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Parkinson’s disease (PD) represents the most common neurodegenerative movement disorder. We recently identified 16 novel genes associated with PD. In this study, we focused the attention on the common and rare variants identified in the lysosomal K+ channel TMEM175. The study includes a detailed clinical and genetic analysis of 400 cases and 300 controls. Molecular studies were performed on patient-derived fibroblasts. The functional properties of the mutant channels were assessed by patch-clamp technique and co-immunoprecipitation. We have found that TMEM175 was highly expressed in dopaminergic neurons of the substantia nigra pars compacta and in microglia of the cerebral cortex of the human brain. Four common variants were associated with PD, including two novel variants rs2290402 (c.-10C > T) and rs80114247 (c.T1022C, p.M341T), located in the Kozak consensus sequence and TM3II domain, respectively. We also disclosed 13 novel highly penetrant detrimental mutations in the TMEM175 gene associated with PD. At least nine of these mutations (p.R35C, p. R183X, p.A270T, p.P308L, p.S348L, p. L405V, p.R414W, p.P427fs, p.R481W) may be sufficient to cause the disease, and the presence of mutations of other genes correlated with an earlier disease onset. In vitro functional analysis of the ion channel encoded by the mutated TMEM175 gene revealed a loss of the K+ conductance and a reduced channel affinity for Akt. Moreover, we observed an impaired autophagic/lysosomal proteolytic flux and an increase expression of unfolded protein response markers in patient-derived fibroblasts. These data suggest that mutations in TMEM175 gene may contribute to the pathophysiology of PD.

Introduction and scope Language is one of the main tools with whom people describe their pain. The semantic value of words plays a fundamental role in the pain perception, intended as a complex process of modulation and processing in the brain. The priming effect is a cognitive process in which a certain stimulus can influence subsequent stimuli. It is therefore plausible that this effect plays a key role in the modulation and perception of pain. This study aimed to investigate the potential relationship between the semantic aspects of language, the priming effect, and the perception of pain. Methods and results A narrative review of the literature was conducted. Sixteen studies were included and categorized in four groups based on the effect of the verbal suggestion on the experimental acute pain and chronic pain and on the effect of pain-related words in free pain and post-surgical subjects. Conclusions There may be a link between language and pain, both at the behavioral and neural level. The processing of semantic information associated with pain influences the pain perception.

Postural instability (PI) is one of the latest clinical manifestations of Parkinson's disease (PD). Due to the limited therapeutic effect of pharmacological therapies, a favorable consideration has now become towards rehabilitation interventions. Thus, this study aimed to synthesize literature evidence to summarize the effects of rehabilitation interventions for improving balance in PD.We conducted a narrative review of randomized-controlled clinical trials (RCTs) comparing the effects of interventions, control interventions, and no interventions on balance-related outcomes. A comprehensive search using the MEDLINE database was conducted from January 2000 to September 2021. This review included the following causes of balance-related impairments: inability to control body weight in the base of support, impaired attention and focus on balance, postural deformities, proprioceptive deficiency, sensory-motor integration, and coordination disorders, including visual and auditory-motor coordination.20 RCTs were included in the review. Various balance-related outcomes were included. The included studies focused on the effectiveness of different rehabilitation interventions, including physical therapy, virtual reality and telerehabilitation, treadmill training, hydrotherapy, action observation training, balance and cues-training interventions, and cognitive rehabilitation.The results suggest that most of the included rehabilitation interventions have promising therapeutic effects in improving balance in PD.

Osteoporotic fractures (OF) may occur without major trauma or injury. This case reports present a spine OF in Parkinson's disease (PD) and Pisa syndrome (PS). A 75-years-old woman diagnosed with PD for 19 years and PS has been developed. She recently has acute and severe low back pain. No recent injury or fall. After clinical examination and radiograph imaging, moderate wedge compression OF at L2 was revealed without a spinal cord or nerve compression. A program of conservative treatment was applied include antiosteoporotic supplementary, 6-days of bed rest, spine orthosis, and 10-weeks of exercises. The study adapted to use the following outcomes: visual analogues scale for low back pain, wall goniometer for lateral trunk flexion, and Oswesrty disability index for disability. After the intervention, the outcomes were improved as these values: visual analogues scales 7 points, lateral trunk flexion 20°, and Oswesrty disability index 60%. The case report suggests that the posture deformity as PS in PD may increase the risk of spine OF. The conservative treatment could be beneficial and safe for the OF in PD and PS. Further studies are required to confirm the role of PD postural deformities in OF and the effectiveness of therapeutic interventions.

