase of ipsilateral middle cerebral artery (MCA) flow velocity, ranging from 5.3% for single stimuli up to 8.5% for triple transcranial magnetic stimuli applied to the motor cortex (frequency 10 Hz, given at intervals of 30 s during a period of 5 min, intensity: 80–100% of maximal stimulator output). In another study from the same group (Sander et al., 1996), 3 and 6 Hz rTMS of the occipital cortex induced an increase of the ipsilateral posterior cerebral artery (PCA) flow velocity between 10.2 and 12.8%. Since previous studies demonstrated a significant increase of CBF following activating (high frequency) rTMS, we were interested whether low-frequency, inhibiting rTMS (0.9 Hz) of the right DLPFC would be able to decrease MCA flow velocity. 2. Subjects and methods 2.1. Subjects Thirty-eight healthy, right-handed, normotensive subjects (aged 21–50 years, mean 30.2 years, SD ¼ 4:9; 17 women) were enrolled in the study. Twenty-five subjects were randomly assigned to active rTMS (mean age 30.2 years, SD ¼ 5:8; 12 women), 13 to sham rTMS (mean age 30.4 years, SD ¼ 2:8; 5 women). Active and sham rTMS group did not differ with respect to age or gender distribution. As required by local ethics committee, all subjects gave their written informed consent to participate in the study. In order to minimize the risk of inducing seizures, the most important exclusion criterion was a positive history of seizures. In addition, subjects with a pacemaker or other metal parts in their body were excluded. 2.2. Repetitive transcranial magnetic stimulation According to the stimulation regimen of Chen et al.
(1997), we performed a 0.9 Hz rTMS using a MagstimRapid w device (The Magstim Company, Whitland, UK). On the initial visit the motor threshold (MT) for the left abductor pollicis brevis muscle was determined using a figure-of8-shaped coil. MT was defined as the lowest intensity which produced 3 MEP responses of at least 50 mV in 4 trials (Rollnik et al., 2000b). Low-frequency rTMS (0.9 Hz, 90% of MT) was performed over a period of 5 min (total of 270 pulses), applied to the DLPFC. The stimulation site (DLPFC) was defined according to George et al. (1997) as 5 cm anterior in a parasagittal plane from the point of maximum stimulation of the contralateral abductor pollicis muscle, as used in previous studies (Rollnik et al., 2000c, 2001). The figure-of-8-shaped coil was held with the extensions of the coil perpendicular to a line running from the site to the subjects’ nose (George et al., 1997). Sham stimulation occurred in the same manner as active rTMS, except that the angle of the coil, rather than being tangential to the skull, was 458 off the skull. 2.3. Transcranial Doppler ultrasonography In order to detect and monitor CBF in the MCA territory, the M1-segment of the ipsilateral and contralateral MCA was examined with transcranial Doppler (TCD) sonography. Measurements of CBF were done continuously and documented over a period of 15 s immediately after, 5 min after, and 10 min after the end of rTMS (example, see Fig. 1a–d). A computer-assisted pulsed 2 MHz Doppler device (DWL Multidop, Sipplingen, Germany) was used. TCD was performed using the following parameters: sample volume, 10–12 mm; depth, 50–52 mm; power, 56–96 mW; filter, 150 Hz; gain 40–60%. The maximal blood flow velocity of the right MCA was documented at baseline and each follow-up (in cm/s). In addition, pulsatility index (PI; (systolic 2 diastolic)/mean), systolic and diastolic blood pressure (sphygmomanometry), and heart rate were measured. Subjects were required to stay in a supine position (on a bed), not to move, and to keep their eyes closed during the whole experiment. The first TCD documentation was done after a resting and relaxation period of at least 5 min. 2.4. Statistics Maximal MCA blood flow velocity before, immediately after, 5 min after, and 10 min after the end of rTMS was compared using paired-samples T tests. Differences were regarded as significant with P , 0:05. 3. Results Mean MT in the active rTMS group was 54.5% (SD ¼ 5:9) of maximal stimulator output, in the sham stimulated group 55.8% (SD ¼ 4:7). No severe adverse events occurred during rTMS, but 5
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Fig. 1. (a–d) Recordings of the MCA blood flow velocity, before (a); immediately after (b); 5 min after (c); and 10 min after the end of rTMS (d). Subject F.H. (female, 26 years). Maximal flow velocity before rTMS was 123 cm/s, immediately after rTMS 116 cm/s, 5 min later 117 cm/s, and 10 min later 121 cm/s (return to baseline).
