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1.  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
2.  A landmark publication in movement disorders 
Brain  2013;136(2):682-684.
doi:10.1093/brain/aws329
PMCID: PMC3572933
3.  The non-motor syndrome of primary dystonia: clinical and pathophysiological implications 
Brain  2011;135(6):1668-1681.
Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications.
doi:10.1093/brain/awr224
PMCID: PMC3359748  PMID: 21933808
primary dystonia; non-motor; sensory; depression; endophenotypes; pathophysiology; quality of life
4.  Widespread abnormality of the γ-aminobutyric acid-ergic system in Tourette syndrome 
Brain  2012;135(6):1926-1936.
Dysfunction of the γ-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive–compulsive disorder. The purpose of this study was to identify a possible dysfunction of the γ-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls. Positron emission tomography procedure: after injection of 20 mCi of [11C]flumazenil, dynamic emission images of the brain were acquired. Structural magnetic resonance imaging scans were obtained to provide an anatomical framework for the positron emission tomography data analysis. Images of binding potential were created using the two-step version of the simplified reference tissue model. The binding potential images then were spatially normalized, smoothed and compared between groups using statistical parametric mapping. We found decreased binding of GABAA receptors in Tourette patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala and right insula. In addition, the GABAA receptor binding was increased in the bilateral substantia nigra, left periaqueductal grey, right posterior cingulate cortex and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in Tourette syndrome patients. In addition, the abnormalities in GABAA receptor binding in the insula and cerebellum appear particularly noteworthy based upon recent evidence implicating these structures in the generation of tics.
doi:10.1093/brain/aws104
PMCID: PMC3359755  PMID: 22577221
Tourette syndrome; tics; GABAA receptors; flumazenil; PET
5.  Dopamine agonists and risk: impulse control disorders in Parkinson's; disease 
Brain  2011;134(5):1438-1446.
Impulse control disorders are common in Parkinson's; disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's; disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a ‘Sure’ choice and a ‘Gamble’ choice of moderate risk. To commence each trial, in the ‘Gain’ condition, individuals started at $0 and in the ‘Loss’ condition individuals started at −$50 below the ‘Sure’ amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk (‘Gamble Risk’). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's; disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the ‘Gain’ relative to the ‘Loss’ condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's; disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's; disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.
doi:10.1093/brain/awr080
PMCID: PMC3097893  PMID: 21596771
Parkinson's; disease; dopamine; gambling; decision making; risk
6.  Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits? 
Brain  2012;135(11):3206-3226.
Tremor in Parkinson's disease has several mysterious features. Clinically, tremor is seen in only three out of four patients with Parkinson's disease, and tremor-dominant patients generally follow a more benign disease course than non-tremor patients. Pathophysiologically, tremor is linked to altered activity in not one, but two distinct circuits: the basal ganglia, which are primarily affected by dopamine depletion in Parkinson's disease, and the cerebello-thalamo-cortical circuit, which is also involved in many other tremors. The purpose of this review is to integrate these clinical and pathophysiological features of tremor in Parkinson's disease. We first describe clinical and pathological differences between tremor-dominant and non-tremor Parkinson's disease subtypes, and then summarize recent studies on the pathophysiology of tremor. We also discuss a newly proposed ‘dimmer-switch model’ that explains tremor as resulting from the combined actions of two circuits: the basal ganglia that trigger tremor episodes and the cerebello-thalamo-cortical circuit that produces the tremor. Finally, we address several important open questions: why resting tremor stops during voluntary movements, why it has a variable response to dopaminergic treatment, why it indicates a benign Parkinson's disease subtype and why its expression decreases with disease progression.
doi:10.1093/brain/aws023
PMCID: PMC3501966  PMID: 22382359
Parkinson's disease; tremor; basal ganglia; cerebellum, thalamus
7.  Neural correlates of bimanual anti-phase and in-phase movements in Parkinson’s disease 
Brain  2010;133(8):2394-2409.
Patients with Parkinson’s disease have great difficulty in performing bimanual movements; this problem is more obvious when they perform bimanual anti-phase movements. The underlying mechanism of this problem remains unclear. In the current study, we used functional magnetic resonance imaging to study the bimanual coordination associated changes of brain activity and inter-regional interactions in Parkinson’s disease. Subjects were asked to perform right-handed, bimanual in-phase and bimanual anti-phase movements. After practice, normal subjects performed all tasks correctly. Patients with Parkinson’s disease performed in-phase movements correctly. However, some patients still made infrequent errors during anti-phase movements; they tended to revert to in-phase movement. Functional magnetic resonance imaging results showed that the supplementary motor area was more activated during anti-phase movement than in-phase movement in controls, but not in patients. In performing anti-phase movements, patients with Parkinson’s disease showed less activity in the basal ganglia and supplementary motor area, and had more activation in the primary motor cortex, premotor cortex, inferior frontal gyrus, precuneus and cerebellum compared with normal subjects. The basal ganglia and dorsolateral prefrontal cortex were less connected with the supplementary motor area, whereas the primary motor cortex, parietal cortex, precuneus and cerebellum were more strongly connected with the supplementary motor area in patients with Parkinson’s disease than in controls. Our findings suggest that dysfunction of the supplementary motor area and basal ganglia, abnormal interactions of brain networks and disrupted attentional networks are probably important reasons contributing to the difficulty of the patients in performing bimanual anti-phase movements. The patients require more brain activity and stronger connectivity in some brain regions to compensate for dysfunction of the supplementary motor area and basal ganglia in order to perform bimanual movements correctly.
doi:10.1093/brain/awq151
PMCID: PMC3139934  PMID: 20566485
Parkinson’s disease; bimanual movements; fMRI; brain activity; effective connectivity
8.  Emotional stimuli and motor conversion disorder 
Brain  2010;133(5):1526-1536.