Purpose The aim of this study was to assess the burden and the quality of life (QoL) perceived by caregivers assisting advanced Parkinson’s disease (PD) patients. Patients and Methods Consecutive advanced PD patients treated with levodopa/carbidopa intestinal gel (LCIG) or continuous subcutaneous apomorphine infusion (CSAI) or care as usual (CU) and their care partners were recruited during routine visits according to a cross-sectional design. Caregiver’s distress was assessed by Zarit Burden Interview (ZBI) and a QoL survey to evaluate and understand the burden experienced by care partners during family and working activities. Results A total of 126 patients (53 LCIG, 19 CSAI and 54 CU) and their care partners were enrolled. The ZBI score boxplot showed that LCIG and CU populations have a similar distribution (ZBI inter-quartile range [IQR] values respectively 18–42 for LCIG and 19–43 for CU group), while the CSAI group has a wider score range (IQR 16–52). Caregivers assisting patients in treatment with LCIG have more time to perform family or household duties (p=0.0022), or to engage in leisure activities (p=0.0073) compared to CU, while no difference was found when compared to CSAI group. Approximately 50% of the care partners showed mood changes in the last 6 months and LCIG and CSAI had less impact on caregiver’s mood compared to CU. Patients treated with LCIG were more independent in taking a bath or shower without assistance and were more able to move and walk without assistance. Conclusion Care partners of advanced PD patients treated with device-aided therapies have more time for their own life and a better perception of their QoL with a tendency to an improvement of mood compared with those of patients treated with CU.

Ataxia management is mainly based on rehabilitation, symptomatic management, and functional improvement. Therefore, it is important to comprehensively assess ataxic symptoms and their impact on function. Recently, the movement disorders society recommended four generic ataxia rating scales: scale for assessment and rating of ataxia (SARA), international cooperative ataxia rating scales, Friedreich’s ataxia rating scale (FARS), and unified multiple system atrophy rating scale (UMSARS). The aim of the study was to analyze and compare the content of the recommended ataxia rating scales by linking them to the international classification of functioning, disability and health (ICF). A total of 125 meaningful concepts from 93 items of the four included scales were linked to 57 different ICF categories. The ICF categories were distributed in body structure (n = 8), body function (n = 26), activity and participation (n = 20), and environmental factors (n = 3) components. UMSARS and FARS were the only ones that have addressed the body structure or environmental factors component. The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.

Continuous subcutaneous apomorphine infusion (CSAI) is a well-recognized therapeutic option for the management of motor fluctuations in Parkinson's disease (PD), although clinical experience suggests that most patients discontinue CSAI after a variable amount of time due to several causes and circumstances. The objective of the present study was to evaluate the reasons of CSAI discontinuation and to investigate which treatment was adopted afterwards. Two independent raters retrospectively reviewed the electronic medical record of 114 patients treated with CSAI for at least 6 months. The records were reviewed regarding efficacy, safety, and evolution of CSAI treatment. Most of PD patients on CSAI had a significant improvement in their clinical condition. Lack of improvement of dyskinesia was the most frequent causes of treatment discontinuation. The second reason for CSAI discontinuation was cognitive deterioration. At CSAI discontinuation, younger patients were more likely to undergo deep brain stimulation (DBS), while older patients and patients with cognitive impairment were more likely switched to oral therapy alone (OTA). CSAI is an effective treatment that unfortunately must be discontinued in a great number of patients with advanced PD. As older age is the main limiting factor for accessing second-level therapies at CSAI discontinuation, CSAI treatment should not be postponed to older age. CSAI might be considered a good first-line and fast strategy in patients undergoing rapid deterioration of their quality of life while waiting for DBS or levodopa/carbidopa intestinal gel therapy.

Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson’s disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.

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.

Background: Subthalamic deep brain stimulation (STN-DBS) effects may decrease with Parkinson’s disease (PD) progression. There is no indication if, when, and how to consider the interruption of DBS treatment in late-stage PD. The objective of the current study was to investigate the percentage of “poor stimulation responders” among late-stage PD patients for elaborating an algorithm to decide whether and when DBS discontinuation may be considered. Methods: Late-stage PD patients (Hoehn Yahr stage ≥4 and Schwab and England Scale

In the last decade the influence of nonmotor symptoms on the motor performance of Parkinson's disease (PD) patients has been the subject of several studies. In this chapter we focus on the role played by emotional processes that have been studied through research conducted in laboratory or clinical settings. The studies reviewed in this chapter clearly show how PD negatively influences the affective life of patients. More specifically, research on emotional processes and expressions suggests that PD patients may exhibit significant deficits in nonverbal communication, with difficulties in producing emotional facial movements and recognizing the emotions of other people. Several studies demonstrate how patients with PD may display deficits in performing emotion recognition tasks; this seems particularly true for experimental tasks involving prosodic stimuli with a negative valence. Other studies have shown mood alterations and emotional dysfunctions including depression, apathy, and anxiety as well as alexithymia.

This study aimed to investigate phosphorylated alpha-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 +/- 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD - OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD -OH, and PD -OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.

