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Pallidotomy does not ameliorate abnormal intracortical inhibition in Parkinson’s disease
Journal of Clinical Neuroscience 17 (2010) 711–716
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Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Pallidotomy does not ameliorate abnormal intracortical inhibition in Parkinson’s disease M.V. Sale a,*, M.A. Nordstrom a, B.P. Brophy b, P.D. Thompson c,d a
Discipline of Physiology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia c Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia d Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia b
a r t i c l e
i n f o
Article history: Received 25 August 2009 Accepted 29 September 2009
Keywords: Intracortical inhibition Motor cortex Pallidotomy Parkinson’s disease TMS
a b s t r a c t Motor cortex excitability was assessed in 12 patients with Parkinson’s disease (PD) using transcranial magnetic stimulation. Patients were studied when mobile and medicated (‘‘ON”) and when immobile after medication withdrawal (‘‘OFF”). Results were compared to eight age-matched and 11 young controls. Cortical excitability was assessed by measurement of resting motor threshold (RMT), intracortical inhibition and cortical silent period duration. In five patients, the studies included assessments following pallidotomy. Cortical excitability was abnormal in patients with PD with reduced RMT in ‘‘ON” and ‘‘OFF” states, and less effective intracortical inhibition. Pallidotomy did not affect cortical excitability in either ‘‘ON” or ‘‘OFF” states, indicating that enhanced motor cortex excitability in patients with PD is unaffected by pallidotomy despite clinical improvement in motor scores. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Dopamine depletion in Parkinson’s disease (PD) leads to abnormal output of the basal ganglia through the internal segment of globus pallidus (Gpi). Activity of Gpi is increased, but the relationship of the activity to the cardinal physical signs of PD is unknown. The resulting pallidal-induced inhibition of the ventral thalamic nuclei would be expected to reduce activation of the cortical targets of the pallidothalamic projection, the supplementary motor area (SMA). This could lead either to a loss of phasic pallido–thalamocortical activation, or alter the level of tonic activity within thalamic–cortical circuits. The former is important in the genesis of bradykinesia in PD, since phasic changes in pallido–thalamic input to SMA are considered important in triggering the switch from one movement to the next in a motor sequence.1 The consequence of any alterations in tonic cortical activation, particularly in relation to other features of Parkinsonism, is unknown. It is generally agreed that motor abnormalities in PD are associated with motor cortical (M1) dysfunction, including a reduced threshold for producing a motor response with transcranial magnetic stimulation (TMS)2–4 and a reduction in short-interval intracortical inhibition (SICI).5 This study sought to investigate whether surgical modifica-
* Corresponding author. Tel.: +61 8 8303 3227; fax: +61 8 8303 3356. E-mail address: [email protected] (M.V. Sale). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2009.09.038
tion of the abnormal pallidal output leads to changes in M1 excitability. 2. Methods 2.1. Patients Twelve patients with idiopathic PD aged 60.7 ± 8.9 years (mean ± standard error of the mean, SEM) and disease duration ranging from 5 to 12 years (mean 9.1 ± 1.1 years) were studied. All patients fulfilled standard diagnostic criteria for PD, exhibiting at least three of the following clinical features: rigidity; resting tremor; bradykinesia; asymmetric onset and slow progression; significant and sustained response to levodopa-containing medications; and the absence of other neurological or systemic disease. Patients were studied when: mobile and often dyskinetic, ‘‘ON”, after taking their usual medication; and rigid, immobile and ‘‘OFF”, having withheld medication overnight or at least 4 hours after the last dose. Clinical scores at the time of the experimental studies were recorded using the Webster Rating Scale, a global assessment of motor dysfunction in PD. Two control groups were used: (i) eight healthy age-matched (aged 60.3 ± 8.2 years); and (ii) 11 young controls (aged 23.4 ± 5.8 years). The study was approved by the University of Adelaide Human Research Ethics Committee. All participants gave informed and signed consent after detailed written and verbal explanation of the procedure.
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2.2. Pallidal surgery Five patients with late-stage PD underwent posteroventral pallidotomy. Patients were studied before and after surgery, in the ‘‘ON” and ‘‘OFF” states. Subjects were assessed 3.8 ± 1.4 months following surgery, and the mean time between experiments (presurgery and post-surgery) was 5.3 ± 1.6 months. Pallidal surgery was performed contralateral to the side with most severe dyskinesias. Surgery was performed in the ‘‘OFF” motor state, medication having been withheld overnight. The pallidal target of Laitinen6 was used with coordinates below the intercommisural plane, 22 mm lateral to the midline, 2 mm anterior to the midcommisural plane. Stereotactic coordinates of the medial segment of globus pallidus were calculated from CT scan of the head on the day of surgery. A 1.8-mm-diameter electrode with a 2-mm exposed tip was introduced into the target and the precise lesion site determined by the effects of electrical stimulation at low (5 Hz) and high (75–100 Hz) stimulation. When the optimal position was found, several lesions were made at 75–78 °C for 60 s. 2.3. Experimental protocol All participants, patients with PD and controls, undertook all aspects of the experimental protocol. Participants were seated with their left or right hand secured in a manipulandum. The left hand was tested in all patients except for four, whose symptoms were more severe on the right-hand side. The hand was placed so that the distal interphalangeal joint of the index finger was aligned with a load cell that measured the force of abduction. Electromyographic (EMG) recordings were made from the first dorsal interosseous (FDI) muscle with bipolar silver/silver chloride surface electrodes. The active electrode was placed over the muscle belly and the reference over the second metacarpophalangeal joint. EMG signals were digitised (2 kHz sampling rate), amplified (bandwidth 20– 5000 Hz), and recorded on digital tape for off-line analysis. TMS was delivered by a Magstim 200 magnetic stimulator (Magstim, Dyfed, UK) using a circular coil (external loop diameter 13 cm). The coil was positioned over the optimal scalp location for producing muscle-evoked potentials (MEP) in FDI, and oriented to stimulate cortical structures contralateral to the test muscle. TMS intensities were expressed as percentages of the maximum stimulator output (MSO) of the magnetic stimulator. 