Publications by authors named "Alfredo Berardelli"

298 Publications

Sudden Onset, Fixed Dystonia and Acute Peripheral Trauma as Diagnostic Clues for Functional Dystonia.

Mov Disord Clin Pract 2021 Oct 10;8(7):1107-1111. Epub 2021 Sep 10.

Neurology Unit, Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences University of Verona Verona Italy.

Background: The differentiation of functional dystonia from idiopathic dystonia may be clinically challenging.

Objective: To identify clinical features suggestive of functional dystonia to guide physicians to distinguish functional dystonia from idiopathic dystonia.

Methods: Patient data were extracted from the Italian Registry of Functional Motor Disorders and the Italian Registry of Adult Dystonia. Patients with functional and idiopathic dystonia were followed up at the same clinical sites, and they were similar in age and sex.

Results: We identified 113 patients with functional dystonia and 125 with idiopathic dystonia. Sudden onset of dystonia, evidence of fixed dystonia, and acute peripheral trauma before dystonia onset were more frequent in the functional dystonia group. No study variable alone achieved satisfactory sensitivity and specificity, whereas a combination of variables yielded 85% sensitivity and 98% specificity. A diagnostic algorithm was developed to reduce the risk of misclassifying functional dystonia.

Conclusion: Our findings extend the current diagnostic approach to functional dystonia by showing that clinical information about symptom onset, fixed dystonia, and history of peripheral trauma may provide key clues in the diagnosis of functional dystonia.
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http://dx.doi.org/10.1002/mdc3.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485608PMC
October 2021

Diagnostic criteria for blepharospasm: A multicenter international study.

Parkinsonism Relat Disord 2021 Sep 8;91:109-114. Epub 2021 Sep 8.

Human Motor Control Section, NINDS, NIH, Bethesda, MD, USA.

Background: There are no widely accepted criteria to aid the physician in diagnosing BSP.

Objective: To validate recently proposed diagnostic criteria for blepharospasm in a larger and geographically diverse population and to develop a screening system for blepharospasm.

Methods: Video-recordings from 211 blepharospasm patients and 166 healthy/disease controls were examined by 8 raters. Agreement for presence of orbicularis oculi spasms, sensory trick, and increased blinking was measured by k statistics. Inability to voluntarily suppress the spasms was asked by the examiner but not captured in the video. Patients/controls were also requested to fill a self-administered questionnaire addressing relevant blepharospasm clinical aspects. The diagnosis at each site was the gold standard for sensitivity/specificity.

Results: All the study items yielded satisfactory inter/intra-observer agreement. Combination of items rather than each item alone reached satisfactory sensitivity/specificity. The combined algorithm started with recognition of spasms followed by sensory trick. In the absence of a sensory trick, including "increased blinking" or "inability to voluntarily suppress the spasms" or both items yielded 88-92% sensitivity and 79-83% specificity. No single question of the questionnaire yielded high sensitivity/specificity. Serial application of the questionnaire to our blepharospasm and control subjects and subsequent clinical examination of subjects screening positive by the validated diagnostic algorithms yielded 78-81% sensitivity and 83-91% specificity.

Conclusion: These results support the use of proposed diagnostic criteria in multi-ethnic, multi-center cohorts. We also propose a case-finding procedure to screen blepharospasm in a given population with less effort than would be required by examination of all subjects.
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http://dx.doi.org/10.1016/j.parkreldis.2021.09.004DOI Listing
September 2021

Effect of Botulinum Toxin on Non-Motor Symptoms in Cervical Dystonia.

Toxins (Basel) 2021 Sep 12;13(9). Epub 2021 Sep 12.

Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università 30, 00185 Rome, Italy.

Patients with cervical dystonia (CD) may display non-motor symptoms, including psychiatric disturbances, pain, and sleep disorders. Intramuscular injection of botulinum toxin type A (BoNT-A) is the most efficacious treatment for motor symptoms in CD, but little is known about its effects on non-motor manifestations. The aim of the present study was to longitudinally assess BoNT-A's effects on CD non-motor symptoms and to investigate the relationship between BoNT-A-induced motor and non-motor changes. Forty-five patients with CD participated in the study. Patients underwent a clinical assessment that included the administration of standardized clinical scales assessing dystonic symptoms, psychiatric disturbances, pain, sleep disturbances, and disability. Clinical assessment was performed before and one and three months after BoNT-A injection. BoNT-A induced a significant improvement in dystonic symptoms, as well as in psychiatric disturbances, pain, and disability. Conversely, sleep disorders were unaffected by BoNT-A treatment. Motor and non-motor BoNT-A-induced changes showed a similar time course, but motor improvement did not correlate with non-motor changes after BoNT-A. Non-motor symptom changes after BoNT-A treatment are a complex phenomenon and are at least partially independent from motor symptom improvement.
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http://dx.doi.org/10.3390/toxins13090647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472845PMC
September 2021

Bradykinesia in motoneuron diseases.

