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1.  Increased volume and impaired function: the role of the basal ganglia in writer's cramp 
Brain and Behavior  2014;e00301.
Abstract
Introduction
The pathophysiology of writer's cramp, a task‐specific dystonia, remains unclear. The objective of this study was to investigate the basal ganglia circuit and the cerebellum during a complex motor sequence learning task carried out with the nonaffected hand in writer's cramp patients.
Methods
We applied structural and functional imaging in 22 writer's cramp patients and 28 matched controls using 3T MRI. With the asymptomatic left hand all participants learned a complex, sequential, five‐element sequence‐tapping task as accurately and quickly as possible. Functional imaging was measured during a repeated (15 times), fixed block design with tapping (30 sec) and rest (30 sec). Additionally, gray matter volume of the basal ganglia was analyzed using voxel‐based morphometry (VBM).
Results
While behavior was comparable between groups, after small volume correction the anterior part of the right putamen and the left globus pallidus exhibited reduced blood oxygen level‐dependent (BOLD) activity in patients during the sequential finger‐tapping task. VBM analysis showed larger gray matter volume bilateral in the posterior part of the putamen and globus pallidus. There were no group differences in the cerebellum.
Conclusion
The results indicate an impairment of anterior basal ganglia loops involved in producing complex sequential movements of the unaffected hand. These findings are in line with previous reports of reduced neuronal activity in the globus pallidus internus. Higher gray matter volume of the putamen and globus pallidus may stem from elevated activity of the direct pathway, which could reflect a compensatory phenomenon or a primary predisposition, that is, endophenotypic trait.
doi:10.1002/brb3.301
PMCID: PMC4309880  PMID: 25642386
Focal hand dystonia; functional magnetic resonance imaging; motor learning; voxel‐based morphometry; writer's cramp
2.  Striatal dopaminergic dysfunction at rest and during task performance in writer’s cramp 
Brain  2013;136(12):3645-3658.
Writer’s cramp is a task-specific focal hand dystonia characterized by involuntary excessive muscle contractions during writing. Although abnormal striatal dopamine receptor binding has been implicated in the pathophysiology of writer’s cramp and other primary dystonias, endogenous dopamine release during task performance has not been previously investigated in writer’s cramp. Using positron emission tomography imaging with the D2/D3 antagonist 11C-raclopride, we analysed striatal D2/D3 availability at rest and endogenous dopamine release during sequential finger tapping and speech production tasks in 15 patients with writer’s cramp and 15 matched healthy control subjects. Compared with control subjects, patients had reduced 11C-raclopride binding to D2/D3 receptors at rest in the bilateral striatum, consistent with findings in previous studies. During the tapping task, patients had decreased dopamine release in the left striatum as assessed by reduced change in 11C-raclopride binding compared with control subjects. One cluster of reduced dopamine release in the left putamen during tapping overlapped with a region of reduced 11C-raclopride binding to D2/D3 receptors at rest. During the sentence production task, patients showed increased dopamine release in the left striatum. No overlap between altered dopamine release during speech production and reduced 11C-raclopride binding to D2/D3 receptors at rest was seen. Striatal regions where D2/D3 availability at rest positively correlated with disease duration were lateral and non-overlapping with striatal regions showing reduced D2/D3 receptor availability, except for a cluster in the left nucleus accumbens, which showed a negative correlation with disease duration and overlapped with striatal regions showing reduced D2/D3 availability. Our findings suggest that patients with writer’s cramp may have divergent responses in striatal dopamine release during an asymptomatic motor task involving the dystonic hand and an unrelated asymptomatic task, sentence production. Our voxel-based results also suggest that writer’s cramp may be associated with reduced striatal dopamine release occuring in the setting of reduced D2/D3 receptor availability and raise the possibility that basal ganglia circuits associated with premotor cortices and those associated with primary motor cortex are differentially affected in primary focal dystonias.
doi:10.1093/brain/awt282
PMCID: PMC3859223  PMID: 24148273
dystonia; dopamine; PET; raclopride; striatum
3.  Cerebellum and processing of negative facial emotions: cerebellar transcranial DC stimulation specifically enhances the emotional recognition of facial anger and sadness 
Cognition & emotion  2011;26(5):786-799.
