RESEARCH
ARTICLE
Increased Intracortical Inhibition in Hyperglycemic Hemichorea-Hemiballism Jie-Yuan Li,1,2,3 and Robert Chen4* 1 Division of Neurology, Kaohsiung Veterans General Hospital, Taiwan, R.O.C. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan, R.O.C. 3 Department of Nursing, Yuh-Ing Junior College of Health Care & Management, Taiwan, R.O.C. 4 Division of Neurology, Department of Medicine and Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada 2
ABSTRACT:
Hemichorea-hemiballism (HC-HB) in uncontrolled diabetes mellitus is an uncommon manifestation of hyperglycemia. The pathophysiology of hyperglycemic HC-HB is not well understood. A previous report showed increased intracortical inhibition in the motor cortex in a patient with diabetes with HC-HB. The objective of this study is to investigate motor cortex excitability in patients with hyperglycemic HC-HB. We hypothesized that intracortical inhibition measured with transcranial magnetic stimulation, which likely reflects the excitability of cortical c-aminobutyric acid (GABA)ergic circuits, would be impaired in patients with hyperglycemic HC-HB. We studied 15 patients with mean age 71.5 years (range, 48-94 y) and 12 age-matched healthy subjects. The motor cortex contralateral to the hemichorea was tested. Transcranial magnetic stimulation measures included motor evoked potential, recruitment curve, GABAA mediated short interval intracortical inhibition, intracortical facilitation, and GABAB mediated silent period duration and long interval intracortical inhibition. No significant difference was found in motor
Hemichorea-hemiballism (HC-HB) is an uncommon movement disorder that presents with unilateral choreic or ballistic movements of the limbs. It is
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*Correspondence to: Dr. Robert Chen, Toronto Western Hospital, 7MC411, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8, E-mail: [email protected]
Funding agencies: This study was supported by grant VGHKS101-013 from Kaohsiung Veterans General Hospital, Taiwan (R.O.C.). Dr. Chen was supported by the Catherine Manson Chair in Movement Disorders. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 23 October 2013; Revised: 22 April 2014; Accepted: 7 May 2014 Published online 11 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25940
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threshold, recruitment curve response, short interval intracortical inhibition, or intracortical facilitation in both rest and active conditions between patients with hyperglycemic HC-HB and normal subjects. However, long interval intracortical inhibition was significantly increased during muscle activation but not at rest in patients with hyperglycemic HC-HB. The silent period duration is also increased in patients with hyperglycemic HC-HB. We concluded that long interval intracortical inhibition and silent period are increased in the motor cortex contralateral to the hemichorea in hyperglycemic HC-HB, but only during muscle activation. Hemichorea-hemiballism may be associated with increased GABAB receptor-mediated inhibitory activity C 2014 International Parkinson and in the motor cortex. V Movement Disorder Society
K e y W o r d s : transcranial magnetic stimulation; intracortical inhibition; hyperglycemia; hemichorea; hemiballism
commonly associated with stroke (ischemia or hemorrhage of the contralateral basal ganglia, particularly the subthalamic nucleus) and infrequently with other focal lesions (such as neoplasm and tuberculoma), immunological disorders (such as systemic lupus erythematosus and Sydenham’s chorea), and iatrogenic causes (such as subthalamotomy).1 Another cause is uncontrolled diabetes mellitus, especially the nonketotic hyperglycemic state.2-4 Most reported cases are in people of east Asian origin, which suggests a possible genetic disposition. Patients with hyperglycemic HC-HB typically show high signal intensity lesions in the striatum on T1-weighted magnetic resonance image (MRI).2,4 The nature of these hyperintensity signals is unclear. Several causes have been proposed, including petechial hemorrhage,5 temporary ischemia
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TABLE 1. Clinical features of patients with hyperglycemic HC-HB Patient no.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age (y)
48 67 79 81 77 61 59 81 94 73 77 60 80 72 63
Sex
F F M F M F F F F M M F F M F
Chorea duration (d)
Distribution of chorea
Medications
28 24 102 60 56 12 6 8 9 88 22 54 38 75 14
R arm, leg R arm, leg, face, tonge L arm, leg tongue, R arm, leg R arm, leg R arm, leg R arm, leg R arm, leg R arm, leg, face L arm, leg L arm, leg, face, tongue R arm, leg L arm, leg, face, tongue L foot L arm, leg
None None None Risperidone 0.5 mg/d 3 4 d None None None None None Haloperidol 0.5 mg/d 3 40 d Risperidone 1 mg/d 3 4 d Risperidone 1 mg/d 3 4 d None Risperidone 0.5 mg/d 3 4 d None
(with or without hyperviscosity),3,4,6 or decreased synthesis of g-aminobutyric acid (GABA) and acetylcholine secondary to metabolic changes.4,7 The pathophysiology of hyperglycemic HC-HB is not well understood. One study showed reduced intracortical inhibition and increased intracortical facilitation in Huntington’s disease,8 but another study found normal intracortical inhibition in patients with chorea due to Huntington’s disease, neuroacanthocytosis, systemic lupus erythematosus, and senile chorea.9 The only study in diabetic HC-HB is a single case report that showed increased intracortical inhibition.10 Because hyperintense lesions on MRI occur in the striatum in patients with hyperglycemic HC-HB, abnormal motor cortical excitability in HC-HB likely arises from aberrant subcortical input. An experimental primate model of HC-HB can be produced by injection of GABA receptor antagonist into the external globus pallidus and the subthalamic nucleus.11 This results in reduced inhibitory output of internal globus pallidus and consequently disinhibition of thalamocortical projections. The increased thalamocortical drive may lead to increased excitability of the motor cortex, and this may contribute to chorea. The aim of this study is to investigate motor cortex excitability in patients with hyperglycemic HC-HB. We hypothesized that intracortical inhibition measured with transcranial magnetic stimulation, which likely reflects the excitability of cortical GABAergic circuits, is reduced in patients with hyperglycemic HC-HB.