Clin Neurophysiol 2021 Oct 19;132(10):2558-2566. Epub 2021 Aug 19.

IRCCS Neuromed Pozzilli (IS), Italy; Department of Human Neurosciences, Sapienza University of Rome, Italy.

Objective: Only few studies investigated voluntary movement abnormalities in patients with motoneuron diseases (MNDs) or their neurophysiological correlates. We aimed to kinematically assess finger tapping abnormalities in patients with amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), as compared to healthy controls (HCs), and their relationship with motoneuron involvement.

Methods: Fourteen ALS and 5 PLS patients were enrolled. Finger tapping was assessed by a motion analysis system. Patients underwent a central motor conduction time assessment, a motor nerve conduction study, and needle electromyography. Data were compared to those of 79 HCs using non-parametric tests. Possible relationships between clinical, kinematic, and neurophysiological data were assessed in patients.

Results: As a major finding, ALS and PLS patients performed finger tapping slower than HCs. In both conditions, movement slowness correlated with muscle strength. In ALS, movement slowness also correlated with the amplitude of the compound muscle action potential recorded from the muscles involved in the task and with denervation activity. No correlations were found between slowness, measures of upper motoneuron involvement, and other clinical and neurophysiological data.

Conclusions: This study provides novel information on voluntary movement abnormalities in MNDs.

Significance: The results highlight the pathophysiological role of motoneurons in generating movement slowness.
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http://dx.doi.org/10.1016/j.clinph.2021.08.006DOI Listing
October 2021

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study.

Clin Neurophysiol 2021 Oct 24;132(10):2519-2531. Epub 2021 Jul 24.

I.R.C.C.S Neuromed, Pozzilli, Italy; Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy. Electronic address:

Objective: To test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1).

Methods: In a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects.

Results: The facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS.

Conclusions: The results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations.

Significance: These observations can be used to optimize iTBS investigational and therapeutic applications.
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http://dx.doi.org/10.1016/j.clinph.2021.06.021DOI Listing
October 2021

Reply to: "A Primary Writing Tremor Is a Form of Dystonic Tremor: Is the Debate Settled?"

Mov Disord 2021 08;36(8):1996-1997

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology University College London, London, United Kingdom.

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http://dx.doi.org/10.1002/mds.28695DOI Listing
August 2021

The contribution of the Italian residents in neurology to the COVID-19 crisis: admirable generosity but neurological training remains their priority.

Neurol Sci 2021 Nov 10;42(11):4425-4431. Epub 2021 Aug 10.

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has severely impacted the Italian healthcare system, underscoring a dramatic shortage of specialized doctors in many disciplines. The situation affected the activity of the residents in neurology, who were also offered the possibility of being formally hired before their training completion.

Aims: (1) To showcase examples of clinical and research activity of residents in neurology during the COVID-19 pandemic in Italy and (2) to illustrate the point of view of Italian residents in neurology about the possibility of being hired before the completion of their residency program.

Results: Real-life reports from several areas in Lombardia-one of the Italian regions more affected by COVID-19-show that residents in neurology gave an outstanding demonstration of generosity, collaboration, reliability, and adaptation to the changing environment, while continuing their clinical training and research activities. A very small minority of the residents participated in the dedicated selections for being hired before completion of their training program. The large majority of them prioritized their training over the option of earlier employment.

Conclusions: Italian residents in neurology generously contributed to the healthcare management of the COVID-19 pandemic in many ways, while remaining determined to pursue their training. Neurology is a rapidly evolving clinical field due to continuous diagnostic and therapeutic progress. Stakeholders need to listen to the strong message conveyed by our residents in neurology and endeavor to provide them with the most adequate training, to ensure high quality of care and excellence in research in the future.
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http://dx.doi.org/10.1007/s10072-021-05346-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353936PMC
November 2021

The importance of assessing interactions between different circuits in primary motor cortex in Parkinson's disease.

