Subthalamic deep brain stimulation induces finely-tuned gamma oscillations in the absence of levodopa.

Finely-tuned gamma (FTG) oscillations can be recorded from cortex or the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) on dopaminergic medication, and have been associated with dyskinesias. When recorded during deep brain stimulation (DBS) on medication the FTG is entrained to half the stimulation frequency. We investigated whether these characteristics are shared off medication by recording local field potentials (LFP) from the STN from externalised DBS leads in 14 PD patients after overnight withdrawal of medication. FTG was induced de-novo by DBS in the absence of dyskinesias in a third of our cohort. The FTG could outlast stimulation or arise only after DBS ceased. FTG frequencies decreased during and across consecutive DBS blocks, but did not shift with changing stimulation frequency off medication. Together with the sustained after-effects this argues against simple entrainment by DBS in the off medication state. We also found significant coherence between STN-LFP and electroencephalogram (EEG) signals at FTG frequencies. We conclude that FTG is a network phenomenon that behaves differently in the off medication state, when it is neither associated with dyskinesias nor susceptible to entrainment.

Hypomimia in Parkinson's disease: an axial sign responsive to levodopa.

BACKGROUND AND PURPOSE: Hypomimia is a prominent clinical feature in people with Parkinson's disease (PD), but it remains under-investigated. We aimed to examine the clinical correlates of hypomimia in PD and to determine whether this is a levodopa-responsive sign. METHODS: We included 89 people with PD. Hypomimia was assessed from digital video recordings by movement disorder specialists. Clinical evaluation included use of the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), and assessment of motor and non-motor symptoms using standardized clinical scales. The relationships between hypomimia and other clinical data were analysed using Mann-Whitney U-tests and regression analysis. RESULTS: Hypomimia occurred in up to 70% of patients with PD. Patients with hypomimia had worse UPDRS-III 'off-medication' scores, mainly driven by bradykinesia and rigidity subscores. Patients with hypomimia also had worse apathy than patients without hypomimia. Finally, we found that hypomimia was levodopa-responsive and its improvement mirrored the change by levodopa in axial motor symptoms. CONCLUSION: Our study provides novel information regarding the clinical correlates of hypomimia in people with PD. A better understanding of hypomimia may be relevant for improving treatment and quality of life in PD.

Opinions and clinical practices related to diagnosing and managing functional (psychogenic) movement disorders: changes in the last decade.

BACKGROUND AND PURPOSE: There is large variability in the diagnostic approach and clinical management in functional movement disorders (FMD). This study aimed to examine whether opinions and clinical practices related to FMD have changed over the past decade. METHODS: Adapted from a 2008 version, we repeated the survey to members of the International Parkinson and Movement Disorder Society (MDS). RESULTS: In all, 864/7689 responses (denominator includes non-neurologists) were received from 92 countries. Respondents were more often male (55%), younger than 45 (65%) and from academic practices (85%). Although the likelihood of ordering neurological investigations prior to delivering a diagnosis of FMD was nearly as high as in 2008 (47% vs. 51%), the percentage of respondents communicating the diagnosis without requesting additional tests increased (27% vs. 19%; P = 0.003), with most envisioning their role as providing a diagnosis and coordinating management (57% vs. 40%; P < 0.001). Compared to patients with other disorders, 64% of respondents were more concerned about missing a diagnosis of another neurological disorder. Avoiding iatrogenic harm (58%) and educating patients about the diagnosis (53%) were again rated as the most effective therapeutic options. Frequent treatment barriers included lack of physician knowledge and training (32%), lack of treatment guidelines (39%), limited availability of referral services (48%) and cultural beliefs about psychological illnesses (50%). The preferred term for communication favored 'functional' over 'psychogenic' (P < 0.001). CONCLUSIONS: Attitudes and management of FMDs have changed over the past decade. Important gaps remain in access to treatment and in the education of neurologists about the inclusionary approach to FMD diagnosis.

Spread of dystonia in patients with idiopathic adult-onset laryngeal dystonia.