Methods
hyperglycemia, HC-HB, and high signal intensity lesions in the striatum on T1-weighted MRI. We studied 15 patients with mean age 71.5 years (range, 4894 years) and 12 age-matched healthy subjects (mean age, 68.4 years; range, 52-77 years) as controls. The demographic data of the patients were shown in Table 1. No neuroleptic was administered before the study in 10 patients. Five patients received neuroleptics (Table 1), which were discontinued 1 day before the examination. The study was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital. Written informed consent was obtained from all subjects. The study protocol required approximately 3.5 hours of testing.
Electromyography Recording Surface electromyography was monitored on a computer screen and via loudspeakers at high gain to provide feedback on the state of muscle relaxation. If electromyography activities were detected in trials that required muscle relaxation, the trials were repeated. In the experiments that require the subject to maintain a constant contraction, auditory feedback was provided through loudspeakers, and visual feedback was provided by passing the electromyography signal through a leaky integrator, and the electromyography level was displayed on an oscilloscope. The signal was amplified (Digitimer D360, Letchworth Garden, UK), filtered (band pass 20 Hz to 2.5 kHz), digitized at 5 kHz (Power 1401, Cambridge Electronics Design, Cambridge, UK), and stored in a laboratory computer for off-line analysis.
Subjects
Transcranial Magnetic Stimulation Studies
We examined consecutive patients with HC-HB admitted to the neurological service of the Kaohsiung Veterans General Hospital from 2004 to 2012. Patients were included in the study if they had
Transcranial magnetic stimulation was performed with a 70-mm figure-of-eight coil and two Magstim 200 Stimulators connected via a Bistim module. The motor cortex contralateral to the hemichorea was
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tested in patients with hyperglycemic HC-HB, and the left or right motor cortex was chosen randomly in normal subjects. Surface electromyography was recorded from the first dorsal interosseous muscle. The optimal coil position over motor cortex for eliciting the motor evoked potential from the contralateral first dorsal interosseous muscle was established with the handle pointing backward and held approximately 45 degrees to the midsagittal line (approximately perpendicular to the presumed direction of the central sulcus). The optimal position was marked on the scalp to ensure identical placement of the coil throughout the experiment.
potential in the contralateral first dorsal interosseous muscle at rest. Single test pulse and paired pulses at interstimulus intervals of 2 and 10 ms (10 trials for each condition) were delivered in random order. For long interval intracortical inhibition (LICI),13 the suprathreshold conditioning stimulus and test stimulus were set to evoke approximately 1 mV motor evoked potential in the contralateral first dorsal interosseous muscle at rest. Test pulse alone and conditioning pulse followed by test pulse at interstimulus intervals of 50, 100, 150, and 200 ms were studied. Each run consisted of 20 trials of the test pulse alone and 10 trials of each interstimulus interval delivered in random order (60 trials).
Motor Threshold Resting motor threshold was the minimum stimulator output that produced motor evoked potentials of 50 mV or greater in at least 5 of 10 trials. Active motor threshold was the minimum stimulator output that produced motor evoked potentials of 100mV or more in at least 5 of 10 trials with a constant background contraction of 20% of the maximum integrated electromyography.
Motor Evoked Potential Recruitment Curve and Silent Period
Data Analysis For transcranial magnetic stimulation studies, the peak-to-peak motor evoked potential amplitude for each trial was measured. The inhibition or facilitation were calculated as a ratio of the conditioned to unconditioned (test pulse alone) motor evoked potential amplitude for each subject. Ratios less than 1 indicate inhibition, and ratios greater than 1 indicate facilitation. Values are expressed as mean 6 standard deviation.
Statistical Analysis
For the motor evoked potential recruitment curve, stimulus intensities of 100%, 110%, 120%, 130%, and 140% of the rest motor threshold for the resting state and of the active motor threshold for the active state (during 10%-20% maximum voluntary contraction) were studied. Ten pulses at each stimulus intensity were delivered 6 seconds apart, and the order of the stimulus intensities was randomized. The trials recorded in the motor evoked potential recruitment study at the active state were also used for measurement of the silent period (SP). The SP was measured from motor evoked potential onset to the first return of voluntary electromyography activity using the unrectified record of each trial.
For motor threshold, SICI, ICF, and LICI at different interstimulus intervals, the data from patients were compared with that from normal subjects using the unpaired Student’s t test. The effects of interstimulus interval on LICI, stimulus intensity on motor evoked potential recruitment curve, and SP duration were evaluated by repeated measures analysis of variance (ANOVA) with interstimulus interval or stimulus intensity as the within subject factor and subject group (patient vs. control) as the between subject factor. Fisher’s protected least significant difference was used for post hoc testing.
Short Interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), and Long Interval Intracortical Inhibition (LICI)
Hemichorea-hemiballism was present on the right side in 9 patients and on the left side in 6 patients. The fasting blood glucose level on the day of transcranial magnetic stimulation study was between 4.39 and 11.33 mmol/L in all patients except in patient 7, in whom it was 19.2 mmol/L. At the time of the study, the HC-HB were intermittent and mild, involving mainly proximal limbs muscles. The patients were able to maintain the first dorsal interosseous muscle in the relaxed state.
The subjects relaxed (rest) or activated (active, 10%-20% maximum background contraction) the right first dorsal interosseous muscle during the experiment. The rest and active conditions were studied in separate runs. For short interval intracortical inhibition (SICI) and intracortical inhibition (ICF), a pairedpulse protocol was used.12 The conditioning stimulus was set at 80% of resting motor threshold for the rest condition and at 95% of active motor threshold for the active condition. The test stimulus for rest and active state were set to evoke 1 mV motor evoked
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Results
Motor Threshold There was no significant difference in rest (HC-HB 52.6 6 11.8% of stimulator output; controls
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interval 3 group interaction were not significant. However, for active LICI, repeated-measures ANOVA demonstrated a significant effect of group (P 5 0.0002) and a significant group 3 interstimulus interval interaction (P 5 0.014). Figure 3B shows that the significant interaction was due to greater motor evoked potential inhibition at longer interstimulus intervals (150 and 200 ms). Post hoc t tests confirmed increased inhibition at interstimulus intervals of 150 ms (P < 0.0001) and 200 ms (P 5 0.003) in patients compared with controls. No significant difference was found in active LICI between patients with and without neuroleptics (Fig. 3C).