Clin Neurophysiol 2021 Oct 24;132(10):2668-2670. Epub 2021 Jul 24.

Department of Human Neurosciences, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli (IS), Italy. Electronic address:

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http://dx.doi.org/10.1016/j.clinph.2021.07.010DOI Listing
October 2021

A Multi-center Genome-wide Association Study of Cervical Dystonia.

Mov Disord 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Lübeck, Lübeck, Germany.

Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility.

Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach.

Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal.

Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823).

Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28732DOI Listing
July 2021

Predictive modeling of spread in adult-onset isolated dystonia: Key properties and effect of tremor inclusion.

Eur J Neurol 2021 Jul 22. Epub 2021 Jul 22.

Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background And Purpose: Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.

Methods: Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation ("dystonia-only") and one accepting dystonia OR tremor in any body part as disease manifestations ("dystonia OR tremor"). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.

Results: Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62-0.70 and 0.62-0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.

Conclusions: This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals' risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.
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http://dx.doi.org/10.1111/ene.15031DOI Listing
July 2021

Driving motor cortex oscillations modulates bradykinesia in Parkinson's disease.

Brain 2021 Jul 10. Epub 2021 Jul 10.

IRCCS Neuromed, Pozzilli (IS), Italy.

In Parkinson's disease (PD) patients, beta (β) and gamma (γ) oscillations are altered in the basal ganglia, and this abnormality contributes to the pathophysiology of bradykinesia. However, it is unclear whether β and γ rhythms at the primary motor cortex (M1) level influence bradykinesia. Transcranial alternating current stimulation (tACS) can modulate cortical rhythms by entraining endogenous oscillations. We tested whether β- and γ-tACS on M1 modulate bradykinesia in PD patients by analyzing the kinematic features of repetitive finger tapping, including movement amplitude, velocity, and sequence effect, recorded during β-, γ-, and sham tACS. We also verified whether possible tACS-induced bradykinesia changes depended on modifications in specific M1 circuits, as assessed by short-interval intracortical inhibition (SICI) and short-latency afferent inhibition (SAI). Patients were studied OFF and ON dopaminergic therapy. Results were compared to those obtained in a group of healthy subjects (HS). In patients, movement velocity significantly worsened during β-tACS and movement amplitude improved during γ-tACS, while the sequence effect did not change. In addition, SAI decreased (reduced inhibition) during β-tACS and SICI decreased during both γ- and β-tACS in PD. The effects of tACS were comparable between OFF and ON sessions. In patients OFF therapy, the degree of SICI modulation during β- and γ-tACS correlated with movement velocity and amplitude changes. Moreover, there was a positive correlation between the effect of γ-tACS on movement amplitude and motor symptoms severity. Our results show that cortical β and γ oscillations are relevant in the pathophysiology of bradykinesia in PD and that changes in inhibitory GABA-A-ergic interneuronal activity may reflect compensatory M1 mechanisms to counteract bradykinesia. In conclusion, abnormal oscillations at the M1 level of the basal ganglia-thalamo-cortical network play a relevant role in the pathophysiology of bradykinesia in PD.
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http://dx.doi.org/10.1093/brain/awab257DOI Listing
July 2021

Motor and non-motor subtypes of cervical dystonia.

Parkinsonism Relat Disord 2021 Jul 18;88:108-113. Epub 2021 Jun 18.

Department of Human Neurosciences, Sapienza, University of Rome, Viale Dell' Università 30, 00185, Rome, Italy; IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy. Electronic address:

Introduction: Cervical dystonia (CD) is a heterogeneous condition. However, while motor subtypes of CD have recently been identified, it is still unknown whether and how non-motor symptoms contribute to CD heterogeneity. In the present cross-sectional study, we aimed to identify clinical CD subtypes on the basis of motor and non-motor symptoms by using a hypothesis-free data-driven approach.

Methods: Fifty-seven patients with CD participated in the study. Patients underwent a clinical evaluation that assessed motor and non-motor features of CD with standardized clinical scales. We investigated five clinical domains, including motor symptoms, psychiatric disturbances, sleep disorders, cognitive impairment and pain. These domains were used as variables in a k-means cluster analysis with two-, three-, and four-cluster solutions.