Introduction Caring for a person with Parkinson’s disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy. Methods This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson’s Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively. Results 126 patients (mean age 69.3 ± 8 years) and their caregivers (mean age 57.9 ± 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 ± 14.4 for LCIG, 35.8 ± 20.2 for CSAI, and 31.4 ± 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 ± 5.67, 11.26 ± 5.55, and 14.22 ± 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients “very much or much improved” in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression–Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers’ judgment of QoL and caregivers’ need to change work. Conclusions Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC.

32-year-old man. Generalized tonic-clonic seizure while in complete well-being. The EEG test did not show any electrical activity related to the seizure.

Background: Progressive supranuclear palsy (PSP) is a rare rapidly progressive, neurodegenerative disease characterized by falls and ocular movement disturbances. The use of health-related quality of life (HR-QoL) measures allows assessing changes in health status induced by therapeutic interventions or disease progress in neurodegenerative diseases. The PSP-QoL is a 45-item, self-administered questionnaire designed to evaluate HR-QoL in PSP. Methods and Results: Here, the PSP-QoL was translated into Italian and validated in 190 PSP (96 women and 94 men; mean age ± standard deviation, 72 ± 6.5; mean disease duration, 4.2 ± 2.3) patients diagnosed according to the Movement Disorder Society criteria and recruited in 16 third level movement disorders centers participating in the Neurecanet project. The mean PSP-QoL total score was 77.8 ± 37 (physical subscore, 46.5 ± 18.7; mental subscore, 33.6 ± 19.2). The internal consistency was high (Cronbach’s alpha = 0.954); corrected item-total correlation was > 0.40 for the majority of items. The significant and moderate correlation of the PSP-QoL with other HR-QoL measures as well as with motor and disability assessments indicated adequate convergent validity of the scale. Gender and geographic location presented a significant impact on the PSP-QoL in our sample with women and patients from the South of Italy scoring higher than their counterparts. Conclusion: In conclusion, the Italian version of the PSP-QoL is an easy, reliable and valid tool for assessment of HR-QoL in PSP.

Whether the primary motor cortex (M1) contributes to the pathophysiology of corticobasal syndrome (CBS) remains unclear. In this study in patients with probable CBS, we tested whether M1 plasticity contributes to the pathophysiology of symptoms in the contralateral “less affected” limb, manifesting only parkinsonism, and in the contralateral “more affected” limb, manifesting parkinsonism plus other motor and nonmotor symptoms. In Experiment 1, we applied intermittent/continuous theta-burst stimulation (iTBS/cTBS) over the M1 contralateral to the less affected limb in 17 patients. In Experiment 2, we applied iTBS/cTBS over the M1 contralateral to the more affected limb in 14 of the 17 patients. We measured iTBS/cTBS-induced plasticity as reflected by motor-evoked potential (MEP) changes. Data were compared with those obtained in 17 healthy subjects (HS). In Experiment 1, TBS over the M1 contralateral to the less affected limb disclosed reduced plasticity in patients than in HS. In Experiment 2, in 5 of 14 patients we recorded abnormally low-amplitude MEPs, preventing the evaluation of plasticity in the M1 contralateral to the more affected limb. In the remaining nine patients, TBS disclosed abnormal plasticity characterized by high intersubject variability. In these nine patients, the response to TBS correlated with specific patients' clinical features. In the present study in patients with probable CBS, we have demonstrated heterogeneous abnormalities of M1 that contribute to the pathophysiology of this condition.

Background The impact of deep brain stimulation (DBS) on cognitive and urinary disorders, falls, and eventually hospitalizations and mortality in Parkinson's disease (PD) is still debated. Objective We compared the rates of dementia, mild cognitive impairment (MCI), urinary incontinence, nocturia, falls, hospitalizations, and mortality in a cohort of PD patients undergoing DBS with a cohort of medically-treated patients chosen as controls. Methods We conducted a retrospective pilot study in six Italian DBS centers. 91 PD patients receiving DBS and 91 age- and gender-matched controls receiving the best medical treatment alone with a minimum follow-up of one year were enrolled. Clinical data were collected from baseline to the last follow-up visit using an ad-hoc developed web-based system. Results The risk of dementia was similar in the two groups while patients in the surgical cohort had lower rates of MCI, urinary incontinence, nocturia, and falls. In contrast, the risk of hospital admissions related to PD was higher in the surgical cohort. However, when excluding hospitalizations related to DBS surgery, the difference between the two cohorts was not significant. The surgical cohort had a lower number of hospitalizations not related to PD. The risk of death was similar in the two groups. Conclusion Despite a higher risk of hospitalization, patients receiving DBS had a lower rate of MCI, urinary incontinence, nocturia and falls, without evidence of an increased risk of dementia and mortality. Although these findings need to be confirmed in prospective studies, they seem to suggest that DBS may play a significant role in the management of non-motor symptoms and common complications of advanced PD.