Some evidence suggests that the cerebellum participates in the complex network processing emotional facial expression. To evaluate the role of the cerebellum in recognizing facial expressions we delivered transcranial direct current stimulation (tDCS) over the cerebellum and prefrontal cortex. A facial emotion recognition task was administered to 21 healthy subjects before and after cerebellar tDCS; we also tested subjects with a visual attention task and a visual analogue scale (VAS) for mood.
Anodal and cathodal cerebellar tDCS both significantly enhanced sensory processing in response to negative facial expressions (anodal tDCS, p=0.0021; cathodal tDCS, p= 0.018), but left positive emotion and neutral facial expressions unchanged (p>0.05). tDCS over the right prefrontal cortex left facial expressions of both negative and positive emotion unchanged.
These findings suggest that the cerebellum is specifically involved in processing facial expressions of negative emotion.
doi:10.1080/02699931.2011.619520
PMCID: PMC4234053  PMID: 22077643
Cerebellum; Cerebellar Dysfunction; Prefrontal Cortex; Emotion; Facial Emotion Recognition; Emotional Disturbances; tDCS
5.  Preclinical and Clinical Neural Network Changes in SCA2 Parkinsonism 
Parkinsonism & related disorders  2012;19(2):158-164.
Background
The pathophysiological changes before the presentation of clinical symptoms in parkinsonism are unclear. In this study, we investigated neural network modulations in persons in the preclinical stage of familial parkinsonism, and how the network interactions change at the clinical stage.
Methods
We performed functional MRI in a family with SCA2 mutation, including 9 asymptomatic carriers and 10 mutation carriers with parkinsonian symptoms. Functional connectivity from the posterior putamen bilaterally and rostral supplementary motor area was used to explore network interactions in the subjects.
Results
Both the asymptomatic carriers and patients had decreased connectivity within the basal ganglia-thalamus-cortical motor loop compared to controls. The asymptomatic carriers showed extensively increased connectivity compared to controls, including the cortico-cortical motor, cortico-cerebellar, cortico-brainstem, and part of the basal ganglia-thalamus-cortical motor circuits. In contrast, the connectivity of most of these networks was decreased in the patients. These abnormalities were relatively normalised after levodopa administration.
Conclusions
In the preclinical stage of SCA2 parkinsonism, the connectivity of a part of the basal ganglia motor loop is weakened as a consequence of dopaminergic deficits; meanwhile, the connectivity of other large-scale brain networks is strengthened presumably to compensate for the dysfunction of the basal ganglia to maintain brain function in the early stage of dopaminergic deficits. The simultaneous effects of progressive disruption of basal ganglia motor circuits and failure of compensatory mechanisms as dopaminergic dysfunction progresses may contribute to the onset of clinical symptoms.
doi:10.1016/j.parkreldis.2012.08.011
PMCID: PMC4182914  PMID: 23000299
parkinsonism; SCA2 mutation; Functional connectivity; Basal ganglia motor circuits; Compensation
6.  Transcranial Direct Current Stimulation for the Treatment of Focal Hand Dystonia 
Background
The treatment of Writer’s Cramp, a task-specific focal hand dystonia, needs new approaches. A deficiency of inhibition in the motor cortex might cause Writer’s Cramp. Transcranial direct current stimulation modulates cortical excitability and may provide a therapeutic alternative.
Methods
In this randomized, double-blind, sham-controlled study, we investigated efficacy of cathodal stimulation of contralateral motor cortex in 3-sessions within one week. Assessment over a 2-week period included clinical scales, subjective ratings, kinematic handwriting analysis and neurophysiological evaluation.
Results
Twelve patients with unilateral dystonic Writer’s Cramp were investigated, 6 received transcranial direct current and 6 sham-stimulation. Cathodal transcranial direct current stimulation had no favorable effects on clinical scales, and failed to restore normal handwriting kinematics and cortical inhibition. Subjective worsening remained unexplained leading to premature study termination.
Conclusion
Repeated sessions of cathodal transcranial direct current stimulation of the motor cortex yielded no favorable results supporting a therapeutic potential in Writer’s Cramp.
doi:10.1002/mds.23691
PMCID: PMC4180819  PMID: 21495074
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Focal Hand Dystonia
7.  Cerebellum and Integration of Neural Networks in Dual-Task Processing 
NeuroImage  2012;65:466-475.