Silent Period Duration Examples of SP in a patient and a control subject are shown in Figure 4A, and the group results are shown in Figure 4B. Repeated-measures ANOVA showed significant effects of group (P < 0.0001) and
FIG. 1. Motor evoked potentials recruitment curves at rest (A) and during voluntary contraction (B). No significant difference was found between patients with hyperglycemic HC-HB and control subjects in both conditions. Error bars represent standard errors. MEP, motorevoked potential; MT, motor threshold.
54.1% 6 7.4%) and active (HC-HB 43.9% 6 8.6%, controls 42.3% 6 6.7%) motor threshold between patients and controls.
Motor Evoked Potential Recruitment Curve Repeated-measures ANOVA demonstrated no significant effect of group but a significant effect of stimulus intensity (P < 0.0001) on motor evoked potential amplitude in both rest and active states (Fig. 1A, B). The group 3 stimulus intensity interaction was not significant.
SICI and ICF The results for rest SICI and ICF are shown in Figure 2A, and active SICI and ICF in Figure 2B. No significant difference was found between patients with HC-HB and normal subjects.
LICI Figure 3A shows rest LICI, and Figure 3B shows active LICI. The effect of interstimulus interval was significant (P < 0.0001) for both rest and active LICI. For rest LICI, the effect of group and the interstimulus
FIG. 2. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in patients with hyperglycemic HC-HB and normal subjects during the rest (A) and active (B) states. No significant difference in SICI or ICF was found between the patients with hyperglycemic HC-HB and controls in both conditions. Ratios < 1 represent inhibition, and ratios > 1 represent facilitation. Error bars represent standard errors.
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duration between patients with and without neuroleptics (Fig. 4C).
Discussion Patients with hyperglycemic HC-HB had similar motor threshold, motor evoked potential recruitment curve, SICI, and ICF in both rest and active conditions
FIG. 3. Long interval intracortical inhibition (LICI) in patients with hyperglycemic HC-HB and normal subjects during the rest (A) and active (B) states. LICI was significantly increased during active state in patients with hyperglycemic HC-HB. (C) No significant difference in active LICI was found between patients who received and those who did not receive neuroleptics. Ratios < 1 represent inhibition, and ratios > 1 represent facilitation. Error bars represent standard errors. The asterisks indicate significant differences between patients and controls.
stimulus intensity (P < 0.0001) on SP duration. The SP was longer in patients than controls, and in both groups it increased with stimulus intensities. The interaction between stimulus intensity and group was not significant. There was no significant difference in SP
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FIG. 4. Silent period (SP) duration at different stimulus intensities. (A) Examples of superimposed tracings of silent periods from first dorsal interosseous muscle at the stimulus intensity of 140% of active MT in a patient with HC-HB and a normal subject. (B) Group results for SP duration. Patients with hyperglycemic HC-HB had significantly longer SP duration than normal subjects at all stimulus intensities tested. (C) No significant difference was seen in SP duration between patients who received and those who did not receive neuroleptics. MT, motor threshold.
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compared with normal subjects. In contrast to our hypothesis, they had increased LICI and SP duration in the motor cortex during muscle activation. Because our patients are elderly diabetic patients who had a recent major illness and still had HC-HB at the time of testing, we did not test the unaffected side to keep the testing within tolerable limits. We cannot exclude the possibility that hyperglycemia may affect the findings but consider this unlikely because not all patients were hyperglycemic at the time of the study, and a previous report found no effect of hyperglycemia on cortical excitability.14
LICI and SP Transcranial magnetic stimulation can be used to investigate the excitatory and inhibitory circuits in the motor cortex in neurological disorders.15 Short interval intracortical inhibition, ICF, and LICI occur in the motor cortex and are mediated by different neuronal populations.12,16 Short interval intracortical inhibition and ICF may provide information on GABAA and glutamatergic systems in the motor cortex.17,18 Because we tested only a single interstimulus interval and conditioning stimulus intensity for SICI and ICF, we cannot exclude subtle changes in SICI and ICF at other interstimulus intervals or conditioning stimulus intensities in HC-HB, but including these parameters will make the testing protocol too long for the patients. Long interval intracortical inhibition also occurs at the cortex and is likely mediated by GABAB receptors,17,19 because it is increased by baclofen.20 The SP refers to the duration of interruption of voluntary motor activity after transcranial magnetic stimulation. The first part of the SP reflects spinal cord inhibition, and the late part is largely attributable to cortical mechanisms.21,22 The late part of the SP is considered to be mediated by long-lasting cortical inhibition mediated through the GABAB receptor because it is increased by GABA reuptake inhibitor tiagabine23 and intrathecal administration of GABAB receptor agonist baclofen.24 Thus, prolonged SPs suggest hyperactivity of GABAB-mediated inhibitory system in the motor cortex. One of the characteristics of choreatic patients is motor impersistence, the inability to maintain a sustained muscle contraction. Although we carefully controlled the level of muscle contraction during the experiment and the level of contraction does not strongly influence SP duration,25 we cannot exclude the possibility that prolonged SP duration is partly attributable to variably sustained muscle contraction. The increased SP duration in our patients with hyperglycemic HC-HB is in agreement with the previous case report.10 The increased LICI and SP duration in our findings both suggest hyperactivity of inhibitory circuit in these patients, and the HC-HB is associated with increased
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GABAB receptor–mediated inhibitory activity (LICI and SP) in the motor cortex. Long interval intracortical inhibition and the SP may be two manifestations of a common long-lasting cortical inhibitory process, with LICI indicating its magnitude and the SP its duration.26 The duration of the SP corresponded to the interstimulus intervals at which LICI was present.27 Thus, the prolonged SP and increased LICI at 150 and 200 ms are likely related.