BACKGROUND AND PURPOSE: Adult-onset laryngeal dystonia (LD) can be isolated or can be associated with dystonia in other body parts. Combined forms can be segmental at the onset or can result from dystonia spread to or from the larynx. The aim of this study was to identify the main clinical and demographic features of adult-onset idiopathic LD in an Italian population with special focus on dystonia spread. METHODS: Data were obtained from the Italian Dystonia Registry (IDR) produced by 37 Italian institutions. Clinical and demographic data of 71 patients with idiopathic adult-onset LD were extracted from a pool of 1131 subjects included in the IDR. RESULTS: Fifty of 71 patients presented a laryngeal focal onset; the remaining subjects had onset in other body regions and later laryngeal spread. The two groups did not show significant differences of demographic features. 32% of patients with laryngeal onset reported spread to contiguous body regions afterwards and in most cases (12 of 16 subjects) dystonia started to spread within 1 year from the onset. LD patients who remained focal and those who had dystonia spread did not show other differences. CONCLUSIONS: Data from IDR show that dystonic patients with focal laryngeal onset will present spread in almost one-third of cases. Spread from the larynx occurs early and is directed to contiguous body regions showing similarities with clinical progression of blepharospasm. This study gives a new accurate description of LD phenomenology that may contribute to improving the comprehension of dystonia pathophysiology.

Correction to: The Italian Dystonia Registry: rationale, design and preliminary findings.

In the original article, Gina Ferrazzano was affiliated to Department of Neurology and Psychiatry, Neuromed Institute IRCCS, Sapienza University of Rome, Pozzilli, Italy.The corrected affiliation should be: Neuromed Institute IRCCS, Pozzilli, IS, Italy.

Spatial Integration of Somatosensory Inputs during Sensory-Motor Plasticity Phenomena Is Normal in Focal Hand Dystonia.

Background: Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results: FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD.

Non-invasive brain stimulation for dystonia: therapeutic implications.

Dystonia is characterized by excessive muscle contractions giving rise to abnormal posture and involuntary twisting movements. Although dystonia syndromes are a heterogeneous group of disorders, certain pathophysiological mechanisms have been consistently identified across different forms. These pathophysiological mechanisms have subsequently been exploited for the development of non-invasive brain stimulation (NIBS) techniques able to modulate neural activity in one or more nodes of the putative network that is altered in dystonia, and the therapeutic role of NIBS has hence been suggested. Here all studies that applied such techniques as a therapeutic intervention in any forms of dystonia, including the few works performed in children, are reviewed and emerging concepts and pitfalls of NIBS are discussed.

The Italian Dystonia Registry: rationale, design and preliminary findings.

The Italian Dystonia Registry is a multicenter data collection system that will prospectively assess the phenomenology and natural history of adult-onset dystonia and will serve as a basis for future etiological, pathophysiological and therapeutic studies. In the first 6 months of activity, 20 movement disorders Italian centres have adhered to the registry and 664 patients have been recruited. Baseline historical information from this cohort provides the first general overview of adult-onset dystonia in Italy. The cohort was characterized by a lower education level than the Italian population, and most patients were employed as artisans, builders, farmers, or unskilled workers. The clinical features of our sample confirmed the peculiar characteristics of adult-onset dystonia, i.e. gender preference, peak age at onset in the sixth decade, predominance of cervical dystonia and blepharospasm over the other focal dystonias, and a tendency to spread to adjacent body parts, The sample also confirmed the association between eye symptoms and blepharospasm, whereas no clear association emerged between extracranial injury and dystonia in a body site. Adult-onset dystonia patients and the Italian population shared similar burden of arterial hypertension, type 2 diabetes, coronary heart disease, dyslipidemia, and hypothyroidism, while hyperthyroidism was more frequent in the dystonia population. Geographic stratification of the study population yielded no major difference in the most clinical and phenomenological features of dystonia. Analysis of baseline information from recruited patients indicates that the Italian Dystonia Registry may be a useful tool to capture the real world clinical practice of physicians that visit dystonia patients.

Cortical excitability in patients with resistance to thyroid hormone compared to patients with hypothyroidism and euthyroid controls: a transcranial magnetic stimulation study.

Resistance to thyroid hormone (RTH) describes a rare syndrome in which serum levels of thyroid hormones are elevated but serum levels of thyroid stimulating hormone (TSH) are unsuppressed. The importance of thyroid hormones for the normal function of the adult brain is corroborated by the frequent association of thyroid dysfunctions with neurological and psychiatric symptoms. In this study we investigated whether adult thyroid hormone resistance affects cortical excitability and modulates inhibitory and excitatory intracortical circuitries by using transcranial magnetic stimulation. Cortical excitability was probed with transcranial magnetic stimulation in 4 patients with thyroid hormone resistance, 10 patients affected by overt hypothyroidism (OH) and 10 age-matched healthy controls. We tested motor thresholds, motor evoked potential recruitment curve, cortical silent period (CSP), short interval intracortical inhibition (SICI) and intracortical facilitation. In both OH and RTH patients, the inhibitory cortical circuits were affected compared with euthyroid controls, but in opposite ways. In OH patients, CSP was prolonged and SICI was decreased. On the contrary, in RTH patients CSP was shortened and SICI was increased. Thyroid hormones may influence cortical excitability and cortical inhibitory circuits.

