Francesca Morgante

Abnormal plasticity of sensorimotor circuits extends beyond the affected body part in focal dystonia.

Objective: To test whether abnormal sensorimotor plasticity in focal hand dystonia is a primary abnormality or is merely a consequence of the dystonic posture. Methods: This study used the paired associative stimulation (PAS) paradigm, an experimental intervention, capable of producing long term potentiation (LTP) like changes in the sensorimotor system in humans. PAS involves transcranial magnetic stimulation combined with median nerve stimulation. 10 patients with cranial and cervical dystonia, who showed no dystonic symptoms in the hand, and nine patients with hemifacial spasm (HFS), a non-dystonic condition, were compared with 10 healthy age matched controls. Motor evoked potential amplitudes and cortical silent period (CSP) duration were measured at baseline before PAS and for up to 60 min (T0, T30 and T60) after PAS in the abductor pollicis brevis and the first dorsal interosseus muscles. Results: Patients with dystonia showed a stronger increase in corticospinal excitability than healthy controls and patients with HFS. In addition, patients with dystonia showed a loss of topographical specificity of PAS induced effects, with a facilitation in both the median and ulnar innervated muscles. While PAS conditioning led to a prolonged CSP in healthy controls and patients with HFS, it had no effect on the duration of the CSP in patients with cranial and cervical dystonia. Conclusion: The data suggests that excessive motor cortex plasticity is not restricted to the circuits clinically affected by dystonia but generalises across the entire sensorimotor system, possibly representing an endophenotypic trait of the disease.

Distinct changes in cortical and spinal excitability following high-frequency repetitive TMS to the human motor cortex

It has been shown that high-frequency repetitive transcranial magnetic stimulation (rTMS) to the human primary motor hand area (M1-HAND) can induce a lasting increase in corticospinal excitability. Here we recorded motor evoked potentials (MEPs) from the right first dorsal interosseus muscle to investigate how sub-threshold high-frequency rTMS to the M1-HAND modulates cortical and spinal excitability. In a first experiment, we gave 1500 stimuli of 5 Hz rTMS. At an intensity of 90% of active motor threshold, rTMS produced no effect on MEP amplitude at rest. Increasing the intensity to 90% of resting motor threshold (RMT), rTMS produced an increase in MEP amplitude. This facilitatory effect gradually built up during the course of rTMS, reaching significance after the administration of 900 stimuli. In a second experiment, MEPs were elicited during tonic contraction using weak anodal electrical or magnetic test stimuli. 1500 (but not 600) conditioning stimuli at 90% of RMT induced a facilitation of MEPs in the contracting FDI muscle. In a third experiment, 600 conditioning stimuli were given at 90% of RMT to the M1-HAND. Using two well-established conditioning-test paradigms, we found a decrease in short-latency intracortical inhibition (SICI), and a facilitation of the first peak of facilitatory I-waves interaction (SICF). There was no correlation between the relative changes in SICI and SICF. These results demonstrate that subthreshold 5 Hz rTMS can induce lasting changes in specific neuronal subpopulations in the human corticospinal motor system, depending on the intensity and duration of rTMS. Short 5 Hz rTMS (600 stimuli) at 90% of RMT can selectively shape the excitability of distinct intracortical circuits, whereas prolonged 5 Hz rTMS (≥900 stimuli) provokes an overall increase in excitability of the corticospinal output system, including spinal motoneurones.

Cortical and spinal abnormalities in psychogenic dystonia

The pathophysiology of psychogenic dystonia has not been examined, but a growing body of literature suggests that abnormal sensory input from repetitive movements can lead to plastic cortical changes. Reduced cortical and spinal inhibition is well documented in organic dystonia. We tested the hypothesis that aberrant sensory input associated with abnormal posture may cause similar abnormalities by testing patients with psychogenic dystonia.

Rapid-rate paired associative stimulation of the median nerve and motor cortex can produce long-lasting changes in motor cortical excitability in humans