participants complained of mild headaches at the stimulation site. Contractions of the ipsilateral masseter, orbicularis oculi, and frontotemporalis muscles could be observed during rTMS. 3.1. Active rTMS Prior to active rTMS (after a 5 min resting period), ipsilateral mean maximal MCA blood flow velocity was 101.6 cm/s (SD ¼ 26:0). Immediately after the end of rTMS, it decreased to 92.6 cm/s (SD ¼ 23:7), T ¼ 5:06,
P , 0:001. This equals a mean decrease of 9.0 cm/s (SD ¼ 8:3) or approximately 8.9% of baseline flow (Fig. 2). Five minutes after the end of rTMS, ipsilateral MCA blood flow velocity returned to baseline (mean 104.9 cm/ s, SD ¼ 26:7). Ten minutes after the end of rTMS, maximal MCA flow velocity was 106.9 cm/s (SD ¼ 18:8). PI significantly decreased from 0.81 (SD ¼ 0:03) to 0.76 (SD ¼ 0:06) after 10 min (T ¼ 2:59, P , 0:05). Contralaterally, maximal MCA flow tended to increase 10 min after rTMS (compared to baseline flow). At baseline, flow of the MCA was 109.7 cm/s (SD ¼ 20:2), and 10 min
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Fig. 2. After active rTMS, there is a significant decrease of ipsilateral maximal MCA blood flow velocity from baseline to the situation immediately after rTMS (P , 0:001). Five and 10 min later, a return to baseline could be observed. After sham stimulation, MCA flow tended to increase. Mean values and (mean) standard errors are illustrated.
after the end of rTMS 117.1 cm/s (SD ¼ 27:8); the mean difference was 7.4 cm/s (SD ¼ 17:5), T ¼ 22:03, P ¼ 0:054. Systolic, diastolic blood pressure, and heart rate did not change significantly during active stimulation. Systolic blood pressure: baseline, 123.0 mmHg (SD ¼ 5:4); immediately after rTMS, 125.0 mmHg (SD ¼ 7:1); 5 min after rTMS, 124.0 mmHg (SD ¼ 4:6); 10 min after rTMS, 123.5 mmHg (SD ¼ 7:8). Diastolic blood pressure: baseline, 81.0 mmHg (SD ¼ 4:6); immediately after rTMS, 83.0 mmHg (SD ¼ 4:2); 5 min after rTMS, 82.0 mmHg (SD ¼ 4:8); 10 min after rTMS, 80.5 mmHg (SD ¼ 5:0). Heart rate: baseline, 84.8 beats per minute (bpm; SD ¼ 6:7); immediately after rTMS, 84.8 bpm (SD ¼ 5:0); 5 min after rTMS, 83.6 bpm (SD ¼ 8:5); 10 min after rTMS, 87.2 bpm (SD ¼ 7:1). 3.2. Sham rTMS No significant changes of ipsilateral MCA maximal blood flow velocity or PI occurred. At baseline ipsilateral maximal MCA flow was 106.5 cm/s (SD ¼ 25:8). Immediately after the end of sham stimulation, velocity tended to increase (114.2 cm/s (SD ¼ 27:3), T ¼ 22:16, P ¼ 0:054). After 5 min, maximal flow was 121.8 cm/s (SD ¼ 30:5), without significant difference (compared to baseline). Ten minutes after the end of sham stimulation, maximal flow returned to baseline (mean 111.3 cm/s, SD ¼ 29:4). No significant PI changes could be found, either. 4. Discussion PET studies suggest that rTMS may alter CBF and glucose metabolism (Fox et al., 1997). The main finding of the present study is that inhibiting, low-frequency rTMS of the right DLPFC – as done in the treatment of major depression (Feinsod et al., 1998) – induced a decrease of CBF of the ipsilateral MCA. These changes could be observed immediately after active rTMS (decrease of
approximately 8.9% of baseline values). The absolute magnitude of the observed changes is comparable to former studies using high-frequency rTMS of the motor cortex (Pecuch et al., 2000; Sander et al., 1995), do not exceed values measured during physiological cortex activation (Matzander et al., 1992), and thus seem to be plausible. PI of the ipsilateral MCA (as a measure of vascular resistance) was significantly decreased 10 min after the end of active rTMS, while maximal flow velocity returned to baseline after 5 and 10 min. These changes were followed by a delayed contralateral increase of MCA CBF 10 min after active rTMS. This finding suggests that the contralateral MCA can compensate the reduction of CBF in the right hemisphere (through the anterior communicating artery) and could explain the return to baseline in the ipsilateral (right) MCA, 5 and 10 min after the end of active rTMS. This finding also supports the hypothesis that the observed changes in CBF might be due to a decrease of cerebral metabolism. Since arterial blood pressure changes can influence the variation of CBF, we monitored blood pressure during the experiment. Systolic and diastolic blood pressure did not change significantly and thus did not account for the observed changes of CBF. Further, sham-stimulated subjects did not exhibit a decrease of ipsilateral