Results: The two-cluster solution best fits our sample. Cluster I (n = 32) included patients who were younger and had less severe non-motor symptoms and a lower disability level than patients included in Cluster II (n = 25). The two clusters showed similar sex distribution and disease duration. Similarly, the type of motor pattern and the occurrence of tremor and sensory trick were equally distributed in the two subtypes.

Conclusions: We identified two clinical subtypes of CD. The two subtypes shared similar motor features but were characterized by different non-motor symptom severity. These findings suggest that motor network dysfunction is a common pathophysiological feature of CD, whereas the extent of non-motor network involvement may differ in CD, with age acting as a possible modulating factor.
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http://dx.doi.org/10.1016/j.parkreldis.2021.06.008DOI Listing
July 2021

Response to "Response to isolated head tremor: A DAT-SPECT and somatosensory temporal discrimination study".

Parkinsonism Relat Disord 2021 06 27;87:168-169. Epub 2021 May 27.

Department of Human Neuroscience, Sapienza University of Rome, Viale Dell'Università 30, 00185, Rome, Italy; IRCCS NEUROMED, Via Atinense 18, 86077, Pozzilli, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2021.05.025DOI Listing
June 2021

Effects of Transcranial Ultrasound Stimulation on Trigeminal Blink Reflex Excitability.

Brain Sci 2021 May 15;11(5). Epub 2021 May 15.

IRCCS Neuromed, 86077 Pozzilli, Italy.

Recent evidence indicates that transcranial ultrasound stimulation (TUS) modulates sensorimotor cortex excitability. However, no study has assessed possible TUS effects on the excitability of deeper brain areas, such as the brainstem. In this study, we investigated whether TUS delivered on the substantia nigra, superior colliculus, and nucleus raphe magnus modulates the excitability of trigeminal blink reflex, a reliable neurophysiological technique to assess brainstem functions in humans. The recovery cycle of the trigeminal blink reflex (interstimulus intervals of 250 and 500 ms) was tested before (T0), and 3 (T1) and 30 min (T2) after TUS. The effects of substantia nigra-TUS, superior colliculus-TUS, nucleus raphe magnus-TUS and sham-TUS were assessed in separate and randomized sessions. In the superior colliculus-TUS session, the conditioned R2 area increased at T1 compared with T0, while T2 and T0 values did not differ. Results were independent of the interstimulus intervals tested and were not related to trigeminal blink reflex baseline (T0) excitability. Conversely, the conditioned R2 area was comparable at T0, T1, and T2 in the nucleus raphe magnus-TUS and substantia nigra-TUS sessions. Our findings demonstrate that the excitability of brainstem circuits, as evaluated by testing the recovery cycle of the trigeminal blink reflex, can be increased by TUS. This result may reflect the modulation of inhibitory interneurons within the superior colliculus.
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http://dx.doi.org/10.3390/brainsci11050645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156436PMC
May 2021

Spread of segmental/multifocal idiopathic adult-onset dystonia to a third body site.

Parkinsonism Relat Disord 2021 06 12;87:70-74. Epub 2021 May 12.

IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

Background: Adult-onset focal dystonia can spread to involve one, or less frequently, two additional body regions. Spread of focal dystonia to a third body site is not fully characterized.

Materials And Methods: We retrospectively analyzed data from the Italian Dystonia Registry, enrolling patients with segmental/multifocal dystonia involving at least two parts of the body or more. Survival analysis estimated the relationship between dystonia features and spread to a third body part.

Results: We identified 340 patients with segmental/multifocal dystonia involving at least two body parts. Spread of dystonia to a third body site occurred in 42/241 patients (17.4%) with focal onset and 10/99 patients (10.1%) with segmental/multifocal dystonia at onset. The former had a greater tendency to spread than patients with segmental/multifocal dystonia at onset. Gender, years of schooling, comorbidity, family history of dystonia/tremor, age at dystonia onset, and disease duration could not predict spread to a third body site. Among patients with focal onset in different body parts (cranial, cervical, and upper limb regions), there was no association between site of focal dystonia onset and risk of spread to a third body site.

Discussion And Conclusion: Spread to a third body site occurs in a relative low percentage of patients with idiopathic adult-onset dystonia affecting two body parts. Regardless of the site of dystonia onset and of other demographic/clinical variables, focal onset seems to confer a greater risk of spread to a third body site in comparison to patients with segmental/multifocal dystonia at onset.
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http://dx.doi.org/10.1016/j.parkreldis.2021.04.022DOI Listing
June 2021

Salivary caffeine in Parkinson's disease.