Performing two tasks simultaneously (dual-task) is common in human daily life. The neural correlates of dual-task processing remain unclear. In the current study, we used a dual motor and counting task with functional MRI (fMRI) to determine whether there are any areas additionally activated for dual-task performance. Moreover, we investigated the functional connectivity of these added activated areas, as well as the training effect on brain activity and connectivity. We found that the right cerebellar vermis, left lobule V of the cerebellar anterior lobe and precuneus are additionally activated for this type of dual-tasking. These cerebellar regions had functional connectivity with extensive motor- and cognitive-related regions. Dual-task training induced less activation in several areas, but increased the functional connectivity between these cerebellar regions and numbers of motor- and cognitive-related areas. Our findings demonstrate that some regions within the cerebellum can be additionally activated with dual-task performance. Their role in dual motor and cognitive task processes is likely to integrate motor and cognitive networks, and may be involved in adjusting these networks to be more efficient in order to perform dual-tasking properly. The connectivity of the precuneus differs from the cerebellar regions. A possible role of the precuneus in dual-task may be monitoring the operation of active brain networks.
doi:10.1016/j.neuroimage.2012.10.004
PMCID: PMC4173076  PMID: 23063842
Dual-task Performance; fMRI; Brain Activity; Network Connectivity; Neural Efficient
8.  Controlled Study of 50 Hz Repetitive Transcranial Magnetic Stimulation for the Treatment of Parkinson’s Disease 
Objective
To investigate the safety and efficacy of 50Hz repetitive Transcranial Magnetic Stimulation(rTMS) in the treatment of motor symptoms in Parkinson’s disease(PD).
Background
Progression of PD is characterized by the emergence of motor deficits, which eventually respond less to dopaminergic therapy and pose a therapeutic challenge. RTMS has shown promising results in improving gait, a major cause of disability, and may provide a therapeutic alternative. Controlled studies suggest increasing stimulation frequency might enhance therapeutic efficacy.
Methods
In this randomized, double blind, sham-controlled study, we investigated safety and efficacy of 50Hz-rTMS of the motor cortices in 8sessions over 2weeks. Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, UPDRS and additional clinical, neurophysiological and neuropsychological parameters. In addition, safety of 50Hz-rTMS was tested with EMG-EEG-monitoring during and after stimulation.
Results
We investigated 26 patients with mild to moderate PD: 13 received 50Hz-rTMS and 13 sham-stimulation. 50Hz-rTMS did not improve gait, bradykinesia, global and motor UPDRS, but there appeared a short-lived “on”-state improvement in activities of daily living (UPDRS II). 50Hz-rTMS lengthened the cortical silent period, but other neurophysiology and neuropsychological measures remained unchanged. EMG/EEG recorded no pathological increase of cortical excitability or epileptic activity. There were no adverse effects.
Conclusion
50Hz-rTMS of the motor cortices appears safe, but fails to improve motor performance and functional status in PD. Prolonged stimulation or other techniques with rTMS might be more efficacious, but need to be established in future research.
doi:10.1177/1545968312445636
PMCID: PMC4169897  PMID: 22593114
repetitive transcranial magnetic stimulation (rTMS); 50 Hz rTMS; non-invasive brain stimulation; therapeutic study; Parkinson’s disease
9.  The TOR1A Polymorphism rs1182 and the Risk of Spread in Primary Blepharospasm 
We studied the influence of the rs1182 polymorphism of the TOR1A gene on the risk of dystonia spread in two representative cohorts of patients presenting with primary blepharospasm (BSP), one from Italy and the other from the United States of America. The relationship between rs1182 polymorphism and spread was estimated by Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted by age and sex, age of BSP onset. In both series, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele. The comparable findings obtained in two independent cohorts support a genetic contribution to BSP spread.
doi:10.1002/mds.22471
PMCID: PMC4167593  PMID: 19202559
TOR1A; single-nucleotide polymorphisms; blepharospasm; primary adult-onset; dystonia; spread
10.  Basal ganglia circuits changes in Parkinson’s disease patients 
Neuroscience letters  2012;524(1):55-59.