Comparison with Previous Studies Intracortical inhibition of the motor cortex has been investigated in other movement disorders and was found to be reduced or absent in focal arm dystonia,28 dyskinesia caused by lesions in the putamen or globus pallidus,29,30 and in patients with cervical dystonia.31 The results of paired-pulse transcranial magnetic stimulation in Huntington’s disease remain controversial. Some studies reported reduced SICI and increased ICF8 in the Huntington’s disease, but others found normal SICI and ICF.29 In another study, SICI was found to be intact in patients with Huntington’s disease, chorea acanthocytosis, systemic lupus erythematosus, and senile chorea.9 In the above studies, patients were studied only at rest. Most studies also reported that the cortical SP in Huntington’s disease had an abnormally long and variable duration,32,33 although others found a slight shortening of the SP in Huntington’s disease.34 Motor cortical excitability also has been studied in Parkinson’s disease. Most studies found that SP durations35,36 are reduced in Parkinson’s disease patients. Many previous studies also reported decreased rest SICI37,38 and rest LICI39 in Parkinson’s disease patients. Most of these changes normalized with dopaminergic treatment.36,40 A recent study found that Parkinson’s disease patients with levodopa-induced dyskinesia had reduced SICI and SP duration, which failed to increase with levodopa.41 Moreover, rest LICI was decreased in dyskinetic compared with nondyskinetic Parkinson’s disease patients.41 Thus, the cortical pathophysiology of levodopa-induced dyskinesia appears to be different from that of hyperglycemic HC-HB. A previous cortical excitability study was performed in a single diabetic patient with HC-HB, but the findings were difficult to interpret because the patient was on haloperidol. The patient had normal SICI and slightly reduced ICF and prolonged SP compared with controls, but had increased SICI and reduced ICF compared with controls who took a single dose of haloperidol.10 Long interval intracortical inhibition was not investigated. Although the authors suggested that reduced ICI is a pathophysiological feature of HC-HB, our study showed that this is not the case, because SICI was normal in a much larger number of
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drug-na€ıve patients, similar to some studies in Huntington’s disease and other choreic disorders.9,29,42 Neuroleptics are unlikely to explain the findings in our study because only 5 of 15 patients were previously treated at low doses, and the drugs were discontinued 1 day before the study. Moreover, no significant difference was found between the neuroleptic-na€ıve patients and those who had been treated with neuroleptics (Figs. 3C and 4C). An interesting finding in our study is that increased LICI was observed only during voluntary muscle activation but not at rest. Clinically, HC-HB was aggravated during muscle activation in all of our patients. Figure 3 shows that LICI at interstimulus intervals of 100 to 200 ms was decreased during voluntary muscle activation compared with rest in controls but not in HC-HB patients. Thus, the absence of normal reduction of LICI with movements accounts for the increased active LICI in HC-HB patients. Both active LICI and SP involve interactions between cortical inhibition and the voluntary motor command. Therefore, our findings suggest that this interaction between voluntary motor control and cortical inhibition is abnormal in hyperglycemic HC-HB. Because SP is caused partly by suppression of the voluntary motor drive,43 the prolonged SP in HC-HB suggest that this suppression is prolonged, and the increased LICI suggests that the magnitude of the suppression is increased. Active LICI but not rest LICI was reported to be decreased in patients with writer’s cramp.44 One study found normal active LICI in Huntington’s disease patients.42
hand dystonia. This reduction in cortical inhibition and the loss of surround inhibition48 may lead to excessive movements and overflow of motor command. Our findings suggest that the pathophysiological mechanisms of hyperglycemic HC-HB are different from those of dystonia. In summary, LICI and SP are increased in the motor cortex contralateral to the hemichorea in hyperglycemic HC-HB, but only during muscle activation. Our findings suggest that HC-HB is associated with increased GABAB receptor–mediated inhibitory activity in the motor cortex.
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Relation to Pathophysiological Models of the Basal Ganglia Current models of basal ganglia circuitry proposed that the chorea may result from increased activity of thalmocortical pathway caused by reduced inhibitory output from the internal segment of globus pallidus.45,46 The increased thalamocortical drive may increase the excitability of both excitatory and inhibitory circuits in the motor cortex.10,33 Although increased excitability of the excitatory circuits may result in excessive movement, the increased active LICI and SP duration we observed may be the correlate of increased excitability of inhibitory circuits. The increased cortical inhibitory activity may be a compensatory phenomenon to reduce the severity of chorea. This interpretation is in agreement with the finding of shortened SP in Parkinson’s disease, which also may be a compensatory mechanism,35 because Parkinson’s disease is associated with increased inhibitory output from the basal ganglia and reduced thalamocortical activity.46,47 By contrast, in other hyperkinetic movement disorders such as dystonia, the abnormalities of excitability are largely loss of cortical inhibition. For example, SICI28 and active LICI44 are reduced in focal
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Tergau F, Wanschura V, Canelo M, et al. Complete suppression of voluntary motor drive during the silent period after transcranial magnetic stimulation. Exp Brain Res 1999;124:447-454.
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Terao Y, Hayashi H, Shimizu T, Tanabe H, Hanajima R, Ugawa Y. Altered motor cortical excitability to magnetic stimulation in a patient with a lesion in globus pallidus. J Neurol Sci 1995;129: 175-178.
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Chen R, Wassermann EM, Canos M, Hallett M. Impaired inhibition in writer’s cramp during voluntary muscle activation. Neurology 1997;49:1054-1059.
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Crossman AR. Functional anatomy of movement disorders. J Anat 2000;196:519-525.
