Maladaptive striatal plasticity and abnormal reward-learning in cervical dystonia

In monogenetic generalized forms of dystonia, in vitro neurophysiological recordings have demonstrated direct evidence for abnormal plasticity at the level of the cortico‐striatal synapse. It is unclear whether similar abnormalities contribute to the pathophysiology of cervical dystonia, the most common type of focal dystonia. We investigated whether abnormal cortico‐striatal synaptic plasticity contributes to abnormal reward‐learning behavior in patients with focal dystonia. Forty patients and 40 controls performed a reward gain and loss avoidance reversal learning task. Participant's behavior was fitted to a computational model of the basal ganglia incorporating detailed cortico‐striatal synaptic learning rules. Model comparisons were performed to assess the ability of four hypothesized receptor specific abnormalities of cortico‐striatal long‐term potentiation (LTP) and long‐term depression (LTD): increased or decreased D1:LTP/LTD and increased or decreased D2: LTP/LTD to explain abnormal behavior in patients. Patients were selectively impaired in the post‐reversal phase of the reward task. Individual learning rates in the reward reversal task correlated with the severity of the patient's motor symptoms. A model of the striatum with decreased D2:LTP/ LTD best explained the patient's behavior, suggesting excessive D2 cortico‐striatal synaptic depotentiation could underpin biased reward‐learning in patients with cervical dystonia. Reversal learning impairment in cervical dystonia may be a behavioral correlate of D2‐specific abnormalities in cortico‐striatal synaptic plasticity. Reinforcement learning tasks with computational modeling could allow the identification of molecular targets for novel treatments based on their ability to restore normal reward‐learning behavior in these patients

Focal Task-specific Dystonia among Professional Musicians in Latin America

The authors read with great interest the article ‘‘Focal Task-specific Dystonia— From Early Descriptions to a New, Modern Formulation’’ by Frucht, which presented a new working conceptual model of focal taskspecific dystonia (FTSD) attempting to integrate phenomenology, physiology, and treatment. Nevertheless, several aspects of FTSD remain unresolved, and Frucht suggests that international working groups focusing on musician’s dystonia (MD) could contribute to better understanding in the field. The estimated prevalence of FTSD is 0.5–1% for all professional musicians, although there is wide variation in different populations and in the type of instrument played.2–5 To investigate the data available from their region, the authors conducted a systematic search of MD in Latin America. The Medline, EMBASE, and LILACS databases were explored using the subject terms musician’s dystonia Latin America, focal dystonia Latin America, and prevalence studies of FTSD in highly skilled musicians from Latin America. The authors searched for articles in English and in Spanish. Data from Latin American countries about MD are scarce, and only isolated reports or small series of cases were found in the English literature

Cerebellum: an explanation for dystonia?

Dystonia is a movement disorder that is characterized by involuntary muscle contractions, abnormal movements and postures, as well as by non-motor symptoms, and is due to abnormalities in different brain areas. In this article, we focus on the growing number of experimental studies aimed at explaining the pathophysiological role of the cerebellum in dystonia. Lastly, we highlight gaps in current knowledge and issues that future research studies should focus on as well as some of the potential applications of this research avenue. Clarifying the pathophysiological role of cerebellum in dystonia is an important concern given the increasing availability of invasive and non-invasive stimulation techniques and their potential therapeutic role in this condition

Regaining Motor Control in Musician's Dystonia by Restoring Sensorimotor Organization

Professional musicians are an excellent human model of long term effects of skilled motor training on the structure and function of the motor system. However, such effects are accompanied by an increased risk of developing motor abnormalities, in particular musician's dystonia. Previously we found that there was an expanded spatial integration of proprioceptive input into the hand area of motor cortex (sensorimotor organisation, SMO) in healthy musicians as tested with a transcranial magnetic stimulation (TMS) paradigm. In musician's dystonia, this expansion was even larger, resulting in a complete lack of somatotopic organisation. We hypothesised that the disordered motor control in musician's dystonia is a consequence of the disordered SMO. In the present paper we test this idea by giving pianists with musician's dystonia 15 min experience of a modified proprioceptive training task. This restored SMO towards that seen in healthy pianists. Crucially, motor control of the affected task improved significantly and objectively as measured with a MIDI piano, and the amount of behavioural improvement was significantly correlated to the degree of sensorimotor re-organisation. In healthy pianists and non-musicians, the SMO and motor performance remained essentially unchanged. These findings suggest a link between the differentiation of SMO in the hand motor cortex and the degree of motor control of intensively practiced tasks in highly skilled individuals

Temporal discrimination: Mechanisms and relevance to adult-onset dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis

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

Dystonia and paroxysmal dyskinesias: under-recognized movement disorders in domestic animals? A comparison with human dystonia/paroxysmal dyskinesias.

Dystonia is defined as a neurological syndrome characterized by involuntary sustained or intermittent muscle contractions causing twisting, often repetitive movements, and postures. Paroxysmal dyskinesias are episodic movement disorders encompassing dystonia, chorea, athetosis, and ballism in conscious individuals. Several decades of research have enhanced the understanding of the etiology of human dystonia and dyskinesias that are associated with dystonia, but the pathophysiology remains largely unknown. The spontaneous occurrence of hereditary dystonia and paroxysmal dyskinesia is well documented in rodents used as animal models in basic dystonia research. Several hyperkinetic movement disorders, described in dogs, horses and cattle, show similarities to these human movement disorders. Although dystonia is regarded as the third most common movement disorder in humans, it is often misdiagnosed because of the heterogeneity of etiology and clinical presentation. Since these conditions are poorly known in veterinary practice, their prevalence may be underestimated in veterinary medicine. In order to attract attention to these movement disorders, i.e., dystonia and paroxysmal dyskinesias associated with dystonia, and to enhance interest in translational research, this review gives a brief overview of the current literature regarding dystonia/paroxysmal dyskinesia in humans and summarizes similar hereditary movement disorders reported in domestic animals

A History of Dystonia: Ancient to Modern

Before 1911, when Hermann Oppenheim introduced the term dystonia, this movement disorder lacked a unifying descriptor. While words like epilepsy, apoplexy, and palsy have had their meanings since antiquity, references to dystonia are much harder to identify in historical documents. Torticollis is an exception, although there is difficulty distinguishing dystonic torticollis from congenital muscular torticollis. There are, nevertheless, possible representations of dystonia in literature and visual art from the pre-modern world. Eighteenth century systematic nosologists such as Linnaeus, de Sauvages, and Cullen had attempted to classify some spasmodic conditions, including torticollis. But only after Charcot's contributions to clinical neuroscience were the various forms of generalized and focal dystonia clearly delineated. They were categorized as névroses: Charcot's term for conditions without an identifiable neuroanatomical cause. For a time thereafter, psychoanalytic models of dystonia based on Freud's ideas about unconscious conflicts transduced into physical symptoms were ascendant, although there was always a dissenting “organic” school. With the rise of subspecialization in movement disorders during the 1970s, the pendulum swung strongly back toward organic causation. David Marsden's clinical and electrophysiological research on the adult-onset focal dystonias was particularly important in establishing a physical basis for these disorders. We are still in a period of “living history” of dystonia, with much yet to be understood about pathophysiology. Rigidly dualistic models have crumbled in the face of evidence of electrophysiological and psychopathological overlap between organic and functional dystonia. More flexible biopsychosocial frameworks may address the demand for new diagnostic and therapeutic rationales