Functional changes in basal ganglia circuitry are responsible for the major clinical features of Parkinson’s disease (PD). Current models of basal ganglia circuitry can only partially explain the cardinal symptoms in PD. We used functional MRI to investigate the causal connectivity of basal ganglia networks from the substantia nigra pars compacta (SNc) in PD in the movement and resting state. In controls, SNc activity predicted increased activity in the supplementary motor area, the default mode network, and dorsolateral prefrontal cortex, but, in patients, activity predicted decreases in the same structures. The SNc had decreased connectivity with the striatum, globus pallidus, subthalamic nucleus, thalamus, supplementary motor area, dorsolateral prefrontal cortex, insula, default mode network, temporal lobe, cerebellum, and pons in patients compared to controls. Levodopa administration partially normalized the pattern of connectivity. Our findings show how the dopaminergic system exerts influences on widespread brain networks, including motor and cognitive networks. The pattern of basal ganglia network connectivity is abnormal in PD secondary to dopamine depletion, and is more deviant in more severe disease. Use of functional MRI with network analysis appears to be a useful method to demonstrate basal ganglia pathways in vivo in human subjects.
doi:10.1016/j.neulet.2012.07.012
PMCID: PMC4163196  PMID: 22813979
Parkinson’s Disease; Basal ganglia circuits; Dopaminergic deficits; Granger Causality analysis; Substantia nigra
11.  Reduced surround inhibition in musicians 
Experimental brain research  2012;219(3):403-408.
To investigate whether surround inhibition (SI) in the motor system is altered in professional musicians, we performed a transcranial magnetic stimulation (TMS) study in 10 professional musicians and 15 age-matched healthy non-musicians. TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the abductor digiti minimi (ADM) muscles were compared between the musicians and non-musicians with the primary analysis being the intervals between 3 and 80 ms (during the movement). A mixed-design ANOVA revealed a significant difference in normalized ADM MEPs during the index finger flexion between groups, with less SI in the musicians. This study demonstrated that the functional operation of SI is less strong in musicians than non-musicians, perhaps due to practice of movement synergies involving both muscles. Reduced SI, however, could lead susceptible musicians to be prone to develop task-specific dystonia.
doi:10.1007/s00221-012-3102-z
PMCID: PMC4161923  PMID: 22543743
Transcranial magnetic stimulation; Surround inhibition; Motor evoked potential; Musician; Dystonia
12.  Transcranial Direct Current Stimulation for the Treatment of Parkinson’s Disease 
Background
Progression of Parkinson’s disease (PD) is characterized by motor deficits, which eventually respond less to dopaminergic therapy and, thus, pose a therapeutic challenge. Deep brain stimulation has proven efficacy, but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative.
Objective
To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD
Design
Randomized, double blind, sham-controlled study.
Setting
Research institution
Methods
We investigated efficacy of anodal tDCS applied to the motor and prefrontal cortices in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.
Results
Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. TDCS improved gait by some measures for a short time and improved bradykinesia in both the on- and off-states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well-being, and self-assessed mobility did not differ between tDCS and sham intervention.
Conclusion
TDCS of the motor and prefrontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
doi:10.1136/jnnp.2009.202556
PMCID: PMC4162743  PMID: 20870863
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Parkinson’s disease
13.  TESTING OBJECTIVE MEASURES OF MOTOR IMPAIRMENT IN EARLY PARKINSON’S DISEASE: FEASIBILITY STUDY OF AN AT-HOME TESTING DEVICE 
We tested the feasibility of a computer based at-home testing device (AHTD) in early-stage, unmedicated Parkinson’s disease (PD) patients over 6 months. We measured compliance, technical reliability, and patient satisfaction to weekly assessments of tremor, small and large muscle bradykinesia, speech, reaction/movement times, and complex motor control. relative to the UPDRS motor score. The AHTD is a 6.5 x 10 computerized assessment battery. Data are stored on a USB memory stick and sent by internet to a central data repository as encrypted data packets. Although not designed or powered to measure change, the study collected data to observe patterns relative to UPDRS motor scores. Fifty-two PD patients enrolled, and 50 completed the six month trial, 48 remaining without medication. Patients complied with 90.6% of weekly 30-minute assessments, and 98.5% of data packets were successfully transmitted and decrypted. On a 100-point scale, patient satisfaction with the program at study end was 87.2 (range 80–100). UPDRS motor scores significantly worsened over 6 months, and trends for worsening over time occurred for alternating finger taps (p=.08), tremor (p=.06) and speech (p=.11). Change in tremor was a significant predictor of change in UPDRS (p=0.047) and was detected in the first month of the study. This new computer-based technology offers a feasible format for assessing PD-related impairment from home. The high patient compliance and satisfaction suggest the feasibility of its incorporation into larger clinical trials, especially when travel is difficult and early changes or frequent data collection are considered important to document.
doi:10.1002/mds.22379
PMCID: PMC4161502  PMID: 19086085
14.  Surround Inhibition in the Motor System 
Experimental brain research  2011;210(2):165-172.