CBF but an (non-significant) increase of MCA CBF. This finding might be explained by arousal effects resulting from the uncommon experimental procedure. We know from former studies that 0.9 Hz rTMS induces a depression of motor cortex excitability (Chen et al., 1997). It has to be mentioned that this decrease of cortical excitability lasted for at least 15 min after the end of rTMS. However, it should be noted that rTMS was performed for a longer period of time (15 min, 810 pulses) in this experiment (Chen et al., 1997). Thus, the observed short-term changes in our study might be due to shorter rTMS stimulation periods. Further, the close coupling of neuronal activity, brain metabolism (mainly reflecting synaptic activity), and CBF (Kuschinsky, 1991; Sander et al., 1995; Wise et al., 1991) suggests that the observed effects might reflect changes of brain metabolism and neuronal activity. It might well be that metabolic changes underlie a time course different from changes of neuronal activity or excitability. This could explain a quick return of MCA flow to baseline. Former studies have shown that activating, highfrequency rTMS elevates CBF of the ipsilateral MCA and PCA (Pecuch et al., 2000; Sander et al., 1995, 1996). This is the first study delivering evidence for changes of cerebral hemodynamics due to inhibiting, low-frequency rTMS. It has to be mentioned that there are some limitations to this study. First of all, the sample size it quite small. Therefore, the results of this pilot study may only be regarded as preliminary. In addition, it would be very interesting – although technically difficult to realize – to investigate long-term effects of low-frequency rTMS on cerebral hemodynamics.
J.D. Rollnik et al. / Clinical Neurophysiology 113 (2002) 951–955
Acknowledgements Professor Andon Kossev is a fellow of the Alexandervon-Humboldt foundation. The study was supported by the Deutsche Forschungsgemeinschaft (DFG).
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different hemisphere-specific brain activities on hemodynamics in the middle cerebral artery territory. J Neurol 1992;237:S28. Pecuch PW, Evers S, Folkerts HW, Michael N, Arolt V. The cerebral hemodynamics of repetitive transcranial magnetic stimulation. Eur Arch Psychiatry Clin Neurosci 2000;250:320–324. Rollnik JD, Huber TJ, Mogk H, Siggelkow S, Kropp S, Dengler R, Emrich HM, Schneider U. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex in schizophrenic patients. NeuroReport 2000a;11:4013–4015. Rollnik JD, Schubert M, Albrecht J, Wohlfarth K, Dengler R. Effects of somatosensory input on central fatigue: a pilot study. Clin Neurophysiol 2000b;111:1843–1846. Rollnik JD, Schubert M, Dengler R. Subthreshold prefrontal repetitive transcranial magnetic stimulation reduces motor cortex excitability. Muscle Nerve 2000c;23:112–114. Rollnik JD, Siggelkow S, Schubert M, Schneider U, Dengler R. Muscle vibration and prefrontal repetitive transcranial magnetic stimulation. Muscle Nerve 2001;24:112–115. Rossini PM, Silvestrini M, Zarola F, Caramia MD, Mariorenzi R, Traversa R, Martino G, Baggio C, Bolcino G. Effects of non-invasive magnetic brain stimulation on transcranial Doppler and computerized EEG. Electroenceph clin Neurophysiol 1990;75:S130. Sander D, Meyer BU, Ro¨ richt S, Klingelho¨ fer J. Effect of hemisphereselective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity. Electroenceph clin Neurophysiol 1995;97:43–48. Sander D, Meyer BU, Ro¨ richt S, Matzander G, Klingelho¨ fer J. Increase of posterior cerebral artery blood flow velocity during threshold repetitive magnetic stimulation of the human visual cortex: hints for neuronal activation without cortical phosphenes. Electroenceph clin Neurophysiol 1996;99:473–478. Schubert M, Wohlfarth K, Rollnik JD, Dengler R. Walking and fatigue in multiple sclerosis: the role of the corticospinal system. Muscle Nerve 1998;21:1068–1070. Schmidt P, Krings T, Willmes K, Roessler F, Reul J, Thron A. Determination of cognitive hemispheric lateralization by ‘functional’ transcranial Doppler cross-validated by functional MRI. Stroke 1999;30:939–945. Stoll M, Hamann GF, Mangold R, Huf O, Winterhoff-Spurk P. Emotionally evoked changes in cerebral hemodynamics measured by transcranial Doppler sonography. J Neurol 1999;246:127–133. Wise R, Chollet F, Hadar U, Friston K, Hoffner E, Frackowiak R. Distribution of cortical neuronal networks involved in word comprehension and word retrieval. Brain 1991;114:1803–1817.