Sci Rep 2021 05 10;11(1):9823. Epub 2021 May 10.

IRCCS NEUROMED, Via Atinense, 18, 86077, Pozzilli, Italy.

We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson's disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.
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http://dx.doi.org/10.1038/s41598-021-89168-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110998PMC
May 2021

Emerging concepts on bradykinesia in non-parkinsonian conditions.

Eur J Neurol 2021 07 18;28(7):2403-2422. Epub 2021 May 18.

IRCCS Neuromed, Pozzilli, Italy.

Background And Purpose: Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease. However, clinical and experimental studies indicate that bradykinesia may also be observed in various neurological diseases not primarily characterized by parkinsonism. These conditions include hyperkinetic movement disorders, such as dystonia, chorea, and essential tremor. Bradykinesia may also be observed in patients with neurological conditions that are not seen as "movement disorders," including those characterized by the involvement of the cerebellum and corticospinal system, dementia, multiple sclerosis, and psychiatric disorders.

Methods: We reviewed clinical reports and experimental studies on bradykinesia in non-parkinsonian conditions and discussed the major findings.

Results: Bradykinesia is a common motor abnormality in non-parkinsonian conditions. From a pathophysiological standpoint, bradykinesia in neurological conditions not primarily characterized by parkinsonism may be explained by brain network dysfunction.

Conclusion: In addition to the pathophysiological implications, the present paper highlights important terminological issues and the need for a new, more accurate, and more widely used definition of bradykinesia in the context of movement disorders and other neurological conditions.
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http://dx.doi.org/10.1111/ene.14851DOI Listing
July 2021

The Signature of Primary Writing Tremor Is Dystonic.

Mov Disord 2021 07 30;36(7):1715-1720. Epub 2021 Mar 30.

Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology University College London, London, UK.

Background: It has been debated for decades whether primary writing tremor is a form of dystonic tremor, a variant of essential tremor, or a separate entity. We wished to test the hypothesis that primary writing tremor and dystonia share a common pathophysiology.

Objectives: The objective of the present study was to investigate the pathophysiological hallmarks of dystonia in patients affected by primary writing tremor.

Methods: Ten patients with idiopathic dystonic tremor syndrome, 7 with primary writing tremor, 10 with essential tremor, and 10 healthy subjects were recruited. They underwent eyeblink classic conditioning, blink recovery cycle, and transcranial magnetic stimulation assessment, including motor-evoked potentials and short- and long-interval intracortical inhibition at baseline. Transcranial magnetic stimulation measures were also recorded after paired-associative plasticity protocol.

Results: Primary writing tremor and dystonic tremor syndrome had a similar pattern of electrophysiological abnormalities, consisting of reduced eyeblink classic conditioning learning, reduced blink recovery cycle inhibition, and a lack of effect of paired-associative plasticity on long-interval intracortical inhibition. The latter 2 differ from those obtained in essential tremor and healthy subjects. Although not significant, slightly reduced short-interval intracortical inhibition and a larger effect of paired-associative plasticity in primary writing tremor and dystonic tremor syndrome, compared with essential tremor and healthy subjects, was observed.

Conclusions: Our initial hypothesis of a common pathophysiology between dystonia and primary writing tremor has been confirmed. Primary writing tremor might be considered a form of dystonic tremor. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28579DOI Listing
July 2021

The effect of gamma oscillations in boosting primary motor cortex plasticity is greater in young than older adults.

Clin Neurophysiol 2021 06 13;132(6):1358-1366. Epub 2021 Mar 13.

IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy; Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università 30, 00185 Rome, Italy.

Objective: In healthy subjects, the long-term potentiation (LTP)-like plasticity of the primary motor cortex (M1) induced by intermittent theta-burst stimulation (iTBS) can be boosted by modulating gamma (γ) oscillations through transcranial alternating current stimulation (tACS). γ-tACS also reduces short-interval intracortical inhibition (SICI). We tested whether the effects of γ-tACS differ between young (YA) and older adults (OA).

Methods: Twenty YA (27.2 ± 2.7 years) and twenty OA (65.3 ± 9.5 years) underwent iTBS-γ tACS and iTBS-sham tACS in randomized sessions. In a separate session, we delivered γ-tACS alone and recorded SICI during stimulation.