2.3.1. Threshold measurements The threshold for magnetic cortical stimulation was determined for the resting (resting motor threshold [RMT]) and isometrically active muscle (10% of the maximum voluntary contraction [MVC]) (active motor threshold [AMT]), and defined as the minimum stimulus intensity required to produce a clearly discernible MEP in three out of five consecutive trials. 2.3.2. Silent period The cortical silent period following TMS was recorded while FDI was contracting (25% MVC) using a stimulus intensity of 150% of RMT. The peripheral silent period was recorded following supramaximal percutaneous electrical stimulation (square pulse 0.1 ms duration, 2 maximum M-wave intensity) of the ulnar nerve at the wrist. For both the peripheral and cortical silent periods, the average of the rectified EMG responses from 10 trials was used. The duration of the silent period was measured from the onset of the MEP (cortical silent period) or M-wave (peripheral silent period), to the point where EMG returned to pre-stimulus levels. 2.3.3. Ipsilateral short-interval intracortical inhibition and facilitation Two magnetic stimulators were connected to the same coil by a Bistim module (Magstim). The effect of the first (conditioning)
stimulus on the response to the second (test) stimulus was investigated in the relaxed muscle. The strength of the conditioning stimulus and the interval between the conditioning and test stimuli were varied separately. Interstimulus intervals (ISI) of 1, 2, 3, 7, 10 and 15 ms were investigated, using a conditioning stimulus strength of 80% RMT. The effect of conditioning stimulus intensity was investigated from 50% to 100% RMT (in 10% increments) at an ISI of 3 ms. The test stimulus intensity was set at half the stimulus strength required to produce a maximal MEP in the relaxed muscle. The order in which the conditioning intensities and intervals were tested was randomised. In each of the trials, 25 test stimuli were given at an inter-trial interval of 6 s. To quantify the effectiveness of the intracortical inhibition and facilitation using the condition-testing paradigm, the amplitude of the MEP produced in trials with a conditioning stimulus preceding the test pulse was expressed as a percentage of the amplitude of the MEP elicited by the test pulse alone. 2.4. Data analysis Webster Rating Scale scores of impairment severity were analysed using the Mann-Whitney paired U-test. The threshold and intracortical inhibition/facilitation data were analysed using between-factor and within-factor repeated-measures analysis of variance (ANOVA). For all analyses, p < 0.05 was chosen as the significance level. All group data are reported as mean ± standard error of the mean (SEM). Fisher’s protected least significant difference (PLSD) post-hoc tests were performed as appropriate. 3. Results Three young participants, one age-matched control, two patients with PD ‘‘OFF” medication, and one patient with PD ‘‘ON” medication did not complete the entire experiment. Reasons included an inability to completely relax muscles and discomfort due to prolonged sitting. Webster Rating Scale scores decreased when patients were ‘‘ON” (7.9 ± 1.3) compared to ‘‘OFF” (11.9 ± 1.3) medication (U-test, p < 0.05). 3.1. Threshold for activation of muscles ANOVA revealed an effect of ‘‘muscle activation” on motor thresholds, with RMT higher than AMT (F1,39 = 102.253; p < 0.001). Therefore, RMT and AMT data were analysed separately. ANOVA revealed an effect of ‘‘group” on RMT (F3,39 = 4.966; p = 0.005): post-hoc analysis revealed that RMT was higher in both control groups compared to both PD groups (young versus [vs.] PD ‘‘OFF”, p = 0.013; young vs. PD ‘‘ON”, p = 0.024; age-matched control vs. PD ‘‘OFF”, p = 0.004; age-matched control vs. PD ‘‘ON”, p = 0.008). There was no difference in RMT between control groups. In the PD patients, medication did not alter RMT. ANOVA revealed an effect of ‘‘group” on AMT (F3,39 = 2.969; p = 0.043): post-hoc analysis revealed higher AMT in age-matched controls compared to both PD groups (age-matched control vs. PD ‘‘OFF”, p = 0.012; age-matched control vs. PD ‘‘ON”, p = 0.021). There was no difference in AMT between young controls and PD patients, or between PD patients ‘‘OFF” and ‘‘ON” medication (Fig. 1). 3.2. Silent period duration ANOVA revealed the cortical silent period was longer than the peripheral silent period (F1,37 = 66.517; p < 0.001). However, there was no difference between groups in the duration of either the
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between young and age-matched controls. Therefore, the control group data were pooled. At short ISI, SICI was influenced by ‘‘group” (F2,68 = 3.504; p = 0.041). Post-hoc analysis revealed SICI was less effective in patients with PD ‘‘OFF” compared to controls (Fisher, p = 0.011). There was no difference in SICI between controls and patients with PD ‘‘ON”, or between PD patients ‘‘OFF” and ‘‘ON” medication (Fisher). The level of SICI was influenced by ISI (F2,68 = 16.357; p < 0.001). Post-hoc analysis revealed less SICI with a 2 ms ISI compared to either an ISI of 1 ms or 3 ms (Fisher, p < 0.001). There was also a ‘‘group” ‘‘interval” interaction (F4,68 = 2.962; p = 0.026), indicating that SICI at individual ISI was influenced by group. Post-hoc analysis revealed less SICI at 2 ms in both groups of patients with PD compared to controls (Fishers, PD ‘‘OFF”, p = 0.037; PD ‘‘ON”, p = 0.002). The reduction in SICI at
Fig. 1. Threshold transcranial magnetic stimulation (TMS) intensity (mean ± SEM) in patients with Parkinson’s disease (PD) in an ‘‘ON” and ‘‘OFF” state compared to two control groups (age-matched and young) showing that the TMS is lower in patients with PD. The threshold TMS was defined as the intensity required to produce a muscle-evoked potential (MEP) in the first dorsal interosseous (FDI) muscle in the resting (RMT, left) and tonically active (AMT, right; 10% maximum voluntary contraction (MVC)) state. Threshold TMS intensity for all groups was significantly lower when the muscle was activated compared to passive (p < 0.05). In the resting state, patients with PD ‘‘OFF” and ‘‘ON” medication had a lower threshold than both the young and age-matched control groups (*, p < 0.05). In the active state (active motor threshold, AMT), PD patients ‘‘OFF” and ‘‘ON” medication had a significantly lower threshold than the age-matched control group (#, p < 0.05), but not the young control group. MSO = maximum stimulator output, RMT = resting motor threshold, SEM = standard error of the mean.
peripheral (F3,37 = 0.458), or the cortical silent period (F3,37 = 1.396) (Fig. 2). 3.3. Short-interval intracortical inhibition and facilitation ANOVA revealed no difference in SICI with short ISI (F1,28 = 0.683) or intracortical facilitation with longer ISI (F1,24 = 0.354)
Fig. 2. The peripheral compared to the mean cortical silent period showing that although the cortical silent period was longer than the peripheral silent period for all groups (*, p < 0.001), the silent period duration is normal in patients with PD. The control group data were pooled to include both the young and age-matched controls. Bars indicate standard errors of the means.