Surround inhibition is a physiological mechanism to focus neuronal activity in the central nervous system. This so-called center-surround organization is well-known in sensory systems, where central signals are facilitated and eccentric signals are inhibited in order to sharpen the contrast between them. There is evidence that this mechanism is relevant for skilled motor behaviour, and it is deficient, for example, in the affected primary motor cortex of patients with focal hand dystonia (FHD). While it is still not fully elucidated how surround inhibition is generated in healthy subjects, the process is enhanced with handedness and task difficulty indicating that it may be an important mechanism for the performance of individuated finger movements. In FHD, where involuntary over-activation of muscles interferes with precise finger movements, a loss of intracortical inhibition likely contributes to the loss of surround inhibition. Several intracortical inhibitory networks are modulated differently in FHD compared to healthy subjects, and these may contribute to the loss of surround inhibition. Surround inhibition can be observed and assessed in the primary motor cortex. It remains unclear, however, if the effects are created in the cortex or if they are derived from, or supported by, motor signals that come from the basal ganglia.
doi:10.1007/s00221-011-2610-6
PMCID: PMC4158822  PMID: 21424259
Human; transcranial magnetic stimulation; contrast
15.  Reliability of a new scale for essential tremor 
Objective
To determine the reliability of a new scale for the clinical assessment of essential tremor.
Background
The Essential Tremor Rating Assessment Scale contains nine performance items that rate action tremor in the head, face, voice, limbs and trunk 0–4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.
Design/Methods
Videos of 44 patients and 6 controls were rated by 10 specialists on two occasions, 1–2 months apart. Inter- and intra-rater reliabilities were assessed with a two-way random effects intraclass correlation, using an absolute agreement definition.
Results
The inter- and intra-rater intraclass correlations for head and upper limb tremor ranged from 0.86 to 0.96, and the intraclass correlations for the total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk and leg were less robust.
Conclusions
This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.
doi:10.1002/mds.25162
PMCID: PMC4157921  PMID: 23032792
essential tremor; rating scale; reliability
16.  Role of posterior parietal cortex in reaching movements in humans. Clinical implication for ‘optic ataxia’ 
Objective
To clarify the spatio-temporal profile of cortical activity related to reaching movement in the posterior parietal cortex (PPC) in humans.
Methods
Four patients with intractable partial epilepsy who underwent subdural electrode implantation were studied as a part of pre-surgical evaluation. We investigated the Bereitschaftspotential (BP) associated with reaching and correlated the findings with the effect of electrical stimulation of the same cortical area.
Results
BPs specific for reaching, as compared with BPs for simple movements by the hand or arm contralateral to the implanted hemisphere, were recognized in all patients, mainly around the intraparietal sulcus (IPS), the superior parietal lobule (SPL) and the precuneus. BPs near the IPS had the earlier onset than BPs in the SPL. Electrical stimulation of a part of the PPC, where the reach-specific BPs were recorded, selectively impaired reaching.
Conclusions
Intracranial BP recording and cortical electrical stimulation delineated human reach-related areas in the PPC.
Significance
The present study for the first time by direct cortical recording in humans demonstrates that parts of the cortices around the IPS and SPL play a crucial role in visually-guided reaching.
doi:10.1016/j.clinph.2013.05.011
PMCID: PMC4157053  PMID: 23831168
Bereitschaftspotential; cortical electrical stimulation; optic ataxia; posterior parietal cortex; reaching
17.  Exploration of Computational Methods for Classification of Movement Intention during Human Voluntary Movement from Single Trial EEG 
Objectives
To explore effective combinations of computational methods for the prediction of movement intention preceding the production of self-paced right and left hand movements from single trial scalp electroencephalogram (EEG).