Repetitive transcranial magnetic stimulation (rTMS) or repetitive electrical peripheral nerve stimulation (rENS) can induce changes in the excitability of the human motor cortex (M1) that is often short‐lasting and variable, and occurs only after prolonged periods of stimulation. In 10 healthy volunteers, we used a new repetitive paired associative stimulation (rPAS) protocol to facilitate and prolong the effects of rENS and rTMS on cortical excitability. Sub‐motor threshold 5 Hz rENS of the right median nerve was synchronized with submotor threshold 5 Hz rTMS of the left M1 at a constant interval for 2 min. The interstimulus interval (ISI) between the peripheral stimulus and the transcranial stimulation was set at 10 ms (5 Hz rPAS10ms) or 25 ms (5 Hz rPAS25ms). TMS was given over the hot spot of the right abductor pollicis brevis (APB) muscle. Before and after rPAS, we measured the amplitude of the unconditioned motor evoked potential (MEP), intracortical inhibition (ICI) and facilitation (ICF), short‐ and long‐latency afferent inhibition (SAI and LAI) in the conditioned M1. The 5 Hz rPAS25ms protocol but not the 5 Hz rPAS10ms protocol caused a somatotopically specific increase in mean MEP amplitudes in the relaxed APB muscle. The 5 Hz rPAS25ms protocol also led to a loss of SAI, but there was no correlation between individual changes in SAI and corticospinal excitability. These after‐effects were still present 6 h after 5 Hz rPAS25ms. There was no consistent effect on ICI, ICF and LAI. The 5 Hz rENS and 5 Hz rTMS protocols failed to induce any change in corticospinal excitability when given alone. These findings show that 2 min of 5 Hz rPAS25ms produce a long‐lasting and somatotopically specific increase in corticospinal excitability, presumably by sensorimotor disinhibition.

Enhanced Long-Term Potentiation-Like Plasticity of the Trigeminal Blink Reflex Circuit in Blepharospasm

Benign essential blepharospasm (BEB) is a focal cranial dystonia affecting eye closure. Here, we tested the hypothesis that BEB is associated with abnormal plasticity of the neuronal circuits mediating reflex blinks. In patients with BEB and healthy age-matched controls, we used the conditioning protocol introduced by Mao and Evinger (2001) to induce long-term potentiation (LTP)-like plasticity in trigeminal wide dynamic range neurons of the blink reflex circuit. High-frequency trains of electrical stimuli were repeatedly given over the right supraorbital nerve (SO) and timed to coincide with the R2 response elicited by a preceding SO stimulus. High-frequency stimulation (HFS) resulted in a long-lasting and input-specific potentiation of the R2 response in both groups, yet the facilitation of the R2 response was markedly increased in patients relative to controls. Botulinum toxin (BTX) injections in both orbicularis oculi muscles normalized the previously enhanced LTP-like plasticity of the R2 response. The increased responsiveness to HFS provides first-time evidence that LTP-like plasticity is increased in the trigeminal reflex circuit of patients affected by BEB. The results also show that the enhanced modifiability is not fixed in BEB, because BTX injections can transiently restore normal LTP-like plasticity. We propose that an abnormal corneal input induced by excessive blinking exacerbates increased LTP-like plasticity in BEB. BTX treatment removes the latter and restores plasticity toward normal values. Our results support the concept that maladaptive reorganization contributes to the pathophysiology of focal dystonias.

Impairments of speed and amplitude of movement in Parkinson's disease: A pilot study

Bradykinesia, characterized by slowness and decreased amplitude of movement, is often considered the most important deficit in Parkinsons disease (PD). The current clinical rating of bradykinesia in PD, based on the motor subscale of the Unified Parkinsons disease Rating Scale (UPDRS‐III), does not individually weigh the impairments in speed and amplitude of rapid alternating movements. We sought to categorize movement in PD to determine whether speed and amplitude have different relationships to current measures of motor impairment and disability. Categories of speed and amplitude (normal, slow/low, and very‐slow/very‐low) were ascertained using an electromagnetic tracking device. Amplitude was disproportionally more affected than speed in the “off” state. UPDRS‐III and the Schwab & England disability scale were worst in patients with very impaired amplitude and best in patients with normal amplitude. A similarly graded relationship was not found for categories of speed impairment. The examiner clinical global impression of change mirrored “off” state amplitude but not speed categories. Levodopa, however, normalized speed to a greater extent than amplitude. Our observations suggest that amplitude and speed impairments may be associated with different functional aspects in PD and deserve separate clinical assessment.

Paired Associative Stimulation of Left and Right Human Motor Cortex Shapes Interhemispheric Motor Inhibition based on a Hebbian Mechanism

This study was designed to examine whether corticocortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Twelve healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. Left-to-right cc-PAS (first pulse given to left M1(HAND)) attenuated left-to-right IHI for one hour after cc-PAS. Left-to-right cc-PAS also increased corticospinal excitability in the conditioned right M1(HAND). These effects were not seen in an asymptomatic individual with callosal agenesis. Additional experiments showed no changes in left-to-right IHI or corticospinal excitability when left-to-right cc-PAS was given at an ISI of 1 ms or at multiple ISIs in random order. At the behavioral level, left-to-right cc-PAS speeded responses with the left but not right index finger during a simple reaction time task. Right-to-left cc-PAS (first pulse given to right M1(HAND)) reduced right-to-left IHI without increasing corticospinal excitability in left M1(HAND). These results provide a proof of principle that cc-PAS can induce associative plasticity in connections between the targeted cortical areas. The efficacy of cc-PAS to induce lasting changes in excitability depends on the exact timing of the stimulus pairs suggesting an underlying Hebbian mechanism.