Clinical neurophysiology of functional motor disorders: IFCN Handbook Chapter.

Functional Motor Disorders are common and disabling. Clinical diagnosis has moved from one of exclusion of other causes for symptoms to one where positive clinical features on history and examination are used to make a "rule in" diagnosis wherever possible. Clinical neurophysiological assessments have developed increasing importance in assisting with this positive diagnosis, not being used simply to demonstrate normal sensory-motor pathways, but instead to demonstrate specific abnormalities that help to positively diagnose these disorders. Here we provide a practical review of these techniques, their application, interpretation and pitfalls. We also highlight particular areas where such tests are currently lacking in sensitivity and specificity, for example in people with functional dystonia and functional tic-like movements.

The role of opicapone in the management of Parkinson's disease: an Italian consensus through a combined Nominal Group Technique and Delphi approach.

OBJECTIVE: Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) combinations in Parkinson's disease (PD) patients with end-of-dose motor fluctuations. While the OPC effectiveness on motor symptoms is well known, there is still uncertainty about the timing of introduction, the management of levodopa dose, and the efficacy on non-motor symptoms (NMS). SUBJECTS AND METHODS: A group of PD experts participated in a consensus activity composed of the Nominal Group Technique (NGT) and the Delphi method to better define the role of OPC. A list of statements was defined with the NGT and voted on through an online Delphi process by a panel of 85 Italian clinicians. RESULTS: 24 statements were selected for the Delphi voting. Most statements (n=15, 62%) reached a consensus. A wide agreement was reached about the efficacy of OPC in treating motor fluctuations, including early morning akinesia and nocturnal akinesia. The panel widely agreed about the effectiveness of OPC in early fluctuating patients. The long-lasting inhibitory effect of OPC was recognized as an advantage over other COMT-i, resulting in a single daily dose and greater ease of introduction into the levodopa therapeutic regimen. CONCLUSIONS: The efficacy of OPC observed in the clinical trials for the management of PD patients with motor fluctuations is also experienced in clinical practice. The review of the current positioning of OPC from the late to early stages of the disease may represent an important step in the evolution of the PD therapeutic approach.

Complications of unintentional dural puncture during labour epidural analgesia: a 10-year retrospective observational study.

INTRODUCTION: Unintentional dural puncture (UDP) occurs in 0.5-1.5% of labour epidural analgesia cases. To date, little is known about evidence of UDP-related complications. This work aimed to assess the incidence of intrapartum and postpartum complications in parturients who experienced UDP. METHODS: This is a 10-year retrospective observational study on parturients admitted to our centre who presented UDP. Data collection gathered UDP-related complications during labour and postpartum. All women who displayed UDP received medical therapy and bed rest. An epidural blood patch (EBP) was not used in this population. Once asymptomatic, patients were discharged from the hospital. RESULTS: Out of 7718 neuraxial analgesia cases, 97 cases of UDP occurred (1.25%). During labour, complications appeared in a small percentage of analgesia procedures performed, including total spinal anaesthesia (1.0%), extended motor block (3%), hypotension (4.1%), abnormal foetal heart rate (2%), inadequate analgesia (14.4%), and general anaesthesia following neuraxial anaesthesia failure (33.3% of emergency caesarean sections). During the postpartum period, 53.6% of parturients exhibited a postdural puncture headache, 13.4% showed neurological symptoms, and 14.4% required neurological consultation and neuroimaging. No patient developed subdural hematoma or cerebral venous sinus thrombosis; one woman presented posterior reversible encephalopathy syndrome associated with eclampsia. Overall, 82.5% of women experienced an extension of hospital stay. CONCLUSION: Major complications occurred in a small percentage of patients during labour. However, since they represent high-risk maternal and neonatal health events, a dedicated anaesthesiologist and a trained obstetric team are essential. No major neurological complications were registered postpartum, and EBP was not performed. Nevertheless, all patients with UDP were carefully monitored and treated until complete recovery before discharge, leading to an extension of their hospitalization.

Finely-tuned gamma oscillations: Spectral characteristics and links to dyskinesia.

Gamma oscillations comprise a loosely defined, heterogeneous group of functionally different activities between 30 and 100 Hz in the cortical and subcortical local field potential (LFP) of the motor network. Two distinct patterns seem to emerge which are easily conflated: Finely-tuned gamma (FTG) oscillations - a narrowband activity with peaks between 60 and 90 Hz - have been observed in multiple movement disorders and are induced by dopaminergic medication or deep brain stimulation (DBS). FTG has been linked with levodopa or DBS-induced dyskinesias, which makes it a putative biomarker for adaptive DBS. On the other hand, gamma activity can also present as a broad phenomenon (30-100 Hz) in the context of motor activation and dynamic processing. Here, we contrast FTG, either levodopa-induced or DBS-induced, from movement-related broadband gamma synchronisation and further elaborate on the functional role of FTG and its potential implications for adaptive DBS. Given the unclear distinction of FTG and broad gamma in literature, we appeal for more careful separation of the two. To better characterise cortical and subcortical FTG as biomarkers for dyskinesia, their sensitivity and specificity need to be investigated in a large clinical trial.

