In Parkinson's disease STN stimulation enhances responsiveness of movement initiation speed to high reward value

Objective: The subthalamic nucleus (STN) is part of the motor, associative, and limbic cortico-striatal circuits through which it can influence a range of behaviours, with preclinical and clinical evidence suggesting that the STN is involved in motivational modulation of behaviour. In the present study, we investigated if in Parkinson’s disease (PD) motivational modulation of movement speed is altered by deep brain stimulation (DBS) of the STN (STN-DBS). / Methods: We studied the effect of monetary incentive on speed of movement initiation and execution in a computer-based simple reaction time task in 10 operated patients with Parkinson’s disease using a STN DBS ON/OFF design and also in 11 healthy participants. / Results: Prospect of reward improved speed of movement initiation in PD patients both with STN-DBS ON and OFF. However, only with STN-DBS ON, the patients showed greater speeding of initiation time with higher reward magnitude, suggesting enhanced responsivity to higher reward value. Also, on the rewarded trials, PD patients ON stimulation made more anticipation errors than on unrewarded trials, reflecting a propensity to impulsive responses triggered by prospect of reward by subthalamic stimulation. The motivational modulation of movement speed was preserved and enhanced in PD with STN-DBS. / Conclusion: Motivational modulation of movement speed in PD is maintained with STN-DBS, with STN stimulation having a further energizing effect on movement initiation in response to greater incentive value. Our results suggest that STN plays a role in integrating motivational influences into motor action, which may explain some previous reports of STN-DBS induced impulsivity with increased motivational salience of stimuli

The role of sensorimotor cortical plasticity in pathophysiology of Parkinson’s disease and dystonia

This PhD thesis is a study of cortical electrophysiology in two basal ganglia disorders: Parkinson’s disease (PD) and dystonia. Two diseases were chosen as being representative of hypokinetic and hyperkinetic movement disorders, respectively. In addition, current treatments seem to be imperfect to control many aspects of both diseases, hence the interest in exploring potential new therapeutic targets. PD and dystonia are basal ganglia diseases, but there is growing body of evidence of impaired cortical function and particularly of abnormal sensorimotor cortical plasticity in both disorders. We however still lack knowledge about functional significance of these cortical changes. Are they maladaptive or compensatory or of little functional significance? Techniques of Transcranial Magnetic (TMS) were used to determine 1) if clinical asymmetry of early PD is reflected in hemispheric asymmetry of sensorimotor cortical plasticity and intracortical inhibition, and 2) how these electrophysiological measures change with disease progression. We found that the hemisphere contralateral to the less affected side had preserved intracortical inhibition and a larger response to the plasticity protocol, whereas on the more affected hemisphere these were reduced. We further demonstrated that the decline in asymmetry of these measures correlated with the reduction in asymmetry of clinical symptoms, suggesting these were compensatory changes. In dystonia patients, we investigated using TMS 1) if change of afferent input induced by botulinum toxin injections may change response to plasticity protocol in primary dystonia, and if 2) secondary and primary dystonia patients share the same pattern of electrophysiological abnormalities. We demonstrated that sensorimotor cortical plasticity in primary dystonia is not permanent abnormality but may be transitory reduced with botulinum injections treatment. Secondary dystonia patients, as opposed to primary dystonia patients did not have enhanced sensorimotor plasticity or impaired cerebellar function. We provide evidence that different types of dystonia do not necessarily have the same neuroanatomical substrates, which might have therapeutic implications

Botulinum Toxin Injections Reduce Associative Plasticity in Patients with Primary Dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long-term potentiation-like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation-evoked motor evoked potentials before and after paired associative stimulation. We also measured the input-output curve, short-interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. (C) 2011 Movement Disorder Societ

Plasticity and dystonia: a hypothesis shrouded in variability.