Fig. 3. The effect of paired-pulse transcranial magnetic stimulation (TMS) at various interstimulus intervals (ISI) on mean muscle-evoked potential (MEP) amplitude showing that intracortical inhibitory circuits activated with shortinterval paired-pulse TMS are abnormal in patients with Parkinson’s disease (PD). The effect of TMS on MEP (A) with a conditioning TMS intensity of 80% resting motor threshold (RMT); and (B) with conditioning TMS intensities of 50% to 100% RMT with an ISI of 3 ms. Patients with PD ‘‘OFF” and ‘‘ON” medication had less intracortical inhibition at a 2 ms ISI compared to controls (*, p < 0.05). PD patients ‘‘OFF” medication had less intracortical inhibition at a 2 ms ISI compared to an ISI of 1 ms (#, p < 0.001). PD patients ‘‘ON” medication had significantly less intracortical inhibition at a 2 ms ISI compared with an ISI of 1 ms or 3 ms ( , p < 0.01). Intracortical facilitation was not different between groups. When the conditioning TMS intensity was altered (B), the overall level of intracortical inhibition in PD patients ‘‘OFF” medication was lower than controls. There was no significant difference between PD ‘‘ON” and controls, or between PD patients ‘‘OFF” and ‘‘ON” medication. The dashed line at 100% indicates the size of the test MEP response in the absence of a conditioning TMS pulse. Open triangles = patients with PD ‘‘OFF” medication, open squares = patients with PD ‘‘ON” medication, filled circles = controls (pooled age-matched and younger groups). Bars indicate standard errors of the means.
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2 ms was restricted to the PD groups, since there was no difference in SICI between ISI in the controls (Fisher). Inhibition with a 2 ms ISI in patients in the PD ‘‘OFF” group was less than at 1 ms (Fisher, p < 0.001). In the patients in the PD ‘‘ON” group, inhibition at the 2 ms ISI was less than both the 1 ms ISI (Fisher, p = 0.004) and the 3 ms ISI (Fisher, p < 0.001). ANOVA revealed no effect of different ISI on the level of intracortical facilitation (F4,64 = 1.489). There was no difference between groups in the amount of intracortical facilitation at longer ISI (F2,64 = 2.439). There was also no significant ‘‘group” ‘‘interval” interaction (F4,64 = 0.383) (Fig. 3). 3.4. Effect of conditioning stimulus intensity on intracortical inhibition at 3 ms ISI A previous study reported differences in SICI between PD patients following pallidotomy and controls at an ISI of 3 ms.7 We sought to investigate more thoroughly potential changes in SICI following pallidotomy and thus investigated the effect of altering the conditioning TMS intensity on SICI circuits at an ISI of 3 ms. There was no difference in suppression of the test response by the conditioning stimulus between young and age-matched controls (F1,80 = 0.015), and therefore the control data were pooled. ANOVA revealed that conditioning stimulus intensity had an effect on SICI (F5,185 = 20.488; p < 0.001): post-hoc analysis revealed less SICI with a conditioning TMS intensity of 50% RMT than with conditioning intensities of 70%, 80%, 90% and 100% RMT (Fisher, p < 0.01). SICI with conditioning TMS intensities of 60% and 100% RMT was less than with conditioning intensities of 70%, 80% and 90% RMT (Fisher, p < 0.001). SICI was influenced by ‘‘group” (F2,185 = 3.278; p = 0.049): post-hoc analysis revealed less effective SICI in PD ‘‘OFF” compared to controls (Fisher, p = 0.011). There was no difference in SICI between PD ‘‘OFF” and PD ‘‘ON” (Fisher), nor between controls and PD ‘‘ON” (Fisher). There was no ‘‘group” ‘‘intensity” interaction (F10,185 = 0.830), indicating the difference in SICI between groups was independent of conditioning intensity.
Fig. 4. The effect of ventrolateral pallidotomy on the duration of the peripheral (A) and cortical (B) silent period in five patients with Parkinson’s disease before (preop, left) and after (post-op, right) surgery showing that pallidotomy does not affect peripheral or cortical silent period duration. Although the cortical silent period was longer than peripheral silent period, there was no significant effect of pallidotomy or medication on silent period duration. Bars indicate standard errors of the means.
3.5. Postoperative studies All five patients with PD who underwent surgical intervention participated in all experimental sessions, with no adverse effects noted. The Webster Rating Scale scores improved following surgery (U-test, p = 0.010), but were unaffected by medication (U-test). Clinical rating scores prior to surgery were 14.8 ± 1.7 ‘‘OFF” medication and 11.8 ± 1.9 ‘‘ON” medication. Following surgery, the scores were 8.8 ± 1.7 ‘‘OFF” medication and 8.0 ± 1.5 ‘‘ON” medication. 3.6. Threshold for activation of muscles ANOVA revealed AMT was less than RMT (F1,4 = 44.563; p = 0.003). There was no effect of surgery (F1,4 = 0.852), or medication (F1,4 = 1.862) on thresholds.
3.8. Intracortical inhibition and facilitation ANOVA revealed an effect of ISI on SICI with short (1–3 ms) ISI: post-hoc analysis revealed SICI with an ISI of 2 ms was less than with either 1 ms or 3 ms ISI (Fisher, p < 0.001). Medication (F1,8 = 4.936) or surgery (F1,8 = 1.471) did not alter SICI. There was no ‘‘interval” ‘‘surgery” interaction (F2,8 = 1.137), indicating the ISI-dependent reduction in SICI was unaffected by surgery. With longer ISI (7–15 ms) there was no effect of ISI (F2,8 = 4.253), medication (F1,8 = 0.085) or surgery (F1,8 = 0.163) on intracortical facilitation (Fig. 5). ANOVA revealed an effect of conditioning strength (F5,20 = 0.163) on SICI. Post-hoc analysis revealed SICI at 50%, 60% and 100% RMT was less than at 70%, 80% and 90% RMT (p < 0.003). There was no effect of medication (F1,20 = 0.867) or surgery (F1,20 = 0.003) on SICI.
3.7. Silent period duration 4. Discussion ANOVA revealed an effect of ‘‘group” (F1,4 = 21.165; p = 0.010), indicating that cortical silent period duration was longer than the peripheral silent period. The data were then split to analyse the peripheral and cortical silent period data separately. The peripheral and cortical silent periods were unaffected by surgery (F1,4 = 0.589; F1,4 = 0.348, respectively) and medication (F1,4 = 3.282; F1,4 = 2.849, respectively) (Fig. 4).
The principal finding from this study is that abnormal M1 excitability and intracortical inhibitory circuits in PD were not normalised by ventrolateral pallidotomy. Prior to surgery, PD patients had significantly lower motor thresholds compared to controls, and abnormally functioning SICI circuits. Despite clinical improvement in motor function, PD patients showed no change in M1
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Fig. 5. The effect of paired-pulse transcranial magnetic stimulation (TMS) at (left) various interstimulus intervals (ISI) and (right) conditioning TMS intensities on mean muscle-evoked potential (MEP) amplitude showing that intracortical circuits activated with short-interval paired-pulse TMS are not modulated by pallidotomy in patients with Parkinson’s disease (PD). Intracortical inhibitory (1–3 ms) and facilitatory (7–15 ms) circuits before pallidotomy were not significantly different after pallidotomy in five patients with PD either ‘‘OFF” medication (A; triangles) or ‘‘ON” medication (B; squares). At conditioning TMS intensities of 50% to 100% resting motor threshold, with 3 ms ISI, the overall level of intracortical inhibition in five PD patients prior to pallidotomy was not affected by surgery either ‘‘OFF” medication (C; triangles) or ‘‘ON” medication (D; squares). The dashed line at 100% indicates the size of the test MEP response in the absence of a conditioning TMS pulse. Open symbols = pre-operative, filled symbols = postoperative.