Results: iTBS-sham tACS produced comparable motor evoked potential (MEP) facilitation between groups. While iTBS-γ tACS boosted MEP facilitation in both the YA and OA groups, the magnitude of its effect was significantly lower in OA. Similarly, γ-tACS-induced modulation of GABA-A-ergic neurotransmission, as tested by SICI, was reduced in OA. The effect of iTBS-γ tACS negatively correlated with the age of OA subjects.

Conclusions: Mechanisms underlying the effects of γ oscillations on LTP-like plasticity become less efficient in older adults. This could reflect age-related changes in neural elements of M1 resonant to γ oscillations, including GABA-A-ergic interneurons.

Significance: The beneficial effect of γ-tACS on iTBS-induced plasticity is reduced in older adults.
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http://dx.doi.org/10.1016/j.clinph.2021.01.032DOI Listing
June 2021

Is Adult-Onset Dystonia a Rare Disease? Time for Population-Based Studies.

Mov Disord 2021 05 16;36(5):1119-1124. Epub 2021 Mar 16.

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1002/mds.28560DOI Listing
May 2021

No evidence of iron deposition in essential tremor: a susceptibility-weighted imaging study.

Neurol Sci 2021 Nov 15;42(11):4667-4672. Epub 2021 Mar 15.

Department of Neurology, Neuromed Institute IRCCS, Via Atinense, 18, 86077, Pozzilli, IS, Italy.

Objective: To evaluate the role of iron deposition in subcortical nuclei of patients with essential tremor (ET).

Methods: Twenty-three patients with ET underwent a standardized 3T-MRI protocol. We specifically assessed iron deposition using susceptibility-weighted angiography (SWAN) images in seven specific regions of interest (ROIs): the thalamus, putamen, globus pallidus, caudate nucleus, substantia nigra, red nucleus, and dentate nucleus. Tremor in ET patients was clinically assessed using the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). ET patient data were compared with data obtained from 23 Parkinson's disease (PD) patients and 14 healthy subjects (HS).

Results: No differences in iron deposition in the seven ROIs were found between ET patients and HS. Conversely, PD patients showed increased iron deposition in the substantia nigra in comparison with both ET patients and HS.

Conclusions: Our results indicate the absence of iron deposition in subcortical nuclei of ET patients, which is generally considered a marker of neurodegeneration.
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http://dx.doi.org/10.1007/s10072-021-05173-7DOI Listing
November 2021

Voice Analysis with Machine Learning: One Step Closer to an Objective Diagnosis of Essential Tremor.

Mov Disord 2021 06 2;36(6):1401-1410. Epub 2021 Feb 2.

Department of Electronic Engineering, University of Rome Tor Vergata, Rome, Italy.

Background: Patients with essential tremor have upper limb postural and action tremor often associated with voice tremor. The objective of this study was to objectively examine voice tremor and its response to symptomatic pharmacological treatment in patients with essential tremor using voice analysis consisting of power spectral analysis and machine learning.

Methods: We investigated 58 patients (24 men; mean age ± SD, 71.7 ± 9.2 years; range, 38-85 years) and 74 age- and sex-matched healthy subjects (20 men; mean age ± SD, 71.0 ± 12.4 years; range, 43-95 years). We recorded voice samples during sustained vowel emission using a high-definition audio recorder. Voice samples underwent sound signal analysis, including power spectral analysis and support vector machine classification. We compared voice recordings in patients with essential tremor who did and did not manifest clinically overt voice tremor and in patients who were and were not under the symptomatic effect of the best medical treatment.

Results: Power spectral analysis demonstrated a prominent oscillatory activity peak at 2-6 Hz in patients who manifested a clinically overt voice tremor. Voice analysis with support vector machine classifier objectively discriminated with high accuracy between controls and patients who did and did not manifest clinically overt voice tremor and between patients who were and were not under the symptomatic effect of the best medical treatment.

Conclusions: In patients with essential tremor, voice tremor is characterized by abnormal oscillatory activity at 2-6 Hz. Voice analysis, including power spectral analysis and support vector machine classification, objectively detected voice tremor and its response to symptomatic pharmacological treatment in patients with essential tremor. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28508DOI Listing
June 2021

Motor dysfunction in mild cognitive impairment as tested by kinematic analysis and transcranial magnetic stimulation.

Clin Neurophysiol 2021 02 2;132(2):315-322. Epub 2020 Dec 2.