Conversion disorder is characterized by neurological signs and symptoms related to an underlying psychological issue. Amygdala activity to affective stimuli is well characterized in healthy volunteers with greater amygdala activity to both negative and positive stimuli relative to neutral stimuli, and greater activity to negative relative to positive stimuli. We investigated the relationship between conversion disorder and affect by assessing amygdala activity to affective stimuli. We conducted a functional magnetic resonance imaging study using a block design incidental affective task with fearful, happy and neutral face stimuli and compared valence contrasts between 16 patients with conversion disorder and 16 age- and gender-matched healthy volunteers. The patients with conversion disorder had positive movements such as tremor, dystonia or gait abnormalities. We also assessed functional connectivity between the amygdala and regions associated with motor preparation. A group by affect valence interaction was observed. Post hoc analyses revealed that whereas healthy volunteers had greater right amygdala activity to fearful versus neutral compared with happy versus neutral as expected, there were no valence differences in patients with conversion disorder. There were no group differences observed. The time course analysis also revealed greater right amygdala activity in patients with conversion disorder for happy stimuli (t = 2.96, P = 0.006) (with a trend for fearful stimuli, t = 1.81, P = 0.08) compared with healthy volunteers, with a pattern suggestive of impaired amygdala habituation even when controlling for depressive and anxiety symptoms. Using psychophysiological interaction analysis, patients with conversion disorder had greater functional connectivity between the right amygdala and the right supplementary motor area during both fearful versus neutral, and happy versus neutral ‘stimuli’ compared with healthy volunteers. These results were confirmed with Granger Causality Modelling analysis indicating a directional influence from the right amygdala to the right supplementary motor area to happy stimuli (P < 0.05) with a similar trend observed to fearful stimuli (P = 0.07). Our data provide a potential neural mechanism that may explain why psychological or physiological stressors can trigger or exacerbate conversion disorder symptoms in some patients. Greater functional connectivity of limbic regions influencing motor preparatory regions during states of arousal may underlie the pathophysiology of motor conversion symptoms.
doi:10.1093/brain/awq054
PMCID: PMC2859149  PMID: 20371508
conversion disorder; arousal; amydala; affect; psychogenic movement disorder
9.  Disordered plasticity in the primary somatosensory cortex in focal hand dystonia 
Brain  2009;132(3):749-755.
Interventional paired associative stimulation (PAS) can induce plasticity in the cortex, and this plasticity was previously shown to be disordered in the primary motor cortex in focal hand dystonia (FHD). This study aimed to test whether associative plasticity is abnormal in the primary somatosensory cortex (S1) in FHD and whether PAS modulates excitatory or inhibitory interneurons within the cortex. Ten FHD patients and 10 healthy volunteers were studied. We investigated the changes in single- and double-pulse somatosensory-evoked potentials before and after PAS, which consisted of peripheral electrical nerve stimulation and subsequent transcranial magnetic stimulation over S1. Four sessions of somatosensory-evoked potentials recordings were performed: before PAS, and immediately, 15 and 30 min after PAS. We compared the time course of the somatosensory-evoked potentials between the FHD and healthy groups. In the single-pulse condition, the P27 amplitudes were significantly higher in FHD immediately after PAS than before PAS, while no changes were observed in healthy subjects. In the double-pulse condition, significant differences in the suppression ratio of P27 were found immediately after and 15 min after PAS, while there were no significant differences in healthy subjects. The P27 suppression tended to normalize toward the level of the healthy volunteer group. In FHD, PAS transiently induced an abnormal increase in excitability in S1. In addition, intracortical inhibition in S1 was found to increase as well. This abnormal plasticity of the intracortical neurons in S1 may contribute to the pathophysiology of dystonia.
doi:10.1093/brain/awn348
PMCID: PMC2724923  PMID: 19151081
associative plasticity; paired associative stimulation; focal hand dystonia; somatosensory-evoked potential
10.  Focal white matter changes in spasmodic dysphonia: a combined DTI and neuropathological study 
Brain : a journal of neurology  2007;131(Pt 2):447-459.
Spasmodic dysphonia (SD) is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although clinical symptoms of SD are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in SD patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes in SD and to target those brain regions for neuropathological examination. DTI showed rightsided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 SD patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus, and cerebellar white and gray matter in SD patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions containing calcium, phosphorus and iron in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus, and cerebellum in the postmortem brain tissue from one SD patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of SD (r = 0.509, p = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of SD.
doi:10.1093/brain/awm303
PMCID: PMC2376833  PMID: 18083751
laryngeal dystonia; corticobulbar tract; basal ganglia; neuroimaging; neuropathology

Results 1-10 (10)