excitability or the function of intracortical inhibitory (or facilitatory) circuits activated by TMS following pallidotomy. 4.1. Motor cortex excitability in PD M1 excitability was enhanced in patients with PD ‘‘ON” and ‘‘OFF” medication, evidenced by a lower RMT (compared to both control groups) and AMT (compared to age-matched controls). A reduced motor threshold has been reported previously;2–4 however, other studies have reported no change.5,8–10 Muscle contraction reduces motor thresholds because motoneurons are activated by voluntary contraction and a lower stimulus intensity is required to discharge the motoneurons.11 However, inadequate relaxation is unlikely to explain the reduced threshold since great care was taken to exclude any trials containing pre-stimulus EMG. Moreover, both RMT and AMT were similarly reduced in patients with PD and therefore the reduced RMT in PD is unlikely due to inadequate FDI relaxation. 4.2. Intracortical inhibition In active muscles, TMS produces a period of EMG silence following the MEP (the cortical silent period12), which is mediated by both spinal and (gamma-amino butyric acid [GABA]B-mediated) cortical mechanisms.13 The later part of the cortical silent period has been largely attributed to cortical inhibitory mechanisms activated by TMS.14–16 Studies of the cortical silent period in PD have reported no difference,5,17,18 a reduction in cortical silent period
duration in PD2,8,19 and a lengthening with dopaminergic therapy.5,15,19,20 We found no difference in the cortical silent period in patients with PD. Differences in clinical symptoms of the PD patients in the different studies may explain these discrepancies, since only rigid PD patients had a reduced silent period in one study.2 4.3. Short-interval intracortical inhibition GABAA-mediated intracortical inhibitory circuits were investigated using a paired-pulse conditioning testing paradigm.21 Our findings of ineffective SICI in patients with PD are similar to previous studies.5,9,10,22,23 We extended the investigation of M1 function in patients with PD to examine the effect of ventrolateral pallidotomy on M1 excitability, SICI and modification of motor function. 4.4. Surgical intervention Stereotactic posteroventral pallidotomy is used in the treatment of PD, particularly in advanced, late stage PD where levodopa-induced dyskinesias are of major concern.7,24,25 Surgical intervention leads to improved motor function, particularly in bradykinesia.25 It remains unclear how disruption in pallidal output modulates M1 function and improves motor function. We reveal M1 abnormalities were not ameliorated following pallidotomy despite an improvement in motor function. These findings are consistent with the absence of any change in intracortical inhibition or facilitation with GPi stimulation despite an improvement in motor function.26
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A previous study reported less SICI in PD patients following surgery compared to controls;7 however, contrary to most findings, SICI in the PD patients (pre-surgery) used in that study was not different to controls. Therefore, it remained unclear whether abnormal SICI in patients with PD is normalised with pallidotomy. The present study shows that pallidotomy does not alter abnormal SICI in patients with PD despite improved motor function. We also report no difference in cortical (or peripheral) silent period duration following pallidotomy. This finding is in agreement with a recent study investigating the effect of deep brain stimulation on cortical silent period duration in advanced PD that found no effect of the intervention on silent period duration.20 Two studies have reported a significant lengthening of the cortical silent period following pallidotomy, indicating an increase in excitability of inhibitory circuits activated during voluntary contraction.27,28 Lengthening of the cortical silent period following pallidotomy only occurred at high contraction levels (30% MVC),27 or high stimulus intensities (200% RMT),28 whereas there was no difference in cortical silent period duration at the stimulus intensity used in the present study (150% RMT). Therefore, surgical modification of basal ganglia output may alter GABAB-mediated inhibition in patients with PD; however these effects may only be evident at high stimulus intensities or contraction levels. The present study has demonstrated that the surgical modification of pallidal output does not influence M1 excitability in PD. This indicates that the improved motor function following pallidotomy is not directly due to a modulation of M1 output. One limitation of the present study is the low number of participants, particularly those undergoing pallidotomy. This may have prevented detection of any subtle changes in cortical excitability. However, even if this shortfall is accepted, it is still clear that surgically-induced changes in M1 excitability are minor, and are not likely to explain the robust changes in motor performance seen following pallidotomy. This raises the question of how, then, does pallidotomy improve motor function in PD? Since ablation of the pallidum cannot restore normal pallidal outflow, any physiological changes after pallidotomy, including improvement in movement, must be related to mechanisms other than restoration of pallido– thalamocortical connectivity.25 Ablation of the abnormal pallidal drive might lead to greater or more effective utilization of external cues in guiding or facilitating voluntary movement.25 This was based on the observations that: (i) improvement in bradykinesia after pallidotomy was greater for sequential limb movements that used external cues than internally generated repetitive movements;25 and (ii) increased blood flow and cerebral metabolism occurred in lateral premotor and inferolateral parietal regions during movement after pallidotomy, suggesting a switch from internal (striatofrontal) to external (parietal–lateral premotor) processing to facilitate movement.29,30 In conclusion, M1 excitability was enhanced, and the function of SICI circuits were reduced, in patients with PD. Pallidotomy improved motor function, but did not modulate the function of the SICI circuits. Therefore, surgical modification of basal ganglia output to M1 improves motor output; however, the clinical improvement is not due to a normalisation of intracortical inhibition in PD, and may be due to normalisation of external cues that facilitate movement. References 1. Picard N, Strick PL. Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex 1996;6:342–53.
