Cortical Excitability is Abnormal in Patients with the Fixed Dystonia Syndrome

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1 Movement Disorders Vol. 23, No. 5, 2008, pp Movement Disorder Society Cortical Excitability is Abnormal in Patients with the Fixed Dystonia Syndrome Laura Avanzino, MD, 1,2 Davide Martino, MD, 1,3 Bart P. C. van de Warrenburg, MD, PhD, 1,4 Susanne A. Schneider, MD, 1 Giovanni Abbruzzese, MD, 2 Giovanni Defazio, PhD, 3 Anette Schrag, MD, 5 Kailash P. Bhatia, MD, 1 and John C. Rothwell, PhD 1 * 1 Sobell Department of Motor Neuroscience, Institute of Neurology, University College London, London, United Kingdom 2 Department of Neurosciences, Ophthalmology and Genetics, University of Genoa, Italy 3 Department of Neurologic and Psychiatric Sciences, University of Bari, Italy 4 Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands 5 Royal Free and University College Medical School, University College London, London, United Kingdom Abstract: A form of fixed dystonia (FD) without evidence of basal ganglia lesions or neurodegeneration has been recently characterized (Schrag et al., Brain 2004;127: ), which may overlap the clinical spectrum of either complex regional pain syndrome or dystonia. Transcranial magnetic stimulation studies in typically mobile dystonia revealed abnormal motor cortical excitability and sensori-motor integration. We compared 12 patients with limb FD to 10 patients with primary adult-onset typically mobile dystonia and 11 agematched healthy volunteers. Measurements at the first digital interosseus representation area on both hemispheres included: short intracortical inhibition (SICI), contralateral silent period (csp), and short and long afferent inhibition (SAI and LAI). Repeated measure ANOVA and post-hoc t-tests were used for statistical analysis. SICI was significantly reduced in both hemispheres of patients with typical and FD, compared to healthy subjects. For both hemispheres, csp duration was shorter in both fixed and typical dystonia patients. SAI and LAI did not significantly differ between the three groups. The abnormal cortical excitability observed in FD might represent an underlying trait predisposing to different clinical forms of dystonia Movement Disorder Society Key words: TMS; dystonia; motor cortex. Primary dystonia is typically mobile and exacerbated by posture or action. Fixed dystonia (FD) is observed usually following basal ganglia lesions, 1 in dystonia (PsychD) and complex regional pain syndrome (CRPS). Schrag et al. characterized FD in 103 patients without basal ganglia lesions or neurodegeneration. 2 Although criteria for PsychD and CRPS were fulfilled in most of these patients, a proportion could be classified neither as primarily neurological nor as. 2 *Correspondence to: Prof. John Rothwell, Sobell Department of Motor Neuroscience, Institute of Neurology, University College London; London WC1N 3BG, United Kingdom. j.rothwell@ion.ucl.ac.uk Received 10 July 2007; Revised 20 September 2007; Accepted 2 October 2007 Published online 3 January 2008 in Wiley InterScience (www. interscience.wiley.com). DOI: /mds Reduced excitability of inhibitory mechanisms at many levels of the motor system was reported in primary focal or segmental dystonia, even beyond the central representations of the affected body parts. 3-5 Abnormal short interval intracortical inhibition (SICI) in both hemispheres was also reported in unilateral dystonia secondary to a contralateral structural lesion, 6 suggesting that reduced inhibition represents a susceptibility trait for dystonia. 7 A lack of cortical and spinal inhibition was described by Espay et al. 7 in affected muscles of patients with PsychD. However, because contralateral unaffected body parts were not examined, these authors could not distinguish whether the changes were a consequence of the long-standing dystonic posture, or an abnormality predisposing to dystonia. We investigated cortical inhibitory mechanisms in 12 patients with FD. Patients were tested on both affected 646