Decrease of middle cerebral artery blood flow velocity after lowfrequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex Jens D. Rollnik a,*, Ariane Du¨sterho¨ft a, Jan Da¨uper a, Andon Kossev b, Karin Weissenborn a, Reinhard Dengler a a
Department of Neurology and Clinical Neurophysiology, Medical School of Hannover, Carl-Neuberg-Strasse 1, 30623, Hannover, Germany b Department of Biophysics, Bulgarian Academy of Sciences, Sofia, Bulgaria Accepted 2 March 2002
Abstract Objectives: Repetitive transcranial magnetic stimulation (rTMS) has been tried therapeutically in a variety of neuropsychiatric disorders. Both, inhibition and activation of cortical areas may be achieved using different stimulation parameters. Using low-frequency rTMS (0.9 Hz), inhibition of cortical areas can be observed. Methods: In the present study, 38 right-handed, healthy, normotensive subjects (aged 21–50 years, mean 30.2 years, SD ¼ 4:9; 17 women) were enrolled. Twenty-five participants received active rTMS (5 min of 0.9 Hz rTMS, stimulus intensity 90% of motor threshold) of the right dorsolateral prefrontal cortex. Sham stimulation (n ¼ 13 subjects) occurred in the same manner as active rTMS, except that the angle of the coil was at 458 off the skull. Simultaneously, ipsilateral and contralateral maximal middle cerebral artery (MCA) flow velocity (and pulsatility index, PI) was monitored using transcranial Doppler sonography. Results: In the group with active rTMS, maximal MCA flow velocity decreased from a baseline (before rTMS) of 101.6 cm/s (SD ¼ 26:0) to a mean of 92.6 cm/s (SD ¼ 23:7) immediately after rTMS, T ¼ 5:06, P , 0:001. This equals a mean decrease of 9.0 cm/s (SD ¼ 8:3) or approximately 8.9% of baseline flow. Five and 10 min after rTMS, there was a return to baseline. PI significantly decreased 10 min after rTMS (mean difference 20.05, SD ¼ 0:05, T ¼ 2:29, P , 0:05). In the contralateral MCA, maximal flow velocity tended to increase 10 min after rTMS (mean difference 17.4 cm/s, SD ¼ 17:5; T ¼ 22:03, P ¼ 0:054). With sham rTMS, no significant changes occurred. Conclusions: The results from our study support the hypothesis that low-frequency rTMS may influence cerebral blood flow (CBF) over short periods of time, inducing a temporary decrease of maximal CBF in the ipsilateral MCA followed by an increase in the contralateral MCA. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Repetitive transcranial magnetic stimulation; Dorsolateral prefrontal cortex; Transcranial Doppler; Cerebral blood flow
1. Introduction Transcranial magnetic stimulation (TMS) allows a noninvasive stimulation of the cerebral cortex and an evaluation of cortical excitability (Kossev et al., 2001; Rollnik et al., 2000b; Schubert et al., 1998). Repetitive TMS (rTMS) may be used to activate or inhibit selected cortical areas, depending on the stimulation parameters. Low-frequency rTMS (0.9 Hz) of the motor cortex induces a decrease of cortical excitability (Chen et al., 1997). Higher stimulation frequencies (e.g. 5 Hz) may lead to an activation of cortical areas (Rollnik et al., 2000c, 2001). These effects have been used * Corresponding author. Tel.: 149-511-532-3578; fax: 149-511-5323115. E-mail address: [email protected] (J.D. Rollnik).