Methods
Twelve naïve subjects performed self-paced movements consisting of three key strokes with either hand. EEG was recorded from 128 channels. The exploration was performed offline on single trial EEG data. We proposed that a successful computational procedure for classification would consist of spatial filtering, temporal filtering, feature selection, and pattern classification. A systematic investigation was performed with combinations of spatial filtering using principal component analysis (PCA), independent component analysis (ICA), common spatial patterns analysis (CSP), and surface Laplacian derivation (SLD); temporal filtering using power spectral density estimation (PSD) and discrete wavelet transform (DWT); pattern classification using linear Mahalanobis distance classifier (LMD), quadratic Mahalanobis distance classifier (QMD), Bayesian classifier (BSC), multi-layer perceptron neural network (MLP), probabilistic neural network (PNN), and support vector machine (SVM). A robust multivariate feature selection strategy using a genetic algorithm was employed.
Results
The combinations of spatial filtering using ICA and SLD, temporal filtering using PSD and DWT, and classification methods using LMD, QMD, BSC and SVM provided higher performance than those of other combinations. Utilizing one of the better combinations of ICA, PSD and SVM, the discrimination accuracy was as high as 75%. Further feature analysis showed that beta band EEG activity of the channels over right sensorimotor cortex was most appropriate for discrimination of right and left hand movement intention.
Conclusions
Effective combinations of computational methods provide possible classification of human movement intention from single trial EEG. Such a method could be the basis for a potential brain-computer interface based on human natural movement, which might reduce the requirement of long-term training.
Significance
Effective combinations of computational methods can classify human movement intention from single trial EEG with reasonable accuracy.
doi:10.1016/j.clinph.2007.08.025
PMCID: PMC4154235  PMID: 17967559
Movement intention; Self-paced movement; Combination; Computational methods; Classification; Movement-related cortical potentials (MRCPs); Event-related desynchronization/synchronization (ERD/ERS); Genetic Algorithm; Brain-computer interface (BCI)
18.  Botulinum neurotoxin treatment improves force regulation in writer's cramp 
Parkinsonism & related disorders  2013;19(6):611-616.
Writer's cramp patients show poor force regulation during handwriting, but also in other experimental tasks requiring fine motor control. Botulinum neurotoxin (BoNT) treatment is clinically effective in a substantial portion of writer's cramp patients, but the full mechanism of action remains enigmatic. BoNT possibly influences α- and γ-motoneurons through chemodenervation not only of extra-, but also intrafusal muscle fibres and might thus influence muscle spindle afferents. Hence, BoNT weakens injected muscles, but may also modulate sensory aspects of force control. Ten patients and 18 controls pressed their index finger on a force sensor tracking two visual targets: The first target consisted of five plateaus with successively higher force levels and alternated with ascending ramps. In the second target condition the same successive plateaus were to be reached by abrupt jumps. The generated force displayed as a time dependant curve. Root mean square of the difference between target and produced force level was calculated for each plateau / ramp / jump. Patients were treated with BoNT at week 4 and measured at baseline, weeks 2, 4, 6 and 8. Disturbed force regulation in patients for the plateaus and the second jump at baseline resolved after BoNT treatment, and the root mean square of force deviation decreased for the ramps. Fine force control was within the 95 % confidence interval of the control group after treatment. In conclusion, force regulation was disturbed in patients and improved after BoNT treatment. This is not compatible with a simple muscle weakening and might thus reflect improved sensorimotor integration.
doi:10.1016/j.parkreldis.2013.02.011
PMCID: PMC4149416  PMID: 23507416
Focal hand dystonia; writer's cramp; force control; botulinum neurotoxin treatment; spindle afferents
19.  Interhemispheric Plasticity in Humans 
Introduction
Chronic unimanual motor practice increases the motor output not only in the trained but also in the non-exercised homologous muscle in the opposite limb. We examined the hypothesis that adaptations in motor cortical excitability of the non-trained primary motor cortex (iM1) and in interhemispheric inhibition (IHI) from the trained to the non-trained M1 mediate this inter-limb cross education.
Methods
Healthy, young volunteers (n = 12) performed 1000 submaximal voluntary contractions (MVC) of the right first dorsal interosseus (FDI) at 80% MVC over 20 sessions.