The published version of this article unfortunately contained a mistake in Table 2. CGI-S and CGI-I values has been interchanged. The Table is corrected here.

Introduction: Caring for a person with Parkinson’s disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy. Methods: This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson’s Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively. Results: 126 patients (mean age 69.3 ± 8years) and their caregivers (mean age 57.9 ± 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 ± 14.4 for LCIG, 35.8 ± 20.2 for CSAI, and 31.4 ± 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 ± 5.67, 11.26 ± 5.55, and 14.22 ± 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients “very much or much improved” in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression–Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers’ judgment of QoL and caregivers’ need to change work. Conclusions: Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC.

Parkinson's disease (PD) is often characterized by asymmetrical symptoms, which are more prominent on the side of the body contralateral to the most extensively affected brain hemisphere. Therefore, lateralized PD presents an opportunity to examine the effects of asymmetric subcortical dopamine deficiencies on cognitive functioning. As it has been hypothesized that inhibitory control relies upon a right-lateralized pathway, we tested whether left-dominant PD (LPD) patients suffered from a more severe deficit in this key executive function than right-dominant PD patients (RPD). To this end, via a countermanding task, we assessed both proactive and reactive inhibition in 20 LPD and 20 RPD patients, and in 20 age-matched healthy subjects. As expected, we found that PD patients were significantly more impaired in both forms of inhibitory control than healthy subjects. However, there were no differences either in reactive or proactive inhibition between LPD and RPD patients. All in all, these data support the idea that brain regions affected by PD play a fundamental role in subserving inhibitory function, but do not sustain the hypothesis according to which this executive function is predominantly or solely computed by the brain regions of the right hemisphere.

Background Clinical studies in patients with MSA document facial motor abnormalities, but no studies have objectively assessed blinking abnormalities in this condition. Methods We enrolled patients diagnosed as having clinically probable MSA, 20 patients of the parkinsonian phenotype (MSA-P) and 10 patients of the cerebellar phenotype (MSA-C) and 20 healthy controls (HCs). Blinking was recorded with a three-dimensional optoelectronic motion system equipped with dedicated software for data analysis. Results During voluntary blinking, the interphase pause duration between the closing and opening phases lasted longer in MSA-P and in MSA-C patients than in HCs; the opening phase had increased duration and reduced peak velocity in MSA-P. During reflex blinking, the opening blink phase also lasted longer in MSA-P patients than in HCs. During spontaneous blinking, the rate and kinematics of the closing and opening blinking phases were lower in MSA-P and in MSA-C patients than in HCs. Blink reflex recovery was higher in patients than in HCs. No difference was found between MSA-P patients receiving or not receiving dopaminergic medication. Conclusions Our objective assessment of upper facial movement documents abnormalities of voluntary, spontaneous, and reflex blinking in patients with MSA-P and MSA-C, reflecting cortical-basal ganglia and brainstem dysfunction. © 2014 Movement Disorder Society

Background By providing a stable and smooth L-dopa plasmatic level, L-dopa/carbidopa intestinal gel reproduces the physiological continuous dopaminergic receptor stimulation in patients with Parkinson disease (PD), and it therefore represents a suitable tool to investigate the role of the altered dopaminergic neurotransmission in the pathophysiology of motor and sensory abnormalities in this condition. Methods We studied 11 patients with advanced PD being treated with L-Dopa/carbidopa intestinal gel (LCIG) and 11 age-matched healthy subjects. Bradykinesia was measured by kinematic recording of repetitive finger movements (finger tapping), whereas sensory abnormalities were evaluated using the somatosensory tactile discrimination threshold. All the patients were studied off and on medication, in 2 different experimental sessions. Results Parkinson disease patients were very slow and hypokinetic during finger tapping, with no progressive reduction in amplitude or speed being observed during movement repetition. Somatosensory temporal discrimination threshold values were higher in PD patients than in healthy subjects. The neurophysiologic assessment of the effects of LCIG in advanced PD patients demonstrates an improvement, although not normalization, of motor and sensory abnormalities. Conclusions The study provides an objective evaluation of the effects of LCIG on motor and sensory abnormalities in PD. The results suggest that besides dopaminergic mechanisms motor and sensory abnormalities in PD reflect a varying combination of pathophysiologic mechanisms.