2 CORTICAL EXCITABILITY IN FIXED DYSTONIA 647 and unaffected sides to verify the presence of cortical inhibition. We found abnormalities similar to those reported in primary dystonia on both sides of the body, suggesting that they represent a predisposing endophenotypic trait for dystonia. 6 PATIENTS AND METHODS Patients Patients with limb FD were recruited from the National Hospital for Neurology and Neurosurgery, London, if they presented with immobile dystonic postures that did not return to the neutral position at rest, and if no cause for their FD was identifiable. 2 FD patients were further diagnosed with clinically definite, probable or possible PsychD, according to the criteria adopted in Schrag et al. 2 CRPS was diagnosed according to the IASP/CRPS criteria. 8 Patients with typically mobile ( typical ) primary adult-onset dystonia 9 (i.e. dystonic postures returning to the neutral position at rest), and healthy adults as control groups were recruited. All participants gave their written informed consent. The experiments conformed to the Declaration of Helsinki standards and the study was approved by the local Ethics Committee. Transcranial Magnetic Stimulation Subjects were seated in a comfortable chair with a mounted head rest during the experiments. Transcranial magnetic stimulation (TMS) was performed with a figure-of-eight coil connected by a Y cable to a pair of linked Magstim bistim magnetic stimulators (Magstim, UK). The coil was placed tangentially to the scalp with the handle pointing backwards and laterally at a 45 angle to the sagittal plane inducing a posterior anterior current in the brain. The magnetic stimuli produced a monophasic pulse with a rise-time of 100 microseconds, decaying back to zero over 0.8 milliseconds. We determined the motor hot spot for activation of the first digital interosseeus (FDI). EMG was recorded with silver disc surface electrodes placed in a tendon belly arrangement over the FDI and the first metacarpophalangeal joint bilaterally. The ground electrode was placed at the wrist. EMG signals were amplified and filtered (20 Hz 1 khz) with a D360 amplifier (Digitimer, UK). The signals were sampled at 5,000 Hz, digitized using a laboratory interface (Power1401; Cambridge Electronics Design (CED), UK), and stored for off-line analysis. Motor-evoked potentials (MEPs) were recorded from both FDI in FD patients, and from the dominant FDI in typical dystonia patients and in healthy subjects, except for one right-handed subject with left-sided writer s cramp, in whom MEPs were recorded from the nondominant (i.e. left) FDI. Resting motor threshold (RMT) and active motor threshold (AMT) were determined. RMT was defined as the minimum stimulus intensity that produced a MEP of at least 50 V in 5 of 10 consecutive trials. AMT was determined during voluntary tonic contraction at 5 to 10% of maximum voluntary contraction and was defined as the minimum intensity which produced a MEP of at least 200 V in at least three of five consecutive trials. SICI is produced when a subthreshold conditioning stimulus is followed, after an interstimulus interval (ISI) of 1 to 5 milliseconds, by a suprathreshold test stimulus. 10 For SICI, we used different conditioning stimulus intensities [CSI (70, 80, and 90% of the AMT)], followed by a test stimulus delivered to the hand area of the motor cortex. The test stimulus was adjusted to produce MEPs of 1 mv in amplitude. Subjects received in a random order either the test stimulus alone or the test stimulus preceded by the conditioning stimulus at ISIs of 2 or 3 milliseconds. Three blocks (one for each CSI) of 30 trials were performed (test alone, ISI 2 milliseconds, ISI 3 milliseconds). Silent period is a period of EMG silence following a suprathreshold TMS pulse over the contralateral motor area when the corresponding muscle is voluntarily contracted. 11 Subjects were asked to squeeze a 2.5-cm block between their thumb and index fingers. Visual feedback on the intensity of muscle contraction was provided to the subjects, and they were instructed to maintain a constant muscle contraction at 30% of maximum voluntary contraction. The contralateral silent period (csp) was tested delivering 10 stimuli with an intensity of 150% the AMT during contraction of the contralateral FDI. The csp duration extended from MEP onset to the reappearance of the continuous (baseline) EMG activity. Peak-to-peak amplitude of active MEP was also measured; to minimize between-subjects variability of csp measures, 12 csp duration/mep amplitude ratios were calculated. When a suprathreshold TMS stimulus over the hand area is preceded by an electrical stimulus delivered at the wrist over the median nerve, there is a reduction in MEP amplitude recorded from the hand muscles. 13 This happens only at short ISIs of around 20 milliseconds (short latency afferent inhibition, SAI) and at longer ISIs of 200 to 600 milliseconds (long latency afferent inhibition, LAI). Both SAI and LAI measure the modulation of cortical excitability by sensory inputs. LAI is probably dependent on cortico-cortical connections involving the