Clinical features of dystonia: a pathophysiological revisitation.

Purpose of reviewTo elucidate the pathophysiology of some clinical features of dystonic patients and to provide some new insight into the mechanisms underlying task-specific dystonia. Recent findingsThere are three general lines of work at the present time that may indicate the physiological substrate for dystonia. All three are persuasive and it is not clear whether they are related to each other or whether one is more important than the others. According to the first line of research, a loss of inhibition at different levels of the central nervous system might contribute for the excessive movement seen in dystonia.Another field of research suggests that dystonic patients may have faulty processing within the lemniscal pathway with abnormalities in the sensory-motor integration.Finally, another convincing line of evidence is that in some susceptible individuals, during the acquisition of new motor skills, the mechanisms of neuroplasticity are subtly abnormal. In the presence of such predisposition, several environmental factors, such as repetitive training or peripheral nervous system injury, can trigger an abnormal maladaptive plasticity, which can lead to an overt dystonia. SummaryThese findings may be relevant in the development of new therapeutic strategies in dystonia.

Psychogenic Facial Movement Disorders: Clinical Features and Associated Conditions

The facial phenotype of psychogenic movement disorders has not been fully characterized. Seven tertiary‐referral movement disorders centers using a standardized data collection on a computerized database performed a retrospective chart review of psychogenic movement disorders involving the face. Patients with organic forms of facial dystonia or any medical or neurological disorder known to affect facial muscles were excluded. Sixty‐one patients fulfilled the inclusion criteria for psychogenic facial movement disorders (91.8% females; age: 37.0 ± 11.3 years). Phasic or tonic muscular spasms resembling dystonia were documented in all patients most commonly involving the lips (60.7%), followed by eyelids (50.8%), perinasal region (16.4%), and forehead (9.8%). The most common pattern consisted of tonic, sustained, lateral, and/or downward protrusion of one side of the lower lip with ipsilateral jaw deviation (84.3%). Ipsi‐ or contralateral blepharospasm and excessive platysma contraction occurred in isolation or combined with fixed lip dystonia (60.7%). Spasms were reported as painful in 24.6% of cases. Symptom onset was abrupt in most cases (80.3%), with at least 1 precipitating psychological stress or trauma identified in 57.4%. Associated body regions involved included upper limbs (29.5%), neck (16.4%), lower limbs (16.4%), and trunk (4.9%). There were fluctuations in severity and spontaneous exacerbations and remissions (60%). Prevalent comorbidities included depression (38.0%) and tension headache (26.4%). Fixed jaw and/or lip deviation is a characteristic pattern of psychogenic facial movement disorders, occurring in isolation or in combination with other psychogenic movement disorders or other psychogenic features.

Long-term assessment of the risk of spread in primary late-onset focal dystonia

Background: Primary late-onset focal dystonias may spread over time to adjacent body regions, but differences in the risk of spread over time among the various focal forms and the influence of age at dystonia onset on the risk of spread are not well established. Methods: Patients presenting with primary late-onset focal blepharospasm (BSP, n = 124), cervical dystonia (CD, n = 73) and focal hand dystonia (FHD, n = 24) with 10 years or more of disease duration (mean ± SD, 15.3 (SD 4.9) years) were included in the study. The relationship between demographic/clinical variables and spread of dystonia was assessed by Kaplan–Meier survival curves and Cox proportional hazard regression models. Results: Patients starting with BSP, CD and FHD had similar age, sex and disease duration. Age at dystonia onset, age at initial spread and the risk of initial spread were significantly higher, whereas time elapsing from onset to initial spread was significantly lower in the BSP group than in those with onset in the neck or in the upper extremities. Conversely, these parameters were similar in the CD and FHD groups. The greater risk of spread in the BSP group was mainly evident in the first 5 years of history; thereafter, it declined and became similar to that of patients with CD/FHD. The difference in the risk of initial spread by site of onset was partly confounded by age at dystonia onset. Site of and age at dystonia onset, and age at first spread, were not significant predictors of the risk of a second spread. Conclusion: This study adds new insights into the phenomenon of spread of primary late-onset focal dystonia and provides the framework for future studies aimed at an indepth investigation of the mechanism(s) of spread.