Several levodopa/carbidopa intestinal gel (LCIG) studies showed a significant reduction of OFF time and a significant increase of ON time, as well as a reduction of dyskinesia, and improvement of non-motor symptoms and quality of life. However, few studies have been conducted in a large population for more than 3 years. Interim outcomes from GREENFIELD observational study on a large Italian cohort of advanced PD patients who started LCIG in routine care between 2007 and 2014, still on treatment at the enrollment, are presented. Comparison between baseline (before LCIG start) and visit 1 (at enrollment) is reported. Primary endpoint was Unified Parkinson’s Disease Rating Scale (UPDRS) IV Item 39; secondary endpoints were UPDRS I and II, as outcome of quality of life. Overall, 145 of 148 enrolled patients from 14 Movement Disorder Centers in Italy were evaluable with a mean LCIG treatment period of 1.38 ± 1.66 years at enrollment. Compared with baseline, the mean score regarding daily time spent in OFF (UPDRS IV Item 39) at visit 1 significantly decreased from 2.1 ± 0.8 to 0.9 ± 0.7 (57 % reduction vs baseline, P

In this study in patients with Parkinson's disease (PD), off and on dopaminergic therapy, with and without L-dopa-induced dyskinesias (LIDs), we tested intermittent theta-burst stimulation (iTBS), a technique currently used for non-invasively inducing long-term potentiation (LTP)-like plasticity in primary motor cortex (M1). The study group comprised 20 PD patients on and off dopaminergic therapy (11 patients without and 9 patients with LIDs), and 14 age-matched healthy subjects. Patients had mild-to-moderate PD, and no additional neuropsychiatric disorders. We clinically evaluated patients using the Unified Parkinson's Disease Rating Scale (UPDRS) and the Unified Dyskinesia Rating Scale (UDysRS). The left M1 was conditioned with iTBS at 80% active motor threshold intensity. Twenty motor evoked potentials (MEPs) were recorded from right first interosseous muscle before and at 5, 15 and 30 min after iTBS. Between-group analysis of variance (ANOVA) testing healthy subjects versus patients with and without LIDs, on and off therapy showed a significant interaction between factors "Group" and "Time". After iTBS, MEP amplitudes in healthy subjects increased significantly at 5, 15 and 30 min (p

Bilateral striopallidodentate calcification, usually termed Fahr's disease, can give rise to various clinical manifestations including hyperkinetic movement disorders or a hypokinetic Parkinsonian syndrome, behavioural and mood changes, cognitive deficits and even frank dementia. We describe four patients all of whom underwent a detailed scintigraphic, neuroradiological and clinical work-up: two had primary, sporadic Fahr's disease and two had Fahr's disease secondary to hypoparathyroidism. The neuroradiological and clinical studies disclosed similar anatomical and pathological changes in the four patients but variable and sometimes unexpected clinical manifestations. Both patients with primary forms had hypokinetic Parkinsonian syndrome, both patients with secondary forms had hyperkinetic movements. Dopamine autotransporter scan brain scintigraphy disclosed an unexpected unilateral putamen involvement despite substantially symmetric calcifications.

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.

We investigated abnormal premotor to motor (PMd-to-M1) connectivity in Parkinson's disease (PD) with repetitive transcranial magnetic stimulation (rTMS). We studied 28 patients off and on dopaminergic therapy and 28 healthy subjects. We delivered 5 Hz rTMS over M1 before and after conditioning PMd with 5 Hz rTMS. In healthy subjects, motor-evoked potentials (MEPs) elicited by M1-rTMS were facilitated and PMd-rTMS left MEPs unchanged. In patients, before PMd-rTMS, M1-rTMS induced no MEP facilitation, whereas after PMd-rTMS, it significantly facilitated MEPs only when patients were on therapy. In the second experiment, we delivered M1-rTMS under 3 different attention-demanding tasks: eyes closed, attention directed to the stimulated hand, and attention directed to the nonstimulated hand. In healthy subjects, a more pronounced MEP facilitation was present when subjects directed attention to the stimulated hand. In patients, the MEP facilitation was present when attention was directed to the stimulated hand only when patients were on therapy. Finally, we delivered M1-rTMS in patients on therapy while they were looking at the stimulated hand, before and after 1 Hz PMd-rTMS. PMd-rTMS reduced the attention-induced MEP facilitation. We conclude that in addition to abnormal M1 plasticity, the reduced MEP facilitation in PD also reflects altered PMd-to-M1 connectivity.

Functional disorders of the brain, such as dystonia and neuropathic pain, may respond poorly to medical therapy. Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the centromedian nucleus of the thalamus (CMN) may alleviate dystonia and neuropathic pain, respectively. A noninvasive alternative to DBS is radiosurgical ablation [internal pallidotomy (IP) and medial thalamotomy (MT)]. The main technical limitation of radiosurgery is that targets are selected only on the basis of MRI anatomy, without electrophysiological confirmation. This means that, to be feasible, image-based targeting must be highly accurate and reproducible. Here, we report on the feasibility of an atlas-based approach to targeting for functional radiosurgery. In this method, masks of the GPi, CMN, and medio-dorsal nucleus were nonrigidly registered to patients' T1-weighted MRI (T1w-MRI) and superimposed on patients' T2-weighted MRI (T2w-MRI). Radiosurgical targets were identified on the T2w-MRI registered to the planning CT by an expert functional neurosurgeon. To assess its feasibility, two patients were treated with the CyberKnife using this method of targeting; a patient with dystonia received an IP (120 Gy prescribed to the 65% isodose) and a patient with neuropathic pain received a MT (120 Gy to the 77% isodose). Six months after treatment, T2w-MRIs and contrast-enhanced T1w-MRIs showed edematous regions around the lesions; target placements were reevaluated by DW-MRIs. At 12 months post-treatment steroids for radiation-induced edema and medications for dystonia and neuropathic pain were suppressed. Both patients experienced significant relief from pain and dystonia-related problems. Fifteen months after treatment edema had disappeared. Thus, this work shows promising feasibility of atlas-based functional radiosurgery to improve patient condition. Further investigations are indicated for optimizing treatment dose.