to treat several neuropsychiatric disorders. rTMS has been found to have therapeutic potential in disturbances associated with frontal hypometabolism, such as major depression or chronic schizophrenia with predominance of negative symptoms (Geller et al., 1997; George et al., 1997; Feinsod et al., 1998). The studies have demonstrated that both – high-frequency (activating) rTMS of the dominant hemisphere as well as low-frequency (inhibiting) rTMS of the contralateral dorsolateral prefrontal cortex (DLPFC) – have antidepressant effects. This effect could be explained by the finding that the left DLPFC shows a relative hypometabolism in major depression, while the contralateral DLPFC shows an increase of metabolic activity. Further, activating rTMS of the DLPFC (dominant hemisphere) has antipsychotic effects (Rollnik et al., 2000a). This finding
1388-2457/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 1388-245 7(02)00063-9
CLINPH 2001559
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might be explained by an improvement of prefrontal cortical hypometabolism, leading to changes of neuronal excitability, cerebral blood flow (CBF), and glucose metabolism (Fox et al., 1997). Fox et al. (1997) stimulated the hand area of primary motor cortex (M1) in the left cerebral hemisphere with TMS while local and remote effects were recorded with positron emission tomography (PET). At the stimulated site, TMS increased blood flow (12–20%) in a highly focal manner, without an inhibitory surround (Fox et al., 1997). Transcranial Doppler ultrasonography (TCD) may detect changes of CBF, induced, e.g. by cognitive stimulation, activating rTMS, or ischemia (Aaslid et al., 1989; Caramia et al., 2000; Conrad and Klingelho¨ fer, 1989; Pecuch et al., 2000; Rossini et al., 1990; Sander et al., 1995, 1996; Schmidt et al., 1999; Stoll et al., 1999). Several studies suggest that there is a close coupling of neuronal activity, brain metabolism (mainly reflecting synaptic activity), and CBF (Kuschinsky, 1991; Sander et al., 1995; Wise et al., 1991). Sander et al. (1995) found a significant increase of ipsilateral middle cerebral artery (MCA) flow velocity, ranging from 5.3% for single stimuli up to 8.5% for triple transcranial magnetic stimuli applied to the motor cortex (frequency 10 Hz, given at intervals of 30 s during a period of 5 min, intensity: 80–100% of maximal stimulator output). In another study from the same group (Sander et al., 1996), 3 and 6 Hz rTMS of the occipital cortex induced an increase of the ipsilateral posterior cerebral artery (PCA) flow velocity between 10.2 and 12.8%. Since previous studies demonstrated a significant increase of CBF following activating (high frequency) rTMS, we were interested whether low-frequency, inhibiting rTMS (0.9 Hz) of the right DLPFC would be able to decrease MCA flow velocity. 2. Subjects and methods 2.1. Subjects Thirty-eight healthy, right-handed, normotensive subjects (aged 21–50 years, mean 30.2 years, SD ¼ 4:9; 17 women) were enrolled in the study. Twenty-five subjects were randomly assigned to active rTMS (mean age 30.2 years, SD ¼ 5:8; 12 women), 13 to sham rTMS (mean age 30.4 years, SD ¼ 2:8; 5 women). Active and sham rTMS group did not differ with respect to age or gender distribution. As required by local ethics committee, all subjects gave their written informed consent to participate in the study. In order to minimize the risk of inducing seizures, the most important exclusion criterion was a positive history of seizures. In addition, subjects with a pacemaker or other metal parts in their body were excluded. 2.2. Repetitive transcranial magnetic stimulation According to the stimulation regimen of Chen et al.