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Repetitive transcranial magnetic stimulation causes a short-term increase in the duration of the cortical silent period in patients with Parkinson’s disease. Neurosci Lett 2000;284: 147–50. 19. Nakashima K, Wang Y, Shimoda M, et al. Shortened silent period produced by magnetic cortical stimulation in patients with Parkinson’s disease. J Neurol Sci 1995;130:209–14. 20. Baumer T, Hidding U, Hamel W, et al. Effects of DBS, premotor rTMS, and levodopa on motor function and silent period in advanced Parkinson’s disease. Mov Disord 2009;24:672–6. 21. Kujirai T, Caramia MD, Rothwell JC, et al. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501–19. 22. Strafella AP, Valzania F, Nassetti SA, et al. Effects of chronic levodopa and pergolide treatment on cortical excitability in patients with Parkinson’s disease: a transcranial magnetic stimulation study. Clin Neurophysiol 2000;111:1198–202. 23. Pierantozzi M, Palmieri MG, Marciani MG, et al. Effect of apomorphine on cortical inhibition in Parkinson’s disease patients: a transcranial magnetic stimulation study. Exp Brain Res 2001;141:52–62. 24. Lozano AM, Lang AE, Galvez-Jimenez N, et al. Effect of GPi pallidotomy on motor function in Parkinson’s disease. Lancet 1995;346:1383–7. 25. Kimber TE, Tsai CS, Semmler J, et al. Voluntary movement after pallidotomy in severe Parkinson’s disease. Brain 1999;122:895–906. 26. Chen R, Garg RR, Lozano AM, et al. Effects of internal globus pallidus stimulation on motor cortex excitability. Neurology 2001;56:716–23. 27. Strafella A, Ashby P, Lozano A, et al. Pallidotomy increases cortical inhibition in Parkinson’s disease. Can J Neurol Sci 1997;24:133–6. 28. Young MS, Triggs WJ, Bowers D, et al. Stereotactic pallidotomy lengthens the transcranial magnetic cortical stimulation silent period in Parkinson’s disease. Neurology 1997;49:1278–83. 29. Ceballos-Baumann AO, Obeso JA, Vitek JL, et al. Restoration of thalamocortical activity after posteroventral pallidotomy in Parkinson’s disease [letter]. Lancet 1994;344:814. 30. Samuel M, Caputo E, Brooks DJ, et al. A study of medial pallidotomy for Parkinson’s disease: clinical outcome, MRI location and complications. Brain 1998;121:59–75.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Pallidotomy does not ameliorate abnormal intracortical inhibition in Parkinson’s disease M.V. Sale a,*, M.A. Nordstrom a, B.P. Brophy b, P.D. Thompson c,d a
Discipline of Physiology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia 5005, Australia Department of Neurosurgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia c Department of Neurology, Royal Adelaide Hospital, Adelaide, South Australia, Australia d Department of Medicine, University of Adelaide, Adelaide, South Australia, Australia b
a r t i c l e
i n f o
Article history: Received 25 August 2009 Accepted 29 September 2009
Keywords: Intracortical inhibition Motor cortex Pallidotomy Parkinson’s disease TMS
a b s t r a c t Motor cortex excitability was assessed in 12 patients with Parkinson’s disease (PD) using transcranial magnetic stimulation. Patients were studied when mobile and medicated (‘‘ON”) and when immobile after medication withdrawal (‘‘OFF”). Results were compared to eight age-matched and 11 young controls. Cortical excitability was assessed by measurement of resting motor threshold (RMT), intracortical inhibition and cortical silent period duration. In five patients, the studies included assessments following pallidotomy. Cortical excitability was abnormal in patients with PD with reduced RMT in ‘‘ON” and ‘‘OFF” states, and less effective intracortical inhibition. Pallidotomy did not affect cortical excitability in either ‘‘ON” or ‘‘OFF” states, indicating that enhanced motor cortex excitability in patients with PD is unaffected by pallidotomy despite clinical improvement in motor scores. Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction Dopamine depletion in Parkinson’s disease (PD) leads to abnormal output of the basal ganglia through the internal segment of globus pallidus (Gpi). Activity of Gpi is increased, but the relationship of the activity to the cardinal physical signs of PD is unknown. The resulting pallidal-induced inhibition of the ventral thalamic nuclei would be expected to reduce activation of the cortical targets of the pallidothalamic projection, the supplementary motor area (SMA). This could lead either to a loss of phasic pallido–thalamocortical activation, or alter the level of tonic activity within thalamic–cortical circuits. The former is important in the genesis of bradykinesia in PD, since phasic changes in pallido–thalamic input to SMA are considered important in triggering the switch from one movement to the next in a motor sequence.1 The consequence of any alterations in tonic cortical activation, particularly in relation to other features of Parkinsonism, is unknown. It is generally agreed that motor abnormalities in PD are associated with motor cortical (M1) dysfunction, including a reduced threshold for producing a motor response with transcranial magnetic stimulation (TMS)2–4 and a reduction in short-interval intracortical inhibition (SICI).5 This study sought to investigate whether surgical modifica-
* Corresponding author. Tel.: +61 8 8303 3227; fax: +61 8 8303 3356. E-mail address: [email protected] (M.V. Sale). 0967-5868/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2009.09.038
tion of the abnormal pallidal output leads to changes in M1 excitability. 2. Methods 2.1. Patients Twelve patients with idiopathic PD aged 60.7 ± 8.9 years (mean ± standard error of the mean, SEM) and disease duration ranging from 5 to 12 years (mean 9.1 ± 1.1 years) were studied. All patients fulfilled standard diagnostic criteria for PD, exhibiting at least three of the following clinical features: rigidity; resting tremor; bradykinesia; asymmetric onset and slow progression; significant and sustained response to levodopa-containing medications; and the absence of other neurological or systemic disease. Patients were studied when: mobile and often dyskinetic, ‘‘ON”, after taking their usual medication; and rigid, immobile and ‘‘OFF”, having withheld medication overnight or at least 4 hours after the last dose. Clinical scores at the time of the experimental studies were recorded using the Webster Rating Scale, a global assessment of motor dysfunction in PD. Two control groups were used: (i) eight healthy age-matched (aged 60.3 ± 8.2 years); and (ii) 11 young controls (aged 23.4 ± 5.8 years). The study was approved by the University of Adelaide Human Research Ethics Committee. All participants gave informed and signed consent after detailed written and verbal explanation of the procedure.