Lower limb involvement in adult-onset primary dystonia: frequency and clinical features.

BACKGROUND AND PURPOSE: Despite the growing number of reports describing adult-onset primary lower limb dystonia (LLD) this entity has never been systematically evaluated in the general population of patients with primary adult-onset dystonia. METHODS: From outpatients with adult-onset primary dystonia attending nine Italian University centres for movement disorders we consecutively recruited 579 patients to undergo a standardized clinical evaluation. RESULTS: Of the 579 patients assessed, 11 (1.9%) (8 women, 3 men) had LLD, either alone (n = 4, 0.7%) or as part of a segmental/multifocal dystonia (n = 7, 1.2%). The age at onset of LLD (47.9 +/- 17 years) was significantly lower than the age at onset of cranial dystonias (57.9 +/- 10.7 years for blepharospasm, and 58.9 +/- 11.8 years for oromandibular dystonia) but similar to that of all the other adult-onset primary dystonias. The lower limb was either the site of dystonia onset (36.4%) or the site of dystonia spread (63.6%). In patients in whom LLD was a site of spread, dystonia seemed to spread following a somatotopic distribution. Only one patient reported a recent trauma involving the lower limb whereas 36.4% of the patients reported pain at the site of LLD. Only 64% of our patients needed treatment for LLD, and similarly to previously reported cases, the most frequently tried treatments was botulinum toxin and trihexyphenidyl. CONCLUSION: The lower limb is an uncommon but possible topographical site of dystonia in adulthood that should be kept in consideration during clinical evaluation.

Abnormal sensorimotor plasticity in organic but not in psychogenic dystonia.

Dystonia is characterized by two main pathophysiological abnormalities: 'reduced' excitability of inhibitory systems at many levels of the sensorimotor system, and 'increased' plasticity of neural connections in sensorimotor circuits at a brainstem and spinal level. A surprising finding in two recent papers has been the fact that abnormalities of inhibition similar to those in organic dystonia are also seen in patients who have psychogenic dystonia. To try to determine the critical feature that might separate organic and psychogenic conditions, we investigated cortical plasticity in a group of 10 patients with psychogenic dystonia and compared the results with those obtained in a matched group of 10 patients with organic dystonia and 10 healthy individuals. We confirmed the presence of abnormal motor cortical inhibition (short-interval intracortical inhibition) in both organic and psychogenic groups. However, we found that plasticity (paired associative stimulation) was abnormally high only in the organic group, while there was no difference between the plasticity measured in psychogenic patients and healthy controls. We conclude that abnormal plasticity is a hallmark of organic dystonia; furthermore it is not a consequence of reduced inhibition since the latter is seen in psychogenic patients who have normal plasticity.

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.

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.

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.

Symptom severity in patients with functional motor symptoms: Patient's perception and doctor's clinical assessment.

BACKGROUND: Beliefs and expectations about symptoms and an abnormal direction of attention towards the body have been proposed as important mechanistic factors in the pathophysiology of functional motor symptoms (FMS). We therefore aimed to evaluate patients' awareness/perception of the presence and severity of their own symptoms before and while watching themselves in a video and to compare this with doctors' assessment of the presence and severity of FMS, based on video evaluation. METHODS: We evaluated 16 patients affected by FMS. Patients were invited to give a "subjective evaluation" of their symptoms. Afterwards, patients were invited to watch a video of themselves and to judge the presence of symptoms in the different body parts and, if so, to rate the severity. Patients' videos were also assessed by a rater with expertise in FMS. RESULTS: Patients judged their symptoms to be more severe on subjective evaluation than when viewing a video of themselves (p = 0.002; t = 3.656). Subjective evaluation of symptom severity by patients was higher than that of raters viewing a video of the patient (p < 0.001, t = 4.860), but there was only a trend towards a difference between video ratings of severity by patients and independent raters (p = 0.017, t = 2.962 with p set at 0.016 according to Bonferroni correction). CONCLUSIONS: Our study shows that patients with FMS tend to overestimate the severity of their symptoms compared independent rating. However, when viewing a video of themselves they rated their symptoms as less severe and closer to those of independent raters.