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DeLong MR, Wichmann T. Circuits and circuit disorders of the basal ganglia. Arch Neurol 2007;64:20-24.
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Kravitz AV, Freeze BS, Parker PR, et al. Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature 2010;466:622-626.
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Sohn YH, Hallett M. Disturbed surround inhibition in focal hand dystonia. Ann Neurol 2004;56:595-599.
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ARTICLE
Increased Intracortical Inhibition in Hyperglycemic Hemichorea-Hemiballism Jie-Yuan Li,1,2,3 and Robert Chen4* 1 Division of Neurology, Kaohsiung Veterans General Hospital, Taiwan, R.O.C. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taiwan, R.O.C. 3 Department of Nursing, Yuh-Ing Junior College of Health Care & Management, Taiwan, R.O.C. 4 Division of Neurology, Department of Medicine and Toronto Western Research Institute, University of Toronto, Toronto, Ontario, Canada 2
ABSTRACT:
Hemichorea-hemiballism (HC-HB) in uncontrolled diabetes mellitus is an uncommon manifestation of hyperglycemia. The pathophysiology of hyperglycemic HC-HB is not well understood. A previous report showed increased intracortical inhibition in the motor cortex in a patient with diabetes with HC-HB. The objective of this study is to investigate motor cortex excitability in patients with hyperglycemic HC-HB. We hypothesized that intracortical inhibition measured with transcranial magnetic stimulation, which likely reflects the excitability of cortical c-aminobutyric acid (GABA)ergic circuits, would be impaired in patients with hyperglycemic HC-HB. We studied 15 patients with mean age 71.5 years (range, 48-94 y) and 12 age-matched healthy subjects. The motor cortex contralateral to the hemichorea was tested. Transcranial magnetic stimulation measures included motor evoked potential, recruitment curve, GABAA mediated short interval intracortical inhibition, intracortical facilitation, and GABAB mediated silent period duration and long interval intracortical inhibition. No significant difference was found in motor
Hemichorea-hemiballism (HC-HB) is an uncommon movement disorder that presents with unilateral choreic or ballistic movements of the limbs. It is
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*Correspondence to: Dr. Robert Chen, Toronto Western Hospital, 7MC411, 399 Bathurst Street, Toronto, Ontario, Canada M5T 2S8, E-mail: [email protected]
Funding agencies: This study was supported by grant VGHKS101-013 from Kaohsiung Veterans General Hospital, Taiwan (R.O.C.). Dr. Chen was supported by the Catherine Manson Chair in Movement Disorders. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 23 October 2013; Revised: 22 April 2014; Accepted: 7 May 2014 Published online 11 June 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.25940
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threshold, recruitment curve response, short interval intracortical inhibition, or intracortical facilitation in both rest and active conditions between patients with hyperglycemic HC-HB and normal subjects. However, long interval intracortical inhibition was significantly increased during muscle activation but not at rest in patients with hyperglycemic HC-HB. The silent period duration is also increased in patients with hyperglycemic HC-HB. We concluded that long interval intracortical inhibition and silent period are increased in the motor cortex contralateral to the hemichorea in hyperglycemic HC-HB, but only during muscle activation. Hemichorea-hemiballism may be associated with increased GABAB receptor-mediated inhibitory activity C 2014 International Parkinson and in the motor cortex. V Movement Disorder Society
K e y W o r d s : transcranial magnetic stimulation; intracortical inhibition; hyperglycemia; hemichorea; hemiballism
commonly associated with stroke (ischemia or hemorrhage of the contralateral basal ganglia, particularly the subthalamic nucleus) and infrequently with other focal lesions (such as neoplasm and tuberculoma), immunological disorders (such as systemic lupus erythematosus and Sydenham’s chorea), and iatrogenic causes (such as subthalamotomy).1 Another cause is uncontrolled diabetes mellitus, especially the nonketotic hyperglycemic state.2-4 Most reported cases are in people of east Asian origin, which suggests a possible genetic disposition. Patients with hyperglycemic HC-HB typically show high signal intensity lesions in the striatum on T1-weighted magnetic resonance image (MRI).2,4 The nature of these hyperintensity signals is unclear. Several causes have been proposed, including petechial hemorrhage,5 temporary ischemia
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TABLE 1. Clinical features of patients with hyperglycemic HC-HB Patient no.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age (y)
48 67 79 81 77 61 59 81 94 73 77 60 80 72 63
Sex
F F M F M F F F F M M F F M F
Chorea duration (d)
Distribution of chorea
Medications
28 24 102 60 56 12 6 8 9 88 22 54 38 75 14
R arm, leg R arm, leg, face, tonge L arm, leg tongue, R arm, leg R arm, leg R arm, leg R arm, leg R arm, leg R arm, leg, face L arm, leg L arm, leg, face, tongue R arm, leg L arm, leg, face, tongue L foot L arm, leg
None None None Risperidone 0.5 mg/d 3 4 d None None None None None Haloperidol 0.5 mg/d 3 40 d Risperidone 1 mg/d 3 4 d Risperidone 1 mg/d 3 4 d None Risperidone 0.5 mg/d 3 4 d None
(with or without hyperviscosity),3,4,6 or decreased synthesis of g-aminobutyric acid (GABA) and acetylcholine secondary to metabolic changes.4,7 The pathophysiology of hyperglycemic HC-HB is not well understood. One study showed reduced intracortical inhibition and increased intracortical facilitation in Huntington’s disease,8 but another study found normal intracortical inhibition in patients with chorea due to Huntington’s disease, neuroacanthocytosis, systemic lupus erythematosus, and senile chorea.9 The only study in diabetic HC-HB is a single case report that showed increased intracortical inhibition.10 Because hyperintense lesions on MRI occur in the striatum in patients with hyperglycemic HC-HB, abnormal motor cortical excitability in HC-HB likely arises from aberrant subcortical input. An experimental primate model of HC-HB can be produced by injection of GABA receptor antagonist into the external globus pallidus and the subthalamic nucleus.11 This results in reduced inhibitory output of internal globus pallidus and consequently disinhibition of thalamocortical projections. The increased thalamocortical drive may lead to increased excitability of the motor cortex, and this may contribute to chorea. The aim of this study is to investigate motor cortex excitability in patients with hyperglycemic HC-HB. We hypothesized that intracortical inhibition measured with transcranial magnetic stimulation, which likely reflects the excitability of cortical GABAergic circuits, is reduced in patients with hyperglycemic HC-HB.