Results
Trained FDI’s MVC increased 49.9% and the untrained FDI’s MVC increased 28.1%. Although corticospinal excitability in iM1, measured with magnetic brain stimulation (TMS) before and after every 5th session, increased 6% at rest, these changes, as those in intracortical inhibition and facilitation, did not correlate with cross education. When weak and strong TMS of iM1 were, respectively, delivered on a background of a weak and strong muscle contraction of the right FDI, excitability of iM1 increased dramatically after 20 sessions. IHI decreased 8.9% acutely within sessions and 30.9% chronically over 20 sessions and these chronic reductions progressively became more strongly associated with cross education. There were no changes in force or TMS measures in the trained group’s left ADM nor were there changes in a non-exercising control group (n = 8).
Conclusions
The findings provide the first evidence for plasticity of interhemispheric connections to mediate cross education produced by a simple motor task.
doi:10.1249/MSS.0b013e31820a94b8
PMCID: PMC4137570  PMID: 21200340
muscle; force; motor cortex; excitability; motor control
20.  Validation of Digital Spiral Analysis as Outcome Parameter for Clinical Trials in Essential Tremor 
Essential tremor, one of the most prevalent movement disorders, is characterized by kinetic and postural tremor affecting activities of daily living. Spiral drawing is commonly used to visually rate tremor intensity, as part of the routine clinical assessment of tremor and as a tool in clinical trials. We present a strategy to quantify tremor severity from spirals drawn on a digitizing tablet. We validate our method against a well-established visual spiral rating method and compare both methods on their capacity to capture a therapeutic effect, as defined by the change in clinical essential tremor rating scale after an ethanol challenge. Fifty-four Archimedes spirals were drawn using a digitizing tablet by nine ethanol-responsive patients with essential tremor before and at five consecutive time points after the administration of ethanol in a standardized treatment intervention. Quantitative spiral tremor severity was estimated from the velocity tremor peak amplitude after numerical derivation and Fourier transformation of pen-tip positions. In randomly ordered sets, spirals were scored by seven trained raters, using Bain and Findley’s 0 to 10 rating scale. Computerized scores correlated with visual ratings (P < 0.0001). The correlation was significant at each time point before and after ethanol (P < 0.005). Quantitative ratings provided better sensitivity than visual rating to capture the effects of an ethanol challenge (P < 0.05). Using a standardized treatment approach, we were able to demonstrate that spirography time-series analysis is a valid, reliable method to document tremor intensity and a more sensitive measure for small effects than currently available visual spiral rating methods.
doi:10.1002/mds.23808
PMCID: PMC4117681  PMID: 21714004
essential tremor; spirography; spiral analysis; digitizing tablet; ethanol
21.  Development and validation of a clinical guideline for diagnosing blepharospasm 
Neurology  2013;81(3):236-240.
Objective:
To design and validate a clinical diagnostic guideline for aiding physicians in confirming or refuting suspected blepharospasm.
Methods:
The guideline was developed and validated in a 3-step procedure: 1) identification of clinical items related to the phenomenology of blepharospasm, 2) assessment of the relevance of each item to the diagnosis of blepharospasm, and 3) evaluation of the reliability and diagnostic sensitivity/specificity of the selected clinical items.
Results:
Of 19 clinical items initially identified, 7 were admitted by content validity analysis to further assessment. Both neurologists and ophthalmologists achieved satisfactory interobserver agreement for all 7 items, including “involuntary eyelid narrowing/closure due to orbicularis oculi spasms,” “bilateral spasms,” “synchronous spasms,” “stereotyped spasm pattern,” “sensory trick,” “inability to voluntarily suppress the spasms,” and “blink count at rest.” Each selected item yielded unsatisfactory accuracy in discriminating patients with blepharospasm from healthy subjects and patients with other eyelid disturbances. Combining the selected items, however, improved diagnostic sensitivity/specificity. The best combination, yielding 93% sensitivity and 90% specificity, was an algorithm starting with the item “stereotyped, bilateral, and synchronous orbicularis oculi spasms inducing eyelid narrowing/closure” and followed by recognition of “sensory trick” or, alternatively, “increased blinking.”