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2.2. Pallidal surgery Five patients with late-stage PD underwent posteroventral pallidotomy. Patients were studied before and after surgery, in the ‘‘ON” and ‘‘OFF” states. Subjects were assessed 3.8 ± 1.4 months following surgery, and the mean time between experiments (presurgery and post-surgery) was 5.3 ± 1.6 months. Pallidal surgery was performed contralateral to the side with most severe dyskinesias. Surgery was performed in the ‘‘OFF” motor state, medication having been withheld overnight. The pallidal target of Laitinen6 was used with coordinates below the intercommisural plane, 22 mm lateral to the midline, 2 mm anterior to the midcommisural plane. Stereotactic coordinates of the medial segment of globus pallidus were calculated from CT scan of the head on the day of surgery. A 1.8-mm-diameter electrode with a 2-mm exposed tip was introduced into the target and the precise lesion site determined by the effects of electrical stimulation at low (5 Hz) and high (75–100 Hz) stimulation. When the optimal position was found, several lesions were made at 75–78 °C for 60 s. 2.3. Experimental protocol All participants, patients with PD and controls, undertook all aspects of the experimental protocol. Participants were seated with their left or right hand secured in a manipulandum. The left hand was tested in all patients except for four, whose symptoms were more severe on the right-hand side. The hand was placed so that the distal interphalangeal joint of the index finger was aligned with a load cell that measured the force of abduction. Electromyographic (EMG) recordings were made from the first dorsal interosseous (FDI) muscle with bipolar silver/silver chloride surface electrodes. The active electrode was placed over the muscle belly and the reference over the second metacarpophalangeal joint. EMG signals were digitised (2 kHz sampling rate), amplified (bandwidth 20– 5000 Hz), and recorded on digital tape for off-line analysis. TMS was delivered by a Magstim 200 magnetic stimulator (Magstim, Dyfed, UK) using a circular coil (external loop diameter 13 cm). The coil was positioned over the optimal scalp location for producing muscle-evoked potentials (MEP) in FDI, and oriented to stimulate cortical structures contralateral to the test muscle. TMS intensities were expressed as percentages of the maximum stimulator output (MSO) of the magnetic stimulator. 2.3.1. Threshold measurements The threshold for magnetic cortical stimulation was determined for the resting (resting motor threshold [RMT]) and isometrically active muscle (10% of the maximum voluntary contraction [MVC]) (active motor threshold [AMT]), and defined as the minimum stimulus intensity required to produce a clearly discernible MEP in three out of five consecutive trials. 2.3.2. Silent period The cortical silent period following TMS was recorded while FDI was contracting (25% MVC) using a stimulus intensity of 150% of RMT. The peripheral silent period was recorded following supramaximal percutaneous electrical stimulation (square pulse 0.1 ms duration, 2 maximum M-wave intensity) of the ulnar nerve at the wrist. For both the peripheral and cortical silent periods, the average of the rectified EMG responses from 10 trials was used. The duration of the silent period was measured from the onset of the MEP (cortical silent period) or M-wave (peripheral silent period), to the point where EMG returned to pre-stimulus levels. 2.3.3. Ipsilateral short-interval intracortical inhibition and facilitation Two magnetic stimulators were connected to the same coil by a Bistim module (Magstim). The effect of the first (conditioning)
stimulus on the response to the second (test) stimulus was investigated in the relaxed muscle. The strength of the conditioning stimulus and the interval between the conditioning and test stimuli were varied separately. Interstimulus intervals (ISI) of 1, 2, 3, 7, 10 and 15 ms were investigated, using a conditioning stimulus strength of 80% RMT. The effect of conditioning stimulus intensity was investigated from 50% to 100% RMT (in 10% increments) at an ISI of 3 ms. The test stimulus intensity was set at half the stimulus strength required to produce a maximal MEP in the relaxed muscle. The order in which the conditioning intensities and intervals were tested was randomised. In each of the trials, 25 test stimuli were given at an inter-trial interval of 6 s. To quantify the effectiveness of the intracortical inhibition and facilitation using the condition-testing paradigm, the amplitude of the MEP produced in trials with a conditioning stimulus preceding the test pulse was expressed as a percentage of the amplitude of the MEP elicited by the test pulse alone. 2.4. Data analysis Webster Rating Scale scores of impairment severity were analysed using the Mann-Whitney paired U-test. The threshold and intracortical inhibition/facilitation data were analysed using between-factor and within-factor repeated-measures analysis of variance (ANOVA). For all analyses, p < 0.05 was chosen as the significance level. All group data are reported as mean ± standard error of the mean (SEM). Fisher’s protected least significant difference (PLSD) post-hoc tests were performed as appropriate. 3. Results Three young participants, one age-matched control, two patients with PD ‘‘OFF” medication, and one patient with PD ‘‘ON” medication did not complete the entire experiment. Reasons included an inability to completely relax muscles and discomfort due to prolonged sitting. Webster Rating Scale scores decreased when patients were ‘‘ON” (7.9 ± 1.3) compared to ‘‘OFF” (11.9 ± 1.3) medication (U-test, p < 0.05). 3.1. Threshold for activation of muscles ANOVA revealed an effect of ‘‘muscle activation” on motor thresholds, with RMT higher than AMT (F1,39 = 102.253; p < 0.001). Therefore, RMT and AMT data were analysed separately. ANOVA revealed an effect of ‘‘group” on RMT (F3,39 = 4.966; p = 0.005): post-hoc analysis revealed that RMT was higher in both control groups compared to both PD groups (young versus [vs.] PD ‘‘OFF”, p = 0.013; young vs. PD ‘‘ON”, p = 0.024; age-matched control vs. PD ‘‘OFF”, p = 0.004; age-matched control vs. PD ‘‘ON”, p = 0.008). There was no difference in RMT between control groups. In the PD patients, medication did not alter RMT. ANOVA revealed an effect of ‘‘group” on AMT (F3,39 = 2.969; p = 0.043): post-hoc analysis revealed higher AMT in age-matched controls compared to both PD groups (age-matched control vs. PD ‘‘OFF”, p = 0.012; age-matched control vs. PD ‘‘ON”, p = 0.021). There was no difference in AMT between young controls and PD patients, or between PD patients ‘‘OFF” and ‘‘ON” medication (Fig. 1). 3.2. Silent period duration ANOVA revealed the cortical silent period was longer than the peripheral silent period (F1,37 = 66.517; p < 0.001). However, there was no difference between groups in the duration of either the
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between young and age-matched controls. Therefore, the control group data were pooled. At short ISI, SICI was influenced by ‘‘group” (F2,68 = 3.504; p = 0.041). Post-hoc analysis revealed SICI was less effective in patients with PD ‘‘OFF” compared to controls (Fisher, p = 0.011). There was no difference in SICI between controls and patients with PD ‘‘ON”, or between PD patients ‘‘OFF” and ‘‘ON” medication (Fisher). The level of SICI was influenced by ISI (F2,68 = 16.357; p < 0.001). Post-hoc analysis revealed less SICI with a 2 ms ISI compared to either an ISI of 1 ms or 3 ms (Fisher, p < 0.001). There was also a ‘‘group” ‘‘interval” interaction (F4,68 = 2.962; p = 0.026), indicating that SICI at individual ISI was influenced by group. Post-hoc analysis revealed less SICI at 2 ms in both groups of patients with PD compared to controls (Fishers, PD ‘‘OFF”, p = 0.037; PD ‘‘ON”, p = 0.002). The reduction in SICI at
Fig. 1. Threshold transcranial magnetic stimulation (TMS) intensity (mean ± SEM) in patients with Parkinson’s disease (PD) in an ‘‘ON” and ‘‘OFF” state compared to two control groups (age-matched and young) showing that the TMS is lower in patients with PD. The threshold TMS was defined as the intensity required to produce a muscle-evoked potential (MEP) in the first dorsal interosseous (FDI) muscle in the resting (RMT, left) and tonically active (AMT, right; 10% maximum voluntary contraction (MVC)) state. Threshold TMS intensity for all groups was significantly lower when the muscle was activated compared to passive (p < 0.05). In the resting state, patients with PD ‘‘OFF” and ‘‘ON” medication had a lower threshold than both the young and age-matched control groups (*, p < 0.05). In the active state (active motor threshold, AMT), PD patients ‘‘OFF” and ‘‘ON” medication had a significantly lower threshold than the age-matched control group (#, p < 0.05), but not the young control group. MSO = maximum stimulator output, RMT = resting motor threshold, SEM = standard error of the mean.
peripheral (F3,37 = 0.458), or the cortical silent period (F3,37 = 1.396) (Fig. 2). 3.3. Short-interval intracortical inhibition and facilitation ANOVA revealed no difference in SICI with short ISI (F1,28 = 0.683) or intracortical facilitation with longer ISI (F1,24 = 0.354)
Fig. 2. The peripheral compared to the mean cortical silent period showing that although the cortical silent period was longer than the peripheral silent period for all groups (*, p < 0.001), the silent period duration is normal in patients with PD. The control group data were pooled to include both the young and age-matched controls. Bars indicate standard errors of the means.