Methods
hyperglycemia, HC-HB, and high signal intensity lesions in the striatum on T1-weighted MRI. We studied 15 patients with mean age 71.5 years (range, 4894 years) and 12 age-matched healthy subjects (mean age, 68.4 years; range, 52-77 years) as controls. The demographic data of the patients were shown in Table 1. No neuroleptic was administered before the study in 10 patients. Five patients received neuroleptics (Table 1), which were discontinued 1 day before the examination. The study was approved by the Institutional Review Board of Kaohsiung Veterans General Hospital. Written informed consent was obtained from all subjects. The study protocol required approximately 3.5 hours of testing.
Electromyography Recording Surface electromyography was monitored on a computer screen and via loudspeakers at high gain to provide feedback on the state of muscle relaxation. If electromyography activities were detected in trials that required muscle relaxation, the trials were repeated. In the experiments that require the subject to maintain a constant contraction, auditory feedback was provided through loudspeakers, and visual feedback was provided by passing the electromyography signal through a leaky integrator, and the electromyography level was displayed on an oscilloscope. The signal was amplified (Digitimer D360, Letchworth Garden, UK), filtered (band pass 20 Hz to 2.5 kHz), digitized at 5 kHz (Power 1401, Cambridge Electronics Design, Cambridge, UK), and stored in a laboratory computer for off-line analysis.
Subjects
Transcranial Magnetic Stimulation Studies
We examined consecutive patients with HC-HB admitted to the neurological service of the Kaohsiung Veterans General Hospital from 2004 to 2012. Patients were included in the study if they had
Transcranial magnetic stimulation was performed with a 70-mm figure-of-eight coil and two Magstim 200 Stimulators connected via a Bistim module. The motor cortex contralateral to the hemichorea was
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tested in patients with hyperglycemic HC-HB, and the left or right motor cortex was chosen randomly in normal subjects. Surface electromyography was recorded from the first dorsal interosseous muscle. The optimal coil position over motor cortex for eliciting the motor evoked potential from the contralateral first dorsal interosseous muscle was established with the handle pointing backward and held approximately 45 degrees to the midsagittal line (approximately perpendicular to the presumed direction of the central sulcus). The optimal position was marked on the scalp to ensure identical placement of the coil throughout the experiment.
potential in the contralateral first dorsal interosseous muscle at rest. Single test pulse and paired pulses at interstimulus intervals of 2 and 10 ms (10 trials for each condition) were delivered in random order. For long interval intracortical inhibition (LICI),13 the suprathreshold conditioning stimulus and test stimulus were set to evoke approximately 1 mV motor evoked potential in the contralateral first dorsal interosseous muscle at rest. Test pulse alone and conditioning pulse followed by test pulse at interstimulus intervals of 50, 100, 150, and 200 ms were studied. Each run consisted of 20 trials of the test pulse alone and 10 trials of each interstimulus interval delivered in random order (60 trials).
Motor Threshold Resting motor threshold was the minimum stimulator output that produced motor evoked potentials of 50 mV or greater in at least 5 of 10 trials. Active motor threshold was the minimum stimulator output that produced motor evoked potentials of 100mV or more in at least 5 of 10 trials with a constant background contraction of 20% of the maximum integrated electromyography.
Motor Evoked Potential Recruitment Curve and Silent Period
Data Analysis For transcranial magnetic stimulation studies, the peak-to-peak motor evoked potential amplitude for each trial was measured. The inhibition or facilitation were calculated as a ratio of the conditioned to unconditioned (test pulse alone) motor evoked potential amplitude for each subject. Ratios less than 1 indicate inhibition, and ratios greater than 1 indicate facilitation. Values are expressed as mean 6 standard deviation.
Statistical Analysis
For the motor evoked potential recruitment curve, stimulus intensities of 100%, 110%, 120%, 130%, and 140% of the rest motor threshold for the resting state and of the active motor threshold for the active state (during 10%-20% maximum voluntary contraction) were studied. Ten pulses at each stimulus intensity were delivered 6 seconds apart, and the order of the stimulus intensities was randomized. The trials recorded in the motor evoked potential recruitment study at the active state were also used for measurement of the silent period (SP). The SP was measured from motor evoked potential onset to the first return of voluntary electromyography activity using the unrectified record of each trial.
For motor threshold, SICI, ICF, and LICI at different interstimulus intervals, the data from patients were compared with that from normal subjects using the unpaired Student’s t test. The effects of interstimulus interval on LICI, stimulus intensity on motor evoked potential recruitment curve, and SP duration were evaluated by repeated measures analysis of variance (ANOVA) with interstimulus interval or stimulus intensity as the within subject factor and subject group (patient vs. control) as the between subject factor. Fisher’s protected least significant difference was used for post hoc testing.
Short Interval Intracortical Inhibition (SICI), Intracortical Facilitation (ICF), and Long Interval Intracortical Inhibition (LICI)
Hemichorea-hemiballism was present on the right side in 9 patients and on the left side in 6 patients. The fasting blood glucose level on the day of transcranial magnetic stimulation study was between 4.39 and 11.33 mmol/L in all patients except in patient 7, in whom it was 19.2 mmol/L. At the time of the study, the HC-HB were intermittent and mild, involving mainly proximal limbs muscles. The patients were able to maintain the first dorsal interosseous muscle in the relaxed state.