(1997), we performed a 0.9 Hz rTMS using a MagstimRapid w device (The Magstim Company, Whitland, UK). On the initial visit the motor threshold (MT) for the left abductor pollicis brevis muscle was determined using a figure-of8-shaped coil. MT was defined as the lowest intensity which produced 3 MEP responses of at least 50 mV in 4 trials (Rollnik et al., 2000b). Low-frequency rTMS (0.9 Hz, 90% of MT) was performed over a period of 5 min (total of 270 pulses), applied to the DLPFC. The stimulation site (DLPFC) was defined according to George et al. (1997) as 5 cm anterior in a parasagittal plane from the point of maximum stimulation of the contralateral abductor pollicis muscle, as used in previous studies (Rollnik et al., 2000c, 2001). The figure-of-8-shaped coil was held with the extensions of the coil perpendicular to a line running from the site to the subjects’ nose (George et al., 1997). Sham stimulation occurred in the same manner as active rTMS, except that the angle of the coil, rather than being tangential to the skull, was 458 off the skull. 2.3. Transcranial Doppler ultrasonography In order to detect and monitor CBF in the MCA territory, the M1-segment of the ipsilateral and contralateral MCA was examined with transcranial Doppler (TCD) sonography. Measurements of CBF were done continuously and documented over a period of 15 s immediately after, 5 min after, and 10 min after the end of rTMS (example, see Fig. 1a–d). A computer-assisted pulsed 2 MHz Doppler device (DWL Multidop, Sipplingen, Germany) was used. TCD was performed using the following parameters: sample volume, 10–12 mm; depth, 50–52 mm; power, 56–96 mW; filter, 150 Hz; gain 40–60%. The maximal blood flow velocity of the right MCA was documented at baseline and each follow-up (in cm/s). In addition, pulsatility index (PI; (systolic 2 diastolic)/mean), systolic and diastolic blood pressure (sphygmomanometry), and heart rate were measured. Subjects were required to stay in a supine position (on a bed), not to move, and to keep their eyes closed during the whole experiment. The first TCD documentation was done after a resting and relaxation period of at least 5 min. 2.4. Statistics Maximal MCA blood flow velocity before, immediately after, 5 min after, and 10 min after the end of rTMS was compared using paired-samples T tests. Differences were regarded as significant with P , 0:05. 3. Results Mean MT in the active rTMS group was 54.5% (SD ¼ 5:9) of maximal stimulator output, in the sham stimulated group 55.8% (SD ¼ 4:7). No severe adverse events occurred during rTMS, but 5
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Fig. 1. (a–d) Recordings of the MCA blood flow velocity, before (a); immediately after (b); 5 min after (c); and 10 min after the end of rTMS (d). Subject F.H. (female, 26 years). Maximal flow velocity before rTMS was 123 cm/s, immediately after rTMS 116 cm/s, 5 min later 117 cm/s, and 10 min later 121 cm/s (return to baseline).
participants complained of mild headaches at the stimulation site. Contractions of the ipsilateral masseter, orbicularis oculi, and frontotemporalis muscles could be observed during rTMS. 3.1. Active rTMS Prior to active rTMS (after a 5 min resting period), ipsilateral mean maximal MCA blood flow velocity was 101.6 cm/s (SD ¼ 26:0). Immediately after the end of rTMS, it decreased to 92.6 cm/s (SD ¼ 23:7), T ¼ 5:06,
P , 0:001. This equals a mean decrease of 9.0 cm/s (SD ¼ 8:3) or approximately 8.9% of baseline flow (Fig. 2). Five minutes after the end of rTMS, ipsilateral MCA blood flow velocity returned to baseline (mean 104.9 cm/ s, SD ¼ 26:7). Ten minutes after the end of rTMS, maximal MCA flow velocity was 106.9 cm/s (SD ¼ 18:8). PI significantly decreased from 0.81 (SD ¼ 0:03) to 0.76 (SD ¼ 0:06) after 10 min (T ¼ 2:59, P , 0:05). Contralaterally, maximal MCA flow tended to increase 10 min after rTMS (compared to baseline flow). At baseline, flow of the MCA was 109.7 cm/s (SD ¼ 20:2), and 10 min
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Fig. 2. After active rTMS, there is a significant decrease of ipsilateral maximal MCA blood flow velocity from baseline to the situation immediately after rTMS (P , 0:001). Five and 10 min later, a return to baseline could be observed. After sham stimulation, MCA flow tended to increase. Mean values and (mean) standard errors are illustrated.