Modulation of the activity of the subthalamic nucleus (STN) using deep brain stimulation (DBS) in patients with advanced Parkinson's disease is the most common procedure performed today by functional neurosurgeons. The STN contours cannot be entirely identified on common 1.5 T images; in particular, the ventromedial border of the STN often blends with the substantia nigra. 3 T magnetic resonance imaging (MRI) provides better resolution and can improve the identification of the STN borders. In this work, we have directly identified the STN using 3 T MR imaging to validate the accuracy of a computer-aided atlas-based procedure for automatic STN identification. Coordinates of the STN were obtained from the Talairach and Tournoux atlas and transformed into the coordinates of the Montreal Neurological Institute (MNI) standard brain volume, creating a mask representation of the STN. 3 T volumetric T1 and T2 weighted (T1w and T2w, respectively) acquisitions were obtained for ten patients. The MNI standard brain volume was registered onto each patient MRI, using a new approach based on global affine, region-of-interest affine, and local nonrigid registrations. The estimated deformation field was then applied to the STN atlas-based mask, providing its location on the patient MRI. The entire procedure required on average about 20 min. Because STN is easily identifiable on 3 T T2w-MRIs, it was manually delineated; the coordinates of the center of mass of the manually and automatically identified structures were compared. Additionally, volumetric overlapping indices were calculated and the spatial relationship between the midcommissural point and the STN center of mass was investigated. All indices indicated, on average, good agreement between manually and automatically identified structures; displacement of the centers of mass of the manually and automatically identified structures was less than or equal to 2.35 mm, and more than 80% of the manually identified volume was covered by the automatic localization, on average. Bland-Altman analysis indicated that the automatic STN identification was within the limits of agreement with the manual localization on 3 T MRIs. Automatic atlas-based STN localization provides an accurate and user-friendly tool and can enhance target identification when 1.5 T scanners with limited capability to identify the STN boundaries are used.

Treatment targets in functional neurosurgery usually consist of selected structures within the thalamus and basal ganglia, which can be stimulated in order to affect specific brain pathways. Chronic electrical stimulation of these structures is a widely used approach for selected patients with advanced movement disorders. An alternative therapeutic solution consists of producing a lesion in the target nucleus, for example by means of radiosurgery, a noninvasive procedure, and this prevents the use of intraoperative microelectrode recording as a method for accurate target definition. The need to have accurate noninvasive localization of the target motivated our previous work on atlas-based identification; the aim of this present work is to provide additional validation of this approach based on the identification of the red nuclei (RN), which are located near the subthalamic nucleus (STN). Coordinates of RN were obtained from the Talairach and Tournoux (TT) atlas and transformed into the coordinates of the Montreal Neurological Institute (MNI) atlas, creating a mask representation of RN. The MNI atlas volume was nonrigidly registered onto the patient magnetic resonance imaging (MRI). This deformation field was then applied to the RN mask, providing its location on the patient MRI. Because RN are easily identifiable on 1.5 T T2-MRI images, they were manually delineated; the coordinates of the centers of mass of the manually and automatically identified structures were compared. Additionally, volumetric overlapping indices were calculated. Ten patients were examined by this technique. All indices indicated a high level of agreement between manually and automatically identified structures. These results not only confirm the accuracy of the method but also allow fine tuning of the automatic identification method to be performed.

Objective The α 2 agonist dexmedetomidine (DEX) is an anesthetic agent that can provide sedation and analgesia without respiratory depression or changes in neuronal activity during microrecordings. The aim of our study was to confirm the efficacy and safety of anesthesia with DEX for unilateral deep brain stimulation of the subthalamic nucleus (STN) in patients with Parkinson disease. Methods In 2013 and 2014, a series of 11 consecutive patients received continuous low-dose DEX infusion during unilateral deep brain stimulation of the STN. Intraoperative microrecordings, stimulation results, and patient reaction times in executing verbal and motor tasks were retrospectively analyzed. Functional outcomes were evaluated by comparing preoperative and 1-year postoperative Unified Parkinson's Disease Rating Scale Part III scores. Results Typical activity of the STN was recorded in all patients, and the delay in the execution of both motor and verbal tasks was ≤2 seconds. No hemorrhagic complications occurred, and no postoperative side effects were observed. The mean percentage of Unified Parkinson's Disease Rating Scale Part III improvement at last follow-up was 39.01% (range, 23.70%–55.60%). The mean percentage of levodopa equivalent dose reduction was 45.86% (range, 21.50%–65.70%). Conclusions The results of our study confirm that the use of DEX in managing patients with Parkinson disease during unilateral deep brain stimulation of the STN is safe and effective and can be considered a promising option for sedation during this type of procedure.