3 648 L. AVANZINO ET AL. motor cortex and both primary and secondary somatosensory cortical areas, 14 whereas SAI is likely to reflect a direct inhibitory modulation of the primary motor cortex, probably mediated by cholinergic pathways. 15 SAI and LAI were tested with a suprathreshold test stimulus preceded by an electrical conditioning stimulus over the median nerve at the wrist (cathode proximal, constant square wave current, duration 200 microseconds, intensity set just above threshold for evoking a small twitch in the opponens pollicis muscle). The ISIs were set at 18, 20, 22, 50, 200, and 600 milliseconds. Statistical Analysis Two-factor ANOVAs with CSI or ISI as within-subject factors, and GROUP as between-subject factor were performed for the SICI and SAI/LAI, respectively. In both cases, the factor GROUP was run twice, once comparing healthy, typical dystonia, and the affected side of FD patients, whereas the second comparison was between healthy, typical dystonia, and the unaffected side of FD patients. In the three FD patients with bilateral symptoms, the less severely affected side was classified as unaffected. The post hoc tests (below) included an analysis after these individuals were omitted from the group data. Post hoc comparisons used paired or unpaired t tests between groups as appropriate. All statistical analyses were conducted with SPSS 11.5, and the level of significance was set at RESULTS Twelve patients with FD were recruited (Table 1). Mean age was years and disease duration range was 4 to 23 years. Dystonia was predominantly unilateral in 9 patients, whereas 3 had severe bilateral involvement, 5 patients had predominant lower limb involvement, 3 had predominant upper limb involvement, and in 4 upper and lower extremities were similarly affected. Four patients were diagnosed with clinically definite PsychD, 4 with probable PsychD, 1 with CRPS type 1, and 3 did not fulfill the criteria for either PsychD or CRPS. Ten patients with primary adult-onset typical dystonia were recruited (mean SD age, years; 7 women, 3 men); disease duration ranged from 2 to 23 years. Four patients had focal cervical dystonia, 3 focal writer s cramp, 1 focal blepharospasm, 1 segmental (blepharospasm and writer s cramp), and 1 multifocal (cervical, laryngeal, and hand) dystonia. All patients underwent a 4-month wash-out from botulinum toxin (BTX) injections, and a week wash-out from oral medications. Eleven healthy subjects were also included (mean SD age, years; 6 women and 5 men). There were no differences in RMT, AMT, mean intensity used to evoke the 1 mv test response, and amplitude of unconditioned MEP (Table 2). Since there was no difference between SICI at ISIs of 2 and 3 milliseconds in any of the groups, all subsequent analyses were performed using a single mean value. Figure 1A illustrates the relationship between CSI and the amount of SICI for all three groups of patients. As previously reported, 16 the threshold for evoking SICI was about 70% AMT. Since many subjects have no SICI at this intensity, we compared the groups using SICI at 80 and 90% AMT. A two-factor ANOVA comparing data from healthy subjects, patients with typical dystonia, and the affected side of FD patients revealed a significant effect of GROUP (F 5.52; P 0.009), but no main effect of CSI or GROUP CSI interaction. To further investigate the effect of GROUP, post hoc t-tests were performed combining data obtained from CSIs of 80 and 90% AMT (Fig. 1B). Patients with typical dystonia had significantly reduced SICI compared to healthy subjects (P ), and SICI was significantly reduced on both sides (i.e. contralateral to the affected and to the unaffected side) in FD patients (P and P , respectively). There was no difference between the amount of SICI in the affected and unaffected sides of FD patients; therefore, the rest of the analysis was performed grouping the affected and unaffected side in a mean value. Excluding patients with bilateral symptoms had no effect on these comparisons (Fig. 1B). Furthermore, there was no difference in the amount of SICI in FD patients with and without involvement of the hand (Fig. 1B). As reported previously, 17 the csp was shorter in patients with typical dystonia than in healthy subjects (P 0.01; Fig. 2). In FD patients, the csp was also shorter than in healthy subjects, on both the affected (P 0.001) and unaffected (P 0.001) sides, but there was no difference between sides. Active MEP amplitude did not differ among all groups (data not shown). The analysis of csp duration/mep amplitude ratios confirmed a significant difference between healthy subjects and typical dystonia (healthy subjects , typical dystonia ; P 0.02), affected (affected side FD ; P 0.01) and unaffected (unaffected side FD ; P 0.02) sides of FD patients. Results were unchanged excluding bilateral FD patients (mean value of affected and unaffected side) (see Fig. 2). There was no difference in csp duration in FD patients with and without hand involvement (see Fig. 2).