Department of Human Neurosciences, Sapienza University of Rome, Italy; IRCCS Neuromed, Pozzilli (IS), Italy.

Objective: Previous studies have demonstrated voluntary movement alterations as well as motor cortex excitability and plasticity changes in patients with mild cognitive impairment (MCI). To investigate the pathophysiology of movement abnormalities in MCI, we tested possible relationships between movement abnormalities and primary motor cortex alterations in patients.

Methods: Fourteen amnestic MCI (aMCI) patients and 16 healthy controls were studied. Cognitive assessment was performed using clinical scales. Finger tapping was recorded by a motion analysis system. Transcranial magnetic stimulation was used to test the input/output curve of motor evoked potentials, intracortical inhibition, and short-latency afferent inhibition. Primary motor cortex plasticity was probed by theta burst stimulation. We investigated correlations between movement abnormalities, clinical scores, and cortical neurophysiological parameters.

Results: MCI patients showed less rhythmic movement but no other movement abnormalities. Cortical excitability measures were normal in patients, whereas plasticity was reduced. Movement rhythm abnormalities correlated with frontal dysfunction scores.

Conclusion: Our study in MCI patients demonstrated abnormal voluntary movement and plasticity changes, with no correlation between the two. Altered rhythm correlated with frontal dysfunction.

Significance: Our results contribute to the understanding of pathophysiological mechanisms of motor impairment in MCI.
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http://dx.doi.org/10.1016/j.clinph.2020.10.028DOI Listing
February 2021

Neuroimaging in idiopathic adult-onset focal dystonia.

Neurol Sci 2021 Jul 3;42(7):2947-2950. Epub 2021 Jan 3.

Department of Medical Science and Public Health, Institute of Neurology, University of Cagliari, Cagliari, Italy.

We aimed to study the attitude of Italian neurologists in the use of conventional MRI in patients with idiopathic adult-onset focal dystonia. Patients were included in the Italian Dystonia Registry by experts working in different Italian centers. MRI was available for 1045 of the 1471 (71%) patients included in the analysis. Using logistic regression analysis, we found that MRI was more likely to be performed in patients with cervical dystonia, spasmodic dysphonia, or non-task-specific upper limb dystonia, whereas it was less likely to be performed in patients with blepharospasm or task-specific upper limb dystonia. We did not find differences in the number of MRIs performed between neurological centers in Northern, Central, and Southern Italy. We conclude that although the diagnosis of idiopathic adult-onset dystonia is mainly based on clinical grounds, many movement disorder experts rely on MRI to confirm a diagnosis of idiopathic dystonia. We suggest that neuroimaging should be used in patients with adult-onset focal dystonia to rule out secondary forms.
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http://dx.doi.org/10.1007/s10072-020-05025-wDOI Listing
July 2021

Correction to: The Use of Botulinum Toxin for Treatment of the Dystonias.

Handb Exp Pharmacol 2021 ;263:285

Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1007/164_2020_414DOI Listing
January 2021

Painful stimulation increases spontaneous blink rate in healthy subjects.

Sci Rep 2020 11 17;10(1):20014. Epub 2020 Nov 17.

IRCCS Neuromed, Pozzilli, IS, Italy.

Spontaneous blink rate is considered a biomarker of central dopaminergic activity. Recent evidence suggests that the central dopaminergic system plays a role in nociception. In the present study, we aimed to investigate whether pain modulates spontaneous blink rate in healthy subjects. We enrolled 15 participants. Spontaneous blink rate was quantified with an optoelectronic system before and after: (1) a painful laser stimulation, and (2) an acoustic startling stimulation. In control experiments, we investigated whether laser stimulation effects depended on stimulation intensity and whether laser stimulation induced any changes in the blink reflex recovery cycle. Finally, we investigated any relationship between spontaneous blink rate modification and pain modulation effect during the cold pressor test. Laser, but not acoustic, stimulation increased spontaneous blink rate. This effect was independent of stimulation intensity and negatively correlated with pain perception. No changes in trigeminal-facial reflex circuit excitability were elicited by laser stimulation. The cold pressor test also induced an increased spontaneous blink rate. Our study provides evidence on the role of dopamine in nociception and suggests that dopaminergic activity may be involved in pain modulation. These findings lay the groundwork for further investigations in patients with pathological conditions characterized by dopaminergic deficit and pain.
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http://dx.doi.org/10.1038/s41598-020-76804-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672065PMC
November 2020

Clinical and Kinematic Features of Valproate-Induced Tremor and Differences with Essential Tremor.