Fig. 3. The effect of paired-pulse transcranial magnetic stimulation (TMS) at various interstimulus intervals (ISI) on mean muscle-evoked potential (MEP) amplitude showing that intracortical inhibitory circuits activated with shortinterval paired-pulse TMS are abnormal in patients with Parkinson’s disease (PD). The effect of TMS on MEP (A) with a conditioning TMS intensity of 80% resting motor threshold (RMT); and (B) with conditioning TMS intensities of 50% to 100% RMT with an ISI of 3 ms. Patients with PD ‘‘OFF” and ‘‘ON” medication had less intracortical inhibition at a 2 ms ISI compared to controls (*, p < 0.05). PD patients ‘‘OFF” medication had less intracortical inhibition at a 2 ms ISI compared to an ISI of 1 ms (#, p < 0.001). PD patients ‘‘ON” medication had significantly less intracortical inhibition at a 2 ms ISI compared with an ISI of 1 ms or 3 ms ( , p < 0.01). Intracortical facilitation was not different between groups. When the conditioning TMS intensity was altered (B), the overall level of intracortical inhibition in PD patients ‘‘OFF” medication was lower than controls. There was no significant difference between PD ‘‘ON” and controls, or between PD patients ‘‘OFF” and ‘‘ON” medication. The dashed line at 100% indicates the size of the test MEP response in the absence of a conditioning TMS pulse. Open triangles = patients with PD ‘‘OFF” medication, open squares = patients with PD ‘‘ON” medication, filled circles = controls (pooled age-matched and younger groups). Bars indicate standard errors of the means.
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2 ms was restricted to the PD groups, since there was no difference in SICI between ISI in the controls (Fisher). Inhibition with a 2 ms ISI in patients in the PD ‘‘OFF” group was less than at 1 ms (Fisher, p < 0.001). In the patients in the PD ‘‘ON” group, inhibition at the 2 ms ISI was less than both the 1 ms ISI (Fisher, p = 0.004) and the 3 ms ISI (Fisher, p < 0.001). ANOVA revealed no effect of different ISI on the level of intracortical facilitation (F4,64 = 1.489). There was no difference between groups in the amount of intracortical facilitation at longer ISI (F2,64 = 2.439). There was also no significant ‘‘group” ‘‘interval” interaction (F4,64 = 0.383) (Fig. 3). 3.4. Effect of conditioning stimulus intensity on intracortical inhibition at 3 ms ISI A previous study reported differences in SICI between PD patients following pallidotomy and controls at an ISI of 3 ms.7 We sought to investigate more thoroughly potential changes in SICI following pallidotomy and thus investigated the effect of altering the conditioning TMS intensity on SICI circuits at an ISI of 3 ms. There was no difference in suppression of the test response by the conditioning stimulus between young and age-matched controls (F1,80 = 0.015), and therefore the control data were pooled. ANOVA revealed that conditioning stimulus intensity had an effect on SICI (F5,185 = 20.488; p < 0.001): post-hoc analysis revealed less SICI with a conditioning TMS intensity of 50% RMT than with conditioning intensities of 70%, 80%, 90% and 100% RMT (Fisher, p < 0.01). SICI with conditioning TMS intensities of 60% and 100% RMT was less than with conditioning intensities of 70%, 80% and 90% RMT (Fisher, p < 0.001). SICI was influenced by ‘‘group” (F2,185 = 3.278; p = 0.049): post-hoc analysis revealed less effective SICI in PD ‘‘OFF” compared to controls (Fisher, p = 0.011). There was no difference in SICI between PD ‘‘OFF” and PD ‘‘ON” (Fisher), nor between controls and PD ‘‘ON” (Fisher). There was no ‘‘group” ‘‘intensity” interaction (F10,185 = 0.830), indicating the difference in SICI between groups was independent of conditioning intensity.
Fig. 4. The effect of ventrolateral pallidotomy on the duration of the peripheral (A) and cortical (B) silent period in five patients with Parkinson’s disease before (preop, left) and after (post-op, right) surgery showing that pallidotomy does not affect peripheral or cortical silent period duration. Although the cortical silent period was longer than peripheral silent period, there was no significant effect of pallidotomy or medication on silent period duration. Bars indicate standard errors of the means.
3.5. Postoperative studies All five patients with PD who underwent surgical intervention participated in all experimental sessions, with no adverse effects noted. The Webster Rating Scale scores improved following surgery (U-test, p = 0.010), but were unaffected by medication (U-test). Clinical rating scores prior to surgery were 14.8 ± 1.7 ‘‘OFF” medication and 11.8 ± 1.9 ‘‘ON” medication. Following surgery, the scores were 8.8 ± 1.7 ‘‘OFF” medication and 8.0 ± 1.5 ‘‘ON” medication. 3.6. Threshold for activation of muscles ANOVA revealed AMT was less than RMT (F1,4 = 44.563; p = 0.003). There was no effect of surgery (F1,4 = 0.852), or medication (F1,4 = 1.862) on thresholds.
3.8. Intracortical inhibition and facilitation ANOVA revealed an effect of ISI on SICI with short (1–3 ms) ISI: post-hoc analysis revealed SICI with an ISI of 2 ms was less than with either 1 ms or 3 ms ISI (Fisher, p < 0.001). Medication (F1,8 = 4.936) or surgery (F1,8 = 1.471) did not alter SICI. There was no ‘‘interval” ‘‘surgery” interaction (F2,8 = 1.137), indicating the ISI-dependent reduction in SICI was unaffected by surgery. With longer ISI (7–15 ms) there was no effect of ISI (F2,8 = 4.253), medication (F1,8 = 0.085) or surgery (F1,8 = 0.163) on intracortical facilitation (Fig. 5). ANOVA revealed an effect of conditioning strength (F5,20 = 0.163) on SICI. Post-hoc analysis revealed SICI at 50%, 60% and 100% RMT was less than at 70%, 80% and 90% RMT (p < 0.003). There was no effect of medication (F1,20 = 0.867) or surgery (F1,20 = 0.003) on SICI.
3.7. Silent period duration 4. Discussion ANOVA revealed an effect of ‘‘group” (F1,4 = 21.165; p = 0.010), indicating that cortical silent period duration was longer than the peripheral silent period. The data were then split to analyse the peripheral and cortical silent period data separately. The peripheral and cortical silent periods were unaffected by surgery (F1,4 = 0.589; F1,4 = 0.348, respectively) and medication (F1,4 = 3.282; F1,4 = 2.849, respectively) (Fig. 4).