4 CORTICAL EXCITABILITY IN FIXED DYSTONIA 649 Patient number Age at study TABLE 1. Demographic and clinical features of patients with fixed dystonia Age at onset Affected limb(s) Right leg and foot 2 (patient no. 32 of 3 (patient no. 28 of 4 56 In her 40s 5 (patient no. 31 of 6 (patient no. 24 of 7 (patient no. 15 of Type and site of onset/precipitating factor Course Clinical diagnosis Gradual in right foot/stress fracture of the right foot Left leg Subacute in left leg/abscesses on thigh psychological stressor Right foot and hand Subacute in right foot/right knee arthroscopy psychological stressor Both hands Gradual in right hand/no clear precipitant Right foot Acute in right foot/tingling and weakness in legs Right foot and hand Acute in right foot/back injury following a motorvehicle accident Right foot Gradual in right foot/peripheral injury Left leg, foot and shoulder Left leg and foot 10 (patient no. 37 of Both hands and feet Subacute in left foot/no clear precipitant Gradual in left foot/no clear precipitant Subacute in left foot/fracture of left hallux Both hands Gradual in right hand/no clear precipitant Left hand Subacute in left hand/fracture of left scaphoid bone Remitting-relapsing Spread to right hand and neck Spread to left hand Spread to right foot Spread to right hand Spread to left shoulder Spread to all four limbs Spread to left hand Does not fulfil criteria for dystonia or CRPS a,b dystonia c dystonia d,e dystonia f dystonia c,f,g dystonia f,g,h dystonia i Does not fulfil criteria for dystonia or CRPS b dystonia c,d,i dystonia a,b,d,f,i Does not fulfil criteria for dystonia or CRPS a CRPS type 1 a,b,e Letters c, d, f, g, h, i are used to specify clinical features of dystonia in individual patients; Letters a, b, e are used to specify clinical features of complex regional pain syndrome in individual patients. a, hyperalgesia or allodynia, which are not limited to the territory of a single peripheral nerve, or are disproportionate to the inciting event; b, edema, changes in skin blood flow or trophic changes; c, previous unexplained complaints despite appropriate investigations; d, obvious psychiatric disturbances; e, painful intermittent spasms; f, multiple somatizations; g, nonanatomical sensory loss; h, false weakness; i, other incongruent movements. The amount of SAI and LAI at various ISIs is shown in Figure 3A,B. Separate two-factor ANOVAs for SAI and LAI both showed an expected main effect of ISI (SAI: F 9.40, P and F 6.13, P for the affected and unaffected side, respectively; LAI: F 6.46, P 0.017, F 8.56, P for the affected and unaffected side, respectively), but there was no main effect of GROUP or ISI GROUP interaction. TABLE 2. Stimulation intensities corresponding to rest motor threshold, active motor threshold, and 1 mv motor-evoked potential (MEP) are expressed as mean percentage of maximum stimulator output (SD) Normal subjects (n 11): LH Primary adult-onset typical dystonia (n 10): LH or affected H Fixed dystonia: Affected side (n 12) Fixed dystonia: Unaffected side (n 12) Rest motor threshold (%) 41.1 (5.9) a 43.5 (4.7) 43.4 (10.7) 43.7 (6.9) Active motor threshold (%) 33.8 (4.8) 33.6 (3.8) 32.1 (7.2) 33.4 (7.1) Intensity 1mV MEP (SICI, SAI, LAI) (%) 50.6 (7.8) 50.5 (4.9) 54.1 (11.3) 56.4 (11.2) Unconditioned TEST MEP Amplitude (mv) 0.85 (0.4) 0.90 (0.3) 0.84 (0.4) 0.88 (0.4) The unconditioned MEP (test alone) amplitude mean value (mv) is also shown. L: left; H: hemisphere. Two-tailed Student s paired t-test showed no difference between the values. a Values within parentheses are SDs.

5 650 L. AVANZINO ET AL. FIG. 2. Silent period duration in healthy subjects, patients with typical dystonia, affected and unaffected side of FD patients, FD patients with only unilateral involvement, and FD patients with and without hand involvement. Abscissa indicates the group of subjects. Ordinate indicates the duration of the silent period expressed in milliseconds. FIG. 1. A. The effect of the conditioning stimulus on the cmep in the three groups of subjects. Abscissa indicates the conditioning stimulus intensity expressed as a percentage of the active motor threshold. Ordinate indicates the size of the conditioned response, expressed as a ratio to the unconditioned test response. B. The data obtained from healthy subjects, patients with typical dystonia, affected and unaffected sides of FD patients, FD patients with only unilateral involvement, and FD patients with ( hand involvement) and without ( hand involvement) hand involvement. Abscissa indicates the group of subjects, while Ordinate indicates the size of the conditioned response, expressed as a ratio to the unconditioned test response. Combined data from CS 80 and 90% AMT are shown; for the FD patients with the unilateral involvement and for the two subgroups of FD patients with and without hand involvement, the mean value of the affected and unaffected side is shown. Since it seems unlikely that unilateral dystonic postures could determine bilateral cortical excitability changes, we conclude that they more likely reflect a dystonia susceptibility trait. Further supporting this, five FD pa- DISCUSSION A recent TMS study on PsychD reported almost the same motor cortical abnormalities observed in primary dystonia. 7 The authors speculated that these might either be a consequence of dystonic posturing, or an endophenotypic trait predisposing individuals to develop dystonia as part of their illness. We examined a subset of the physiological markers previously investigated in PsychD 7 showing similar changes (reduced SICI and shorter csp) in both patients with FD (most of whom classified as clinically definite or probable PsychD) and patients with typical primary dystonia. Our FD patients differed clinically from those studied by Espay et al., 7 none of whom presented with a fixed form of PsychD. Importantly, even though FD in our patients was predominantly unilateral, cortical abnormalities were bilateral. FIG. 3. Results from SAI (A) and LAI (B). Effect of the conditioning electrical stimulus on the MEP in the three groups of subjects (healthy subjects, typical dystonia, and affected and unaffected side of FD patients). In all the graphs, Abscissa indicates the interstimulus intervals; Ordinate indicates the size of the conditioned response, expressed as a percentage of the unconditioned test response.