Metabolink is a smartphone-based telemedicine solution that allows the proactive participation of elderly people or patients with chronic diseases to the monitoring of their own lifestyles. The patient uses a smartphone to collect and to send to doctors or caregivers information about his/her lifestyle or about physiological parameters measured using integrated medical devices. The doctors use a tablet or a computer to communicate with their patients, to check real-time their health, to receive alerts about unsafe health conditions and to update the treatment. The data collected by the patients populates the personal health records and can be used afterwards to find correlations between lifestyles and the onset or progression of chronic diseases. This solution empowers the patients for active ageing and enables them to easily cooperate with the doctors in the management of their wellness or chronic diseases.

Switching off hyperactive nuclei is a widely used approach for selected patients with movement disorders (such as Parkinson’s disease and dystonia) and is now being considered as a possible treatment for epilepsy and psychiatric disorders. Besides deep brain stimulation (DBS), another possible therapeutic solution consists of producing a lesion in the target nucleus, for example by means of radiosurgery. For that, the need to have an accurate, non-invasive localization of the target arises and the aim of our work consists of developing atlas-based identifications. Subthalamic and centromedian nuclei coordinates were obtained from the Talairach atlas. They were transformed into the coordinates of the Montreal Neurological Institute (MNI) atlas by means of linear piecewise transformation, creating a mask representative of these structures. The MNI atlas volume was registered onto the patient MRI by a global affine transformation followed by a local nonrigid. This deformation field was therefore applied to the masks of the structure to be targeted, providing the location of that structure on the patient MRI. Five patients undergoing DBS implantation (four within the subthalamic nucleus to treat Parkinson’s disease, one within the centromedian nucleus to treat central pain) were examined by this technique. The distance between the implanted pacemaker and the surface of the registered structure mask provided an idea of the quality of this technique. It was less than 1 mm for those patients who had a very satisfactory outcome (UPDRS scale improvement equal or superior to 50% in 2 patients with Parkinson’s disease; more than 50% pain reduction in one patient with central pain). It was about 1 mm for the patient with a less satisfactory outcome (30 to 40% UPDRS improvement in the remaining parkinsonian patient). It was much larger than 1 mm for the patient with a complete unsatisfactory outcome.

Many studies have addressed practice effects in motor sequences in Parkinson's disease (PD). Most studied short-term practice and showed that treated patients with mild-to-moderate disease achieve normal or slightly abnormal improvement. Less attention has focused on practice effects after prolonged training (days), and the results are inconclusive. Here, we studied the kinematic changes induced by prolonged practice in a group of medicated patients with mild-to-moderate PD and a healthy control group. We did so by analyzing an internally determined sequential arm movement performed as fast and accurately as possible before and after a 2-week training period. After 1-day's practice, movement duration, pause duration, and movement accuracy improved similarly in patients and controls, indicating that patients benefitted normally from short-term practice. After 1-week's practice, movement and pause duration improved further in both groups, whereas movement accuracy remained unchanged. After 2-weeks' practice, healthy controls continued to improve but patients did not, indicating reduced prolonged practice benefit in PD. Because short-term practice benefit on motor performance is thought to be mediated predominantly by cerebellar activation, whereas long-term practice benefit relies predominantly on the basal ganglia, we attribute our findings to the underlying basal ganglia dysfunction in PD. Our study may be relevant for planning and executing rehabilitation programs in these patients.

Objective : These experiments examined short interval paired-pulse paradigms for intracortical inhibition (ICI) and facilitation (ICF). We tested whether pairs of subthreshold conditioning stimuli interact, and whether they showed rapid periodicity similar to that observed in subthreshold I-wave interaction. Methods : Transcranial magnetic stimulation (TMS) was given over left M1 to evoke a motor-evoked potential (MEP) of approximately 1 mV peak-to-peak amplitude in the contralateral first dorsal interosseous (FDI) muscle. Each test shock (TS) was preceded by single or paired subthreshold conditioning stimuli (CS 1 and CS 2 ) at short interstimulus intervals (ISIs 1–15 ms). Intensities of CS were set just below thresholds for intracortical inhibition (ICI) or intracortical facilitation (ICF). Results : Each CS single alone had no effect on the test MEP, but with two CS, clear inhibition was elicited at certain intervals. With a CS 2 -TS interval of 2 ms, maximum suppression occurred if CS 1 was applied 1–2.5 ms before CS 2 . This inhibitory effect tapered off gradually as the CS 2 -CS 1 interval was increased up to 13 ms. When facilitation was present with a CS single -TS interval of 10 ms, a small but non-significant extra-facilitation occurred at ISIs between CS 2 and CS 1 of 6–15 ms. Conclusions : Two subthreshold conditioning stimuli facilitate inhibition that lacks the rapid periodicity typical of I-wave interaction. The data would be compatible with a model in which synaptic inputs converge on a common inhibitory interneurone.