The principal finding from this study is that abnormal M1 excitability and intracortical inhibitory circuits in PD were not normalised by ventrolateral pallidotomy. Prior to surgery, PD patients had significantly lower motor thresholds compared to controls, and abnormally functioning SICI circuits. Despite clinical improvement in motor function, PD patients showed no change in M1
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Fig. 5. The effect of paired-pulse transcranial magnetic stimulation (TMS) at (left) various interstimulus intervals (ISI) and (right) conditioning TMS intensities on mean muscle-evoked potential (MEP) amplitude showing that intracortical circuits activated with short-interval paired-pulse TMS are not modulated by pallidotomy in patients with Parkinson’s disease (PD). Intracortical inhibitory (1–3 ms) and facilitatory (7–15 ms) circuits before pallidotomy were not significantly different after pallidotomy in five patients with PD either ‘‘OFF” medication (A; triangles) or ‘‘ON” medication (B; squares). At conditioning TMS intensities of 50% to 100% resting motor threshold, with 3 ms ISI, the overall level of intracortical inhibition in five PD patients prior to pallidotomy was not affected by surgery either ‘‘OFF” medication (C; triangles) or ‘‘ON” medication (D; squares). The dashed line at 100% indicates the size of the test MEP response in the absence of a conditioning TMS pulse. Open symbols = pre-operative, filled symbols = postoperative.
excitability or the function of intracortical inhibitory (or facilitatory) circuits activated by TMS following pallidotomy. 4.1. Motor cortex excitability in PD M1 excitability was enhanced in patients with PD ‘‘ON” and ‘‘OFF” medication, evidenced by a lower RMT (compared to both control groups) and AMT (compared to age-matched controls). A reduced motor threshold has been reported previously;2–4 however, other studies have reported no change.5,8–10 Muscle contraction reduces motor thresholds because motoneurons are activated by voluntary contraction and a lower stimulus intensity is required to discharge the motoneurons.11 However, inadequate relaxation is unlikely to explain the reduced threshold since great care was taken to exclude any trials containing pre-stimulus EMG. Moreover, both RMT and AMT were similarly reduced in patients with PD and therefore the reduced RMT in PD is unlikely due to inadequate FDI relaxation. 4.2. Intracortical inhibition In active muscles, TMS produces a period of EMG silence following the MEP (the cortical silent period12), which is mediated by both spinal and (gamma-amino butyric acid [GABA]B-mediated) cortical mechanisms.13 The later part of the cortical silent period has been largely attributed to cortical inhibitory mechanisms activated by TMS.14–16 Studies of the cortical silent period in PD have reported no difference,5,17,18 a reduction in cortical silent period
duration in PD2,8,19 and a lengthening with dopaminergic therapy.5,15,19,20 We found no difference in the cortical silent period in patients with PD. Differences in clinical symptoms of the PD patients in the different studies may explain these discrepancies, since only rigid PD patients had a reduced silent period in one study.2 4.3. Short-interval intracortical inhibition GABAA-mediated intracortical inhibitory circuits were investigated using a paired-pulse conditioning testing paradigm.21 Our findings of ineffective SICI in patients with PD are similar to previous studies.5,9,10,22,23 We extended the investigation of M1 function in patients with PD to examine the effect of ventrolateral pallidotomy on M1 excitability, SICI and modification of motor function. 4.4. Surgical intervention Stereotactic posteroventral pallidotomy is used in the treatment of PD, particularly in advanced, late stage PD where levodopa-induced dyskinesias are of major concern.7,24,25 Surgical intervention leads to improved motor function, particularly in bradykinesia.25 It remains unclear how disruption in pallidal output modulates M1 function and improves motor function. We reveal M1 abnormalities were not ameliorated following pallidotomy despite an improvement in motor function. These findings are consistent with the absence of any change in intracortical inhibition or facilitation with GPi stimulation despite an improvement in motor function.26
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A previous study reported less SICI in PD patients following surgery compared to controls;7 however, contrary to most findings, SICI in the PD patients (pre-surgery) used in that study was not different to controls. Therefore, it remained unclear whether abnormal SICI in patients with PD is normalised with pallidotomy. The present study shows that pallidotomy does not alter abnormal SICI in patients with PD despite improved motor function. We also report no difference in cortical (or peripheral) silent period duration following pallidotomy. This finding is in agreement with a recent study investigating the effect of deep brain stimulation on cortical silent period duration in advanced PD that found no effect of the intervention on silent period duration.20 Two studies have reported a significant lengthening of the cortical silent period following pallidotomy, indicating an increase in excitability of inhibitory circuits activated during voluntary contraction.27,28 Lengthening of the cortical silent period following pallidotomy only occurred at high contraction levels (30% MVC),27 or high stimulus intensities (200% RMT),28 whereas there was no difference in cortical silent period duration at the stimulus intensity used in the present study (150% RMT). Therefore, surgical modification of basal ganglia output may alter GABAB-mediated inhibition in patients with PD; however these effects may only be evident at high stimulus intensities or contraction levels. The present study has demonstrated that the surgical modification of pallidal output does not influence M1 excitability in PD. This indicates that the improved motor function following pallidotomy is not directly due to a modulation of M1 output. One limitation of the present study is the low number of participants, particularly those undergoing pallidotomy. This may have prevented detection of any subtle changes in cortical excitability. However, even if this shortfall is accepted, it is still clear that surgically-induced changes in M1 excitability are minor, and are not likely to explain the robust changes in motor performance seen following pallidotomy. This raises the question of how, then, does pallidotomy improve motor function in PD? Since ablation of the pallidum cannot restore normal pallidal outflow, any physiological changes after pallidotomy, including improvement in movement, must be related to mechanisms other than restoration of pallido– thalamocortical connectivity.25 Ablation of the abnormal pallidal drive might lead to greater or more effective utilization of external cues in guiding or facilitating voluntary movement.25 This was based on the observations that: (i) improvement in bradykinesia after pallidotomy was greater for sequential limb movements that used external cues than internally generated repetitive movements;25 and (ii) increased blood flow and cerebral metabolism occurred in lateral premotor and inferolateral parietal regions during movement after pallidotomy, suggesting a switch from internal (striatofrontal) to external (parietal–lateral premotor) processing to facilitate movement.29,30 In conclusion, M1 excitability was enhanced, and the function of SICI circuits were reduced, in patients with PD. Pallidotomy improved motor function, but did not modulate the function of the SICI circuits. Therefore, surgical modification of basal ganglia output to M1 improves motor output; however, the clinical improvement is not due to a normalisation of intracortical inhibition in PD, and may be due to normalisation of external cues that facilitate movement. References 1. Picard N, Strick PL. Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex 1996;6:342–53.
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