6 CORTICAL EXCITABILITY IN FIXED DYSTONIA 651 tients had exclusive leg involvement, yet their results were still abnormal even though SICI and csp were measured in hand muscles only. Such a widespread trait could also explain the contralateral spread of FD observed in a proportion of patients. 2,18 The abnormal cortical excitability in FD patients, most of whom diagnosed with PsychD, seemingly reduces the separation between organic and dystonia. However, other electrophysiological findings proved helpful in discriminating organic from movement disorders. 19 The pathophysiology of movement disorders is highly complex, their clinical presentation is highly diverse, and factors modulating their phenotype are currently unknown. 19 In keeping with Espay et al., 7 we hypothesize that, in the presence of a predisposing psychopathology, an underlying abnormal cortical excitability might act as a modulator of phenotype, and drive the organic counterpart of the illness toward dystonia. Although less likely, abnormal cortical excitability could still be explained by prolonged abnormal posturing, via changes in peripheral sensory input. The postural abnormality in FD is more severe than the one in typical primary dystonia, or in intermittent PsychD. 7 However, peripherally induced cortical disinhibition was reported only contralaterally to the affected limb. 20 Alternatively, changes in the unaffected limb might derive from overuse following dystonia onset in the affected limb. Although we cannot exclude that BTX induced longterm plastic changes in cortical excitability, this is unlikely. Previous studies found either no effect of BTX on cortical excitability, or effects lasting only as long as the peripheral effects of BTX on muscle function. 21,22 FD is often painful. 2 Pain syndromes (e.g. CRPS I) were associated with bilaterally reduced SICI, despite unilateral symptoms and absence of dystonia. 23 However, the amount of SICI reduction did not correlate to pain intensity or duration, suggesting that it might not be a mere effect of pain. This consideration notwithstanding, a link between pain and cortical disinhibition cannot be totally excluded in FD. Why would reduced excitability of cortical inhibitory circuits predispose toward development of dystonia? These circuits might work preventing undesired muscle contractions during carefully focused motor actions. Another part of the motor system might partially compensate for their dysfunction; however, if these other structures become compromised, then symptoms emerge. Another possibility relates to the link between levels of inhibition and mechanisms of cortical plasticity. In animal models it is difficult to induce long-term potentiation (LTP) by repetitive electrical stimulation of cortex unless GABAergic inhibition is reduced by application of bicuculline. 24 Thus it may be that reduced inhibition in the motor cortex of susceptible individuals predisposes excessive synaptic plasticity. Indeed, increased LTP- and long-term depression-like plasticity has been described in primary dystonia patients, who also have reduced SICI and csp. 25,26 In FD patients, prolonged assumption of fixed postures may lead to excessive plastic changes in the motor system that reinforce the posture and lead to development of dystonia. SAI and LAI were normal in both fixed and typical dystonia. Previous reports suggested LAI abnormalities in the affected hand of patients with writer s cramp, but not in patients with cervical dystonia. 14 This may explain the lack of effect in our mixed typical dystonia group. SAI is generally reported to be normal in patients with writer s cramp, suggesting a different mechanism from LAI. 14,27 Altogether, it is difficult to make any definite conclusions about the amount of afferent inhibition in FD. Our samples were relatively small, and we cannot exclude that a difference between patients and healthy subjects could become evident with larger samples. Moreover, other studies in typical dystonia showed abnormal afferent inhibition only in affected muscles. 14 In the present study, some patients had FD only in the leg while inhibition was examined only in the arm, making it possible that we overlooked a subtle afferent inhibition change. 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