after the end of rTMS 117.1 cm/s (SD ¼ 27:8); the mean difference was 7.4 cm/s (SD ¼ 17:5), T ¼ 22:03, P ¼ 0:054. Systolic, diastolic blood pressure, and heart rate did not change significantly during active stimulation. Systolic blood pressure: baseline, 123.0 mmHg (SD ¼ 5:4); immediately after rTMS, 125.0 mmHg (SD ¼ 7:1); 5 min after rTMS, 124.0 mmHg (SD ¼ 4:6); 10 min after rTMS, 123.5 mmHg (SD ¼ 7:8). Diastolic blood pressure: baseline, 81.0 mmHg (SD ¼ 4:6); immediately after rTMS, 83.0 mmHg (SD ¼ 4:2); 5 min after rTMS, 82.0 mmHg (SD ¼ 4:8); 10 min after rTMS, 80.5 mmHg (SD ¼ 5:0). Heart rate: baseline, 84.8 beats per minute (bpm; SD ¼ 6:7); immediately after rTMS, 84.8 bpm (SD ¼ 5:0); 5 min after rTMS, 83.6 bpm (SD ¼ 8:5); 10 min after rTMS, 87.2 bpm (SD ¼ 7:1). 3.2. Sham rTMS No significant changes of ipsilateral MCA maximal blood flow velocity or PI occurred. At baseline ipsilateral maximal MCA flow was 106.5 cm/s (SD ¼ 25:8). Immediately after the end of sham stimulation, velocity tended to increase (114.2 cm/s (SD ¼ 27:3), T ¼ 22:16, P ¼ 0:054). After 5 min, maximal flow was 121.8 cm/s (SD ¼ 30:5), without significant difference (compared to baseline). Ten minutes after the end of sham stimulation, maximal flow returned to baseline (mean 111.3 cm/s, SD ¼ 29:4). No significant PI changes could be found, either. 4. Discussion PET studies suggest that rTMS may alter CBF and glucose metabolism (Fox et al., 1997). The main finding of the present study is that inhibiting, low-frequency rTMS of the right DLPFC – as done in the treatment of major depression (Feinsod et al., 1998) – induced a decrease of CBF of the ipsilateral MCA. These changes could be observed immediately after active rTMS (decrease of
approximately 8.9% of baseline values). The absolute magnitude of the observed changes is comparable to former studies using high-frequency rTMS of the motor cortex (Pecuch et al., 2000; Sander et al., 1995), do not exceed values measured during physiological cortex activation (Matzander et al., 1992), and thus seem to be plausible. PI of the ipsilateral MCA (as a measure of vascular resistance) was significantly decreased 10 min after the end of active rTMS, while maximal flow velocity returned to baseline after 5 and 10 min. These changes were followed by a delayed contralateral increase of MCA CBF 10 min after active rTMS. This finding suggests that the contralateral MCA can compensate the reduction of CBF in the right hemisphere (through the anterior communicating artery) and could explain the return to baseline in the ipsilateral (right) MCA, 5 and 10 min after the end of active rTMS. This finding also supports the hypothesis that the observed changes in CBF might be due to a decrease of cerebral metabolism. Since arterial blood pressure changes can influence the variation of CBF, we monitored blood pressure during the experiment. Systolic and diastolic blood pressure did not change significantly and thus did not account for the observed changes of CBF. Further, sham-stimulated subjects did not exhibit a decrease of ipsilateral CBF but an (non-significant) increase of MCA CBF. This finding might be explained by arousal effects resulting from the uncommon experimental procedure. We know from former studies that 0.9 Hz rTMS induces a depression of motor cortex excitability (Chen et al., 1997). It has to be mentioned that this decrease of cortical excitability lasted for at least 15 min after the end of rTMS. However, it should be noted that rTMS was performed for a longer period of time (15 min, 810 pulses) in this experiment (Chen et al., 1997). Thus, the observed short-term changes in our study might be due to shorter rTMS stimulation periods. Further, the close coupling of neuronal activity, brain metabolism (mainly reflecting synaptic activity), and CBF (Kuschinsky, 1991; Sander et al., 1995; Wise et al., 1991) suggests that the observed effects might reflect changes of brain metabolism and neuronal activity. It might well be that metabolic changes underlie a time course different from changes of neuronal activity or excitability. This could explain a quick return of MCA flow to baseline. Former studies have shown that activating, highfrequency rTMS elevates CBF of the ipsilateral MCA and PCA (Pecuch et al., 2000; Sander et al., 1995, 1996). This is the first study delivering evidence for changes of cerebral hemodynamics due to inhibiting, low-frequency rTMS. It has to be mentioned that there are some limitations to this study. First of all, the sample size it quite small. Therefore, the results of this pilot study may only be regarded as preliminary. In addition, it would be very interesting – although technically difficult to realize – to investigate long-term effects of low-frequency rTMS on cerebral hemodynamics.
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Acknowledgements Professor Andon Kossev is a fellow of the Alexandervon-Humboldt foundation. The study was supported by the Deutsche Forschungsgemeinschaft (DFG).
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