Cerebellum 2021 Jun 16;20(3):374-383. Epub 2020 Nov 16.

IRCCS Neuromed, Pozzilli (IS), Italy.

Tremor is a common movement disorder that can be induced by medications, including valproate, which is used for the treatment of epilepsy. However, the clinical and neurophysiological features of valproate-induced tremor are still under-investigated. We performed a clinical and kinematic assessment of valproate-induced tremor by considering tremor body distribution and activation conditions. We investigated possible correlations between demographic and clinical data and kinematic features. Valproate-induced tremor results were also compared with those collected in a large sample of patients with essential tremor. Sixteen valproate-induced tremor patients and 93 essential tremor patients were enrolled. All participants underwent a standardised neurological examination and video recording. Patients also underwent an objective assessment of postural, kinetic and rest tremor of the upper limbs and head tremor through kinematic analysis. Nonparametric tests were used for statistical comparisons between the two groups. Clinical evaluation showed a higher occurrence of rest tremor as well as head or voice, and lower limb involvement in patients with valproate-induced tremor. Kinematic analysis showed a substantial variability in the tremor features of patients with valproate-induced tremor. Compared to essential tremor, we found a higher occurrence of rest tremor of the upper limbs and the involvement of more body segments in valproate-induced tremor patients. Valproate-induced tremor has distinctive clinical and kinematic features, which may suggest that valproate interferes with the cerebellar functions.
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http://dx.doi.org/10.1007/s12311-020-01216-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213593PMC
June 2021

Development of a Clinical Rating Scale for the Severity of Apraxia of Eyelid Opening, Either Isolated or Associated with Blepharospasm.

Mov Disord Clin Pract 2020 Nov 22;7(8):950-954. Epub 2020 Sep 22.

Department of Medical Sciences and Public Health, Institute of Neurology University of Cagliari and AOU-Cagliari Cagliari Italy.

Background: Apraxia of eyelid opening is a movement disorder characterized by an inability to raise the eyelids without any overt contractions of the orbicularis oculi muscle. There is currently no clinical scale to rate the severity of this condition.

Objectives: To develop and validate a novel scale that considers phenomenological aspects relevant to the severity of the condition.

Methods: The study sample included 20 patients with apraxia of eyelid opening, either isolated (9 patients) or associated with blepharospasm (11 patients). To validate the scale, selected features were checked for reliability, reliable items were combined to generate the scale, and clinimetric properties were evaluated.

Results: The novel severity scale yielded acceptable reliability, scaling assumptions, internal consistency, and sensitivity to change; a lack of floor and ceiling effects; and no correlation with the blepharospasm severity rating scale.

Conclusions: We propose a severity scale that considers the most relevant apraxia of eyelid opening motor abnormalities based on objective criteria. This scale can be reliably administered by general neurologists after a brief training.
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http://dx.doi.org/10.1002/mdc3.13083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604665PMC
November 2020

Reversal of Temporal Discrimination in Cervical Dystonia after Low-Frequency Sensory Stimulation.

Mov Disord 2021 03 7;36(3):761-766. Epub 2020 Nov 7.

Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology, London, UK.

Background: Somatosensory temporal discrimination is abnormal in dystonia and reflects reduced somatosensory inhibition. In healthy individuals, both the latter are enhanced by high-frequency repetitive somatosensory stimulation, whereas opposite effects are observed in patients with cervical dystonia.

Objectives: We tested whether low-frequency repetitive sensory stimulation, which in healthy individuals worsens discrimination, might have the opposite effect in patients with cervical dystonia at the physiological level and, in turn, improve their perceptual performance.

Methods: Somatosensory temporal discrimination and several electrophysiological measures of sensorimotor inhibition were collected before and after 45 minutes of low-frequency repetitive sensory stimulation.

Results: As predicted, and opposite to what happened in controls, low-frequency repetitive sensory stimulation in patients enhanced sensorimotor inhibition and normalized somatosensory temporal discrimination.

Conclusions: Patients with cervical dystonia have an abnormal response to repetitive sensory stimulation, which we hypothesize is attributed to abnormally sensitive homeostatic mechanisms of inhibitory circuitry in both sensory and motor systems. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28369DOI Listing
March 2021
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