The subjects relaxed (rest) or activated (active, 10%-20% maximum background contraction) the right first dorsal interosseous muscle during the experiment. The rest and active conditions were studied in separate runs. For short interval intracortical inhibition (SICI) and intracortical inhibition (ICF), a pairedpulse protocol was used.12 The conditioning stimulus was set at 80% of resting motor threshold for the rest condition and at 95% of active motor threshold for the active condition. The test stimulus for rest and active state were set to evoke 1 mV motor evoked
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Results
Motor Threshold There was no significant difference in rest (HC-HB 52.6 6 11.8% of stimulator output; controls
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interval 3 group interaction were not significant. However, for active LICI, repeated-measures ANOVA demonstrated a significant effect of group (P 5 0.0002) and a significant group 3 interstimulus interval interaction (P 5 0.014). Figure 3B shows that the significant interaction was due to greater motor evoked potential inhibition at longer interstimulus intervals (150 and 200 ms). Post hoc t tests confirmed increased inhibition at interstimulus intervals of 150 ms (P < 0.0001) and 200 ms (P 5 0.003) in patients compared with controls. No significant difference was found in active LICI between patients with and without neuroleptics (Fig. 3C).
Silent Period Duration Examples of SP in a patient and a control subject are shown in Figure 4A, and the group results are shown in Figure 4B. Repeated-measures ANOVA showed significant effects of group (P < 0.0001) and
FIG. 1. Motor evoked potentials recruitment curves at rest (A) and during voluntary contraction (B). No significant difference was found between patients with hyperglycemic HC-HB and control subjects in both conditions. Error bars represent standard errors. MEP, motorevoked potential; MT, motor threshold.
54.1% 6 7.4%) and active (HC-HB 43.9% 6 8.6%, controls 42.3% 6 6.7%) motor threshold between patients and controls.
Motor Evoked Potential Recruitment Curve Repeated-measures ANOVA demonstrated no significant effect of group but a significant effect of stimulus intensity (P < 0.0001) on motor evoked potential amplitude in both rest and active states (Fig. 1A, B). The group 3 stimulus intensity interaction was not significant.
SICI and ICF The results for rest SICI and ICF are shown in Figure 2A, and active SICI and ICF in Figure 2B. No significant difference was found between patients with HC-HB and normal subjects.
LICI Figure 3A shows rest LICI, and Figure 3B shows active LICI. The effect of interstimulus interval was significant (P < 0.0001) for both rest and active LICI. For rest LICI, the effect of group and the interstimulus
FIG. 2. Short interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in patients with hyperglycemic HC-HB and normal subjects during the rest (A) and active (B) states. No significant difference in SICI or ICF was found between the patients with hyperglycemic HC-HB and controls in both conditions. Ratios < 1 represent inhibition, and ratios > 1 represent facilitation. Error bars represent standard errors.
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duration between patients with and without neuroleptics (Fig. 4C).
Discussion Patients with hyperglycemic HC-HB had similar motor threshold, motor evoked potential recruitment curve, SICI, and ICF in both rest and active conditions
FIG. 3. Long interval intracortical inhibition (LICI) in patients with hyperglycemic HC-HB and normal subjects during the rest (A) and active (B) states. LICI was significantly increased during active state in patients with hyperglycemic HC-HB. (C) No significant difference in active LICI was found between patients who received and those who did not receive neuroleptics. Ratios < 1 represent inhibition, and ratios > 1 represent facilitation. Error bars represent standard errors. The asterisks indicate significant differences between patients and controls.
stimulus intensity (P < 0.0001) on SP duration. The SP was longer in patients than controls, and in both groups it increased with stimulus intensities. The interaction between stimulus intensity and group was not significant. There was no significant difference in SP
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FIG. 4. Silent period (SP) duration at different stimulus intensities. (A) Examples of superimposed tracings of silent periods from first dorsal interosseous muscle at the stimulus intensity of 140% of active MT in a patient with HC-HB and a normal subject. (B) Group results for SP duration. Patients with hyperglycemic HC-HB had significantly longer SP duration than normal subjects at all stimulus intensities tested. (C) No significant difference was seen in SP duration between patients who received and those who did not receive neuroleptics. MT, motor threshold.
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compared with normal subjects. In contrast to our hypothesis, they had increased LICI and SP duration in the motor cortex during muscle activation. Because our patients are elderly diabetic patients who had a recent major illness and still had HC-HB at the time of testing, we did not test the unaffected side to keep the testing within tolerable limits. We cannot exclude the possibility that hyperglycemia may affect the findings but consider this unlikely because not all patients were hyperglycemic at the time of the study, and a previous report found no effect of hyperglycemia on cortical excitability.14
LICI and SP Transcranial magnetic stimulation can be used to investigate the excitatory and inhibitory circuits in the motor cortex in neurological disorders.15 Short interval intracortical inhibition, ICF, and LICI occur in the motor cortex and are mediated by different neuronal populations.12,16 Short interval intracortical inhibition and ICF may provide information on GABAA and glutamatergic systems in the motor cortex.17,18 Because we tested only a single interstimulus interval and conditioning stimulus intensity for SICI and ICF, we cannot exclude subtle changes in SICI and ICF at other interstimulus intervals or conditioning stimulus intensities in HC-HB, but including these parameters will make the testing protocol too long for the patients. Long interval intracortical inhibition also occurs at the cortex and is likely mediated by GABAB receptors,17,19 because it is increased by baclofen.20 The SP refers to the duration of interruption of voluntary motor activity after transcranial magnetic stimulation. The first part of the SP reflects spinal cord inhibition, and the late part is largely attributable to cortical mechanisms.21,22 The late part of the SP is considered to be mediated by long-lasting cortical inhibition mediated through the GABAB receptor because it is increased by GABA reuptake inhibitor tiagabine23 and intrathecal administration of GABAB receptor agonist baclofen.24 Thus, prolonged SPs suggest hyperactivity of GABAB-mediated inhibitory system in the motor cortex. One of the characteristics of choreatic patients is motor impersistence, the inability to maintain a sustained muscle contraction. Although we carefully controlled the level of muscle contraction during the experiment and the level of contraction does not strongly influence SP duration,25 we cannot exclude the possibility that prolonged SP duration is partly attributable to variably sustained muscle contraction. The increased SP duration in our patients with hyperglycemic HC-HB is in agreement with the previous case report.10 The increased LICI and SP duration in our findings both suggest hyperactivity of inhibitory circuit in these patients, and the HC-HB is associated with increased
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GABAB receptor–mediated inhibitory activity (LICI and SP) in the motor cortex. Long interval intracortical inhibition and the SP may be two manifestations of a common long-lasting cortical inhibitory process, with LICI indicating its magnitude and the SP its duration.26 The duration of the SP corresponded to the interstimulus intervals at which LICI was present.27 Thus, the prolonged SP and increased LICI at 150 and 200 ms are likely related.