Studying plasticity mechanisms with Professor John Rothwell was a shared highlight of our careers. In this article, we discuss non-invasive brain stimulation techniques which aim to induce and quantify plasticity, the mechanisms and nature of their inherent variability and use such observations to review the idea that excessive and abnormal plasticity is a pathophysiological substrate of dystonia. We have tried to define the tone of our review by a couple of Professor John Rothwell's many inspiring characteristics; his endless curiosity to refine knowledge and disease models by scientific exploration and his wise yet humble readiness to revise scientific doctrines when the evidence is supportive. We conclude that high variability of response to non-invasive brain stimulation plasticity protocols significantly clouds the interpretation of historical findings in dystonia research. There is an opportunity to wipe the slate clean of assumptions and armed with an informative literature in health, re-evaluate whether excessive plasticity has a causal role in the pathophysiology of dystonia

Ileal vaginoplasty as vaginal reconstruction in transgender women and patients with disorders of sex development: an international, multicentre, retrospective study on surgical characteristics and outcomes

OBJECTIVE: To describe the surgical outcomes of ileal vaginoplasty in transgender women and patients with disorders of sex development (DSD). PATIENTS AND METHODS: Transgender women and patients with DSD, who underwent ileal vaginoplasty at the VU University Medical Center Amsterdam, University Hospital Trieste, University Hospital Essen, and Belgrade University Hospital, were retrospectively identified. A chart review was performed, recording surgical technique, intraoperative characteristics, complications, and re-operations. RESULTS: We identified a total of 32 patients (27 transgender and five non-transgender), with a median (range) age of 35 (6-63) years. Ileal vaginoplasty was performed as the primary procedure in three and as a revision procedure in the remaining 29. The mean (sd) operative time was 288 (103) min. The procedure was performed laparoscopically (seven patients) or open (25). An ileal 'U-pouch' was created in five patients and a single lumen in 27. Intraoperative complications occurred in two patients (one iatrogenic bladder damage and one intraoperative blood loss necessitating transfusion). The median (range) hospitalisation was 12 (6-30) days. Successful neovaginal reconstruction was achieved in all. The mean (sd) achieved neovaginal depth was 13.2 (3.1) cm. The median (range) clinical follow-up was 35 (3-159) months. In one patient a recto-neovaginal fistula occurred, which lead to temporary ileostomy. Introital stenosis occurred in four patients (12.5%). CONCLUSION: Ileal vaginoplasty can be performed with few intra- and postoperative complications. It appears to have similar complication rates when compared to sigmoid vaginoplasty. It now seems to be used predominantly for revision procedures

High motor variability in DYT1 dystonia is associated with impaired visuomotor adaptation.

For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted

Motivational modulation of bradykinesia in Parkinson's disease off and on dopaminergic medication.

Motivational influence on bradykinesia in Parkinson's disease may be observed in situations of emotional and physical stress, a phenomenon known as paradoxical kinesis. However, little is known about motivational modulation of movement speed beyond these extreme circumstances. In particular, it is not known if motivational factors affect movement speed by improving movement preparation/initiation or execution (or both) and how this effect relates to the patients' medication state. In the present study, we tested if provision of motivational incentive through monetary reward would speed-up movement initiation and/or execution in Parkinson's disease patients and if this effect depended on dopaminergic medication. We studied the effect of monetary incentive on simple reaction time in 11 Parkinson's disease patients both "off" and "on" dopaminergic medication and in 11 healthy participants. The simple reaction time task was performed across unrewarded and rewarded blocks. The initiation time and movement time were quantified separately. Anticipation errors and long responses were also recorded. The prospect of reward improved initiation times in Parkinson's disease patients both "off" and "on" dopaminergic medication, to a similar extent as in healthy participants. However, for "off" medication, this improvement was associated with increased frequency of anticipation errors, which were eliminated by dopamine replacement. Dopamine replacement had an additional, albeit small effect, on reward-related improvement of movement execution. Motivational strategies are helpful in overcoming bradykinesia in Parkinson's disease. Motivational factors may have a greater effect on bradykinesia when patients are "on" medication, as dopamine appears to be required for overcoming speed-accuracy trade-off and for improvement of movement execution. Thus, medication status should be an important consideration in movement rehabilitation programmes for patients with Parkinson's disease