Recent studies have shown that low-frequency repetitive transcranial magnetic stimulation (rTMS) to the left dorsal premotor cortex has a lasting influence on the excitability of specific neuronal subpopulations in the ipsilateral primary motor hand area (M1HAND). Here we asked how these premotor to motor interactions are shaped by the intensity and frequency of rTMS and the orientation of the stimulating coil. We confirmed that premotor rTMS at 1 Hz and an intensity of 90% active motor threshold (AMT) produced a lasting decrease in corticospinal excitability probed with single-pulse TMS over the left M1HAND. Reducing the intensity to 80% AMT increased paired-pulse excitability at an interstimulus interval (ISI) of 7 ms. Opposite effects occurred if rTMS was given at 5 Hz: at 90% AMT, corticospinal excitability increased; at 80% AMT, paired-pulse excitability at ISI = 7 ms decreased. No effects were seen if rTMS was applied at the same intensities to prefrontal or primary motor cortices. These findings indicate that the intensity of premotor rTMS determines the net effect of conditioning on distinct populations of neurones in the ipsilateral M1HAND, but it is the frequency of rTMS that determines the direction of the induced change. By selecting the appropriate intensity and frequency, premotor rTMS allows to induce a predictable up- or down-regulation of the excitability in distinct neuronal circuits of human M1HAND.

By analyzing the kinematics of repetitive, constant-amplitude, finger oppositions, we compared the impairment of individual and nonindividual finger movements in patients with Parkinson's disease. In one task, subjects tapped only the index finger against the thumb (individual oppositions); in the other task, they tapped all four fingers together against the thumb pad (nonindividual oppositions). We used an optoelectronic motion analysis system to record movements in three-dimensional space and recorded three 5-second trials for each task. We counted how many finger oppositions subjects performed during each trial and measured the duration and amplitude of the flexions and extensions. We also calculated the duration of the pauses after flexion and extension. We assessed the deterioration of motor performance in patients by investigating the changes in speed and amplitude with task completion. During both tasks, normal subjects and patients performed finger flexions faster than extensions, and they invariably paused longer after flexion than after extension. Patients performed individual and nonindividual finger movements slowly and with reduced amplitude. Patients were disproportionately slow during flexion and in switching from flexion to extension. Movement slowness increased as finger oppositions progressed but predominantly when patients had to move fingers individually. In conclusion, in patients with Parkinson's disease, the motor performance deteriorated with task completion more during individual than during nonindividual finger movements. Parkinson's disease, therefore, impairs individual finger movements more than gross hand movements. This distinction reflects the finer cortical control needed to promote and sustain this highly fractionated type of motor output.

Introduction somatosensory temporal discrimination threshold (STDT) measures the ability to perceive two stimuli as being sequential. Altered STDT has been reported in Parkinson's disease (PD). The cerebellum seems to play a role in the pathophysiology of PD, and may consequently be involved in the pathophysiology of STDT abnormalities. Methods STDT was investigated in fifteen PD patients who underwent real and sham cerebellar continuous theta burst stimulation (cTBS) in the OFF condition. Eight patients underwent a further real cTBS session in ON condition. STDT was measured on both hands before, 5 and 25 min after real and sham cTBS delivered over the cerebellar hemisphere ipsilateral to the more affected side. We controlled the efficacy of our protocol by monitoring primary motor cortex (M1) excitability. Ten healthy subjects acted as control group. Results STDT values were increased in PD patients in the OFF condition compared with healthy subjects and PD patients in the ON condition. In PD patients OFF condition, real but not sham cerebellar cTBS, significantly reduced STDT values only in the hand ipsilateral to the stimulated cerebellar hemisphere. Cerebellar cTBS also decreased motor evoked potentials (MEP) size in the contralateral M1. When PD patients were tested in the ON condition, cerebellar cTBS failed to modify STDT values. Conclusion cerebellar cTBS improved STDT values in PD patients exclusively in OFF condition. We hypothesize that cerebellar stimulation partially compensates for increased STDT values only when patients are OFF dopaminergic therapy. This suggests that the cerebellum may act as compensatory system in PD.