Conclusion:
This study provides an accurate and valid clinical guideline for diagnosing blepharospasm. Use of this guideline would make it easier for providers to recognize dystonia in clinical and research settings.
doi:10.1212/WNL.0b013e31829bfdf6
PMCID: PMC3770163  PMID: 23771487
22.  Response Inhibition in Motor Conversion Disorder 
Conversion disorders (CDs) are unexplained neurological symptoms presumed to be related to a psychological issue. Studies focusing on conversion paralysis have suggested potential impairments in motor initiation or execution. Here we studied CD patients with aberrant or excessive motor movements and focused on motor response inhibition. We also assessed cognitive measures in multiple domains. We compared 30 CD patients and 30 age-, sex-, and education-matched healthy volunteers on a motor response inhibition task (go/no go), along with verbal motor response inhibition (color-word interference) and measures of attention, sustained attention, processing speed, language, memory, visuospatial processing, and executive function including planning and verbal fluency. CD patients had greater impairments in commission errors on the go/no go task (P <.001) compared with healthy volunteers, which remained significant after Bonferroni correction for multiple comparisons and after controlling for attention, sustained attention, depression, and anxiety. There were no significant differences in other cognitive measures. We highlight a specific deficit in motor response inhibition that may play a role in impaired inhibition of unwanted movement such as the excessive and aberrant movements seen in motor conversion. Patients with nonepileptic seizures, a different form of conversion disorder, are commonly reported to have lower IQ and multiple cognitive deficits. Our results point toward potential differences between conversion disorder subgroups.
doi:10.1002/mds.25435
PMCID: PMC4096145  PMID: 23554084
conversion disorder; psychogenic movement disorder; response inhibition; IQ; cognition
23.  Psychiatric Symptoms Associated with Focal Hand Dystonia 
Myoclonus dystonia and idiopathic dystonia are associated with a greater frequency of obsessive compulsive disorder (OCD) and major depression. We investigated the frequency of OCD in 39 patients with primary focal hand dystonia (FHD) using a semistructured interview. OCD and subsyndromal OCD was diagnosed in 5 of 39 (12.82%) patients with FHD, whereas OCD occurs in 2.3% of the general population. Recurrent depression occurred in (7 of 39) 17.95% of patients with FHD along with a family history of depression in (16 of 39) 41.02%. Overlapping mechanisms manifesting as FHD may also predispose to OC symptoms and likely implicates a common striatal dysfunction.
doi:10.1002/mds.23250
PMCID: PMC4082988  PMID: 20737548
obsessive compulsive disorder; depression; dystonia; striatum; obsession; compulsion
24.  Action-effect binding is decreased in motor conversion disorder: implications for sense of agency 
BACKGROUND
The abnormal movements seen in motor conversion disorder are affected by distraction and entrainment, similar to voluntary movement. Unlike voluntary movement, however, patients lack a sense of control for the abnormal movements, a failure of “self-agency.” The action-effect binding paradigm has been used to quantify the sense of self-agency, because subjective contraction of time between an action and its effect only occurs if the subject feels that they are the agent responsible for the action. We used this paradigm, coupled with emotional stimuli, to investigate the sense of agency with voluntary movements in patients with motor conversion disorder.
METHODS
Twenty patients with motor conversion disorder and 20 age- and gender-matched healthy volunteers used a rotating clock to judge the time of their own voluntary keypresses (action) and a subsequent auditory tone (effect), after completing conditioning blocks in which high, medium and low tones were coupled to images of happy, fearful and neutral faces.
RESULTS
The results replicate those shown previously: an effect following a voluntary action was reported as occurring earlier, and the preceding action later, compared to trials of only keypresses or tones. Patients had reduced overall binding scores relative to healthy volunteers, suggesting a reduced sense of agency. There was no effect of the emotional stimuli (faces) or other interaction effects. Healthy volunteers with subclinical depressive symptoms had higher overall binding scores.
CONCLUSIONS
We show that motor conversion disorder patients have decreased action-effect binding for normal voluntary movements compared to healthy volunteers, consistent with the greater experience of lack of control.
doi:10.1002/mds.25408
PMCID: PMC3701023  PMID: 23494975
agency; action-effect binding; conversion disorder; psychogenic movement disorder; forward model
25.  Phenomenology and classification of dystonia: a consensus update 
This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during three in-person meetings and manuscript review by mail.
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along two axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features), and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment.
We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia.
doi:10.1002/mds.25475
PMCID: PMC3729880  PMID: 23649720

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