Comparison with Previous Studies Intracortical inhibition of the motor cortex has been investigated in other movement disorders and was found to be reduced or absent in focal arm dystonia,28 dyskinesia caused by lesions in the putamen or globus pallidus,29,30 and in patients with cervical dystonia.31 The results of paired-pulse transcranial magnetic stimulation in Huntington’s disease remain controversial. Some studies reported reduced SICI and increased ICF8 in the Huntington’s disease, but others found normal SICI and ICF.29 In another study, SICI was found to be intact in patients with Huntington’s disease, chorea acanthocytosis, systemic lupus erythematosus, and senile chorea.9 In the above studies, patients were studied only at rest. Most studies also reported that the cortical SP in Huntington’s disease had an abnormally long and variable duration,32,33 although others found a slight shortening of the SP in Huntington’s disease.34 Motor cortical excitability also has been studied in Parkinson’s disease. Most studies found that SP durations35,36 are reduced in Parkinson’s disease patients. Many previous studies also reported decreased rest SICI37,38 and rest LICI39 in Parkinson’s disease patients. Most of these changes normalized with dopaminergic treatment.36,40 A recent study found that Parkinson’s disease patients with levodopa-induced dyskinesia had reduced SICI and SP duration, which failed to increase with levodopa.41 Moreover, rest LICI was decreased in dyskinetic compared with nondyskinetic Parkinson’s disease patients.41 Thus, the cortical pathophysiology of levodopa-induced dyskinesia appears to be different from that of hyperglycemic HC-HB. A previous cortical excitability study was performed in a single diabetic patient with HC-HB, but the findings were difficult to interpret because the patient was on haloperidol. The patient had normal SICI and slightly reduced ICF and prolonged SP compared with controls, but had increased SICI and reduced ICF compared with controls who took a single dose of haloperidol.10 Long interval intracortical inhibition was not investigated. Although the authors suggested that reduced ICI is a pathophysiological feature of HC-HB, our study showed that this is not the case, because SICI was normal in a much larger number of
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drug-na€ıve patients, similar to some studies in Huntington’s disease and other choreic disorders.9,29,42 Neuroleptics are unlikely to explain the findings in our study because only 5 of 15 patients were previously treated at low doses, and the drugs were discontinued 1 day before the study. Moreover, no significant difference was found between the neuroleptic-na€ıve patients and those who had been treated with neuroleptics (Figs. 3C and 4C). An interesting finding in our study is that increased LICI was observed only during voluntary muscle activation but not at rest. Clinically, HC-HB was aggravated during muscle activation in all of our patients. Figure 3 shows that LICI at interstimulus intervals of 100 to 200 ms was decreased during voluntary muscle activation compared with rest in controls but not in HC-HB patients. Thus, the absence of normal reduction of LICI with movements accounts for the increased active LICI in HC-HB patients. Both active LICI and SP involve interactions between cortical inhibition and the voluntary motor command. Therefore, our findings suggest that this interaction between voluntary motor control and cortical inhibition is abnormal in hyperglycemic HC-HB. Because SP is caused partly by suppression of the voluntary motor drive,43 the prolonged SP in HC-HB suggest that this suppression is prolonged, and the increased LICI suggests that the magnitude of the suppression is increased. Active LICI but not rest LICI was reported to be decreased in patients with writer’s cramp.44 One study found normal active LICI in Huntington’s disease patients.42
hand dystonia. This reduction in cortical inhibition and the loss of surround inhibition48 may lead to excessive movements and overflow of motor command. Our findings suggest that the pathophysiological mechanisms of hyperglycemic HC-HB are different from those of dystonia. In summary, LICI and SP are increased in the motor cortex contralateral to the hemichorea in hyperglycemic HC-HB, but only during muscle activation. Our findings suggest that HC-HB is associated with increased GABAB receptor–mediated inhibitory activity in the motor cortex.
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Relation to Pathophysiological Models of the Basal Ganglia Current models of basal ganglia circuitry proposed that the chorea may result from increased activity of thalmocortical pathway caused by reduced inhibitory output from the internal segment of globus pallidus.45,46 The increased thalamocortical drive may increase the excitability of both excitatory and inhibitory circuits in the motor cortex.10,33 Although increased excitability of the excitatory circuits may result in excessive movement, the increased active LICI and SP duration we observed may be the correlate of increased excitability of inhibitory circuits. The increased cortical inhibitory activity may be a compensatory phenomenon to reduce the severity of chorea. This interpretation is in agreement with the finding of shortened SP in Parkinson’s disease, which also may be a compensatory mechanism,35 because Parkinson’s disease is associated with increased inhibitory output from the basal ganglia and reduced thalamocortical activity.46,47 By contrast, in other hyperkinetic movement disorders such as dystonia, the abnormalities of excitability are largely loss of cortical inhibition. For example, SICI28 and active LICI44 are reduced in focal
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