Effects of deep brain stimulation of the subthalamic nucleus on patients with Parkinson's disease: a machine-learning voice analysis.

Introduction: Deep brain stimulation of the subthalamic nucleus (STN-DBS) can exert relevant effects on the voice of patients with Parkinson's disease (PD). In this study, we used artificial intelligence to objectively analyze the voices of PD patients with STN-DBS. Materials and methods: In a cross-sectional study, we enrolled 108 controls and 101 patients with PD. The cohort of PD was divided into two groups: the first group included 50 patients with STN-DBS, and the second group included 51 patients receiving the best medical treatment. The voices were clinically evaluated using the Unified Parkinson's Disease Rating Scale part-III subitem for voice (UPDRS-III-v). We recorded and then analyzed voices using specific machine-learning algorithms. The likelihood ratio (LR) was also calculated as an objective measure for clinical-instrumental correlations. Results: Clinically, voice impairment was greater in STN-DBS patients than in those who received oral treatment. Using machine learning, we objectively and accurately distinguished between the voices of STN-DBS patients and those under oral treatments. We also found significant clinical-instrumental correlations since the greater the LRs, the higher the UPDRS-III-v scores. Discussion: STN-DBS deteriorates speech in patients with PD, as objectively demonstrated by machine-learning voice analysis.

Clinical assessment of a new wearable tool for continuous and objective recording of motor fluctuations and ON/OFF states in patients with Parkinson's disease.

Clinical rating scales typically includes subjective evaluations, and their time-limited duration may fail to capture daily fluctuations in motor symptoms resulting from Parkinson's disease (PD). Recently, a new tool (i.e. the PD-Watch) has been proposed for the objective and continuous assessment of PD motor manifestations based on evaluating frequency data from a wrist-worn tri-axial accelerometer and identifying specific movement patterns typically associated with disorders. This reduces the probability of confusing physiological or pathological movements occurring at the same frequency. In this work, we present a new method for assessing motor fluctuations through a wrist-worn accelerometer. We also explore the agreement between the continuous data generated by the proposed method and data reported in the patient diaries. In this study, twelve PD patients were recruited with an overall recording duration of 528 hours. Results of this preliminary study show that the proposed tool has suitable and adequate performances for analysing the motor signs of PD patients, and the estimated sensitivity, specificity, and accuracy of the tool are 85%, 94%, and 91%, respectively.

Clinical correlates of "pure" essential tremor: the TITAN study.

Background: To date, there are no large studies delineating the clinical correlates of "pure" essential tremor (ET) according to its new definition. Methods: From the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of "pure" ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum. Results: Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) "pure" ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options. Discussion: The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of "pure" ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of "pure" ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.

The Italian tremor Network (TITAN): rationale, design and preliminary findings.

INTRODUCTION: The recently released classification has revised the nosology of tremor, defining essential tremor (ET) as a syndrome and fueling an enlightened debate about some newly conceptualized entities such as ET-plus. As a result, precise information of demographics, clinical features, and about the natural history of these conditions are lacking. METHODS: The ITAlian tremor Network (TITAN) is a multicenter data collection platform, the aim of which is to prospectively assess, according to a standardized protocol, the phenomenology and natural history of tremor syndromes. RESULTS: In the first year of activity, 679 patients have been recruited. The frequency of tremor syndromes varied from 32% of ET and 41% of ET-plus to less than 3% of rare forms, including focal tremors (2.30%), task-specific tremors (1.38%), isolated rest tremor (0.61%), and orthostatic tremor (0.61%). Patients with ET-plus were older and had a higher age at onset than ET, but a shorter disease duration, which might suggest that ET-plus is not a disease stage of ET. Familial aggregation of tremor and movement disorders was present in up to 60% of ET cases and in about 40% of patients with tremor combined with dystonia. The body site of tremor onset was different between tremor syndromes, with head tremor being most commonly, but not uniquely, associated with dystonia. CONCLUSIONS: The TITAN study is anticipated to provide clinically relevant prospective information about the clinical correlates of different tremor syndromes and their specific outcomes and might serve as a basis for future etiological, pathophysiological, and therapeutic research.

GBA-Related Parkinson's Disease: Dissection of Genotype-Phenotype Correlates in a Large Italian Cohort.

BACKGROUND: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear. OBJECTIVES: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time. METHODS: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. ß-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed. RESULTS: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest ß-glucocerebrosidase activity. CONCLUSIONS: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society.

Effects of COVID-19 Lockdown on Movement Disorders Patients With Deep Brain Stimulation: A Multicenter Survey.

Background: The containment measures taken by Italian government authorities during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic caused the interruption of neurological activities of outpatient clinics. Vulnerable patients, as Parkinson's disease (PD) and dystonic patients with deep brain stimulation (DBS), may have an increased risk of chronic stress related to social restriction measures and may show a potential worsening of motor and psychiatric symptoms. Methods: This cross-sectional multicenter study was carried out during the SARS-CoV-2 pandemic and was based on a structured survey administered during a telephone call. The questionnaire was designed to gather motor and/or psychiatric effects of the lockdown and coronavirus disease 2019 (COVID-19) epidemiologic information in PD and dystonic patients with a functioning DBS implant. Results: One hundred four patients were included in the study, 90 affected by PD and 14 by dystonia. Forty-nine patients reported a subjective perception of worsening of global neurological symptoms (motor and/or psychiatric) related to the containment measures. In the multivariate analysis, having problems with the DBS device was the only independent predictor of motor worsening [odds ratio (OR) = 3.10 (1.22-7.91), p = 0.018]. Independent predictors of psychiatric worsening were instrumental activities of daily living (IADL) score [OR = 0.78 (0.64-0.95), p = 0.012] and problems with DBS [OR = 5.69 (1.95-16.62), p = 0.001]. Only one patient underwent nasopharyngeal swabs, both negative, and no patient received a diagnosis of COVID-19. Conclusions: Lockdown restriction measures were associated with subjective worsening of motor and psychiatric symptoms in PD and dystonic patients treated with DBS, and they may have exacerbated the burden of neurological disease and increased the chronic stress related to the DBS management.

Extended release levodopa at bedtime as a treatment for nocturiain Parkinson's disease: An open label study.

BACKGROUND: Bladder dysfunction may cause disabling symptoms in Parkinson's disease (PD) patients. The majority patients' experience symptoms as urinary urgency and nocturia suggest overactive bladder. This seems to be due to an altered brain-bladder relationship because of alteration in fronto-basal ganglia D1-dopaminergic circuit that normally suppresses micturition-reflex. Previous studies demonstrated beneficial effect of D1/D2 dopamine-receptors chronic-stimulation on detrusor overactivity of PD-patients.The present study was aimed to evaluate possible effect of extended-release (ER) Levodopa administered at bed-time on both nocturia and nocturia-related quality-of-life (NQoL) in PD-patients. METHODS: 106 PD-patients (Hoehn and Yahr>1 and < 4, mean age 66 years, 59 females and 47 males) were enrolled by 7 Movement Disorders out-patients clinics. Patients undergo to International Prostatic Symptoms Scale-IPSS, including 1-item about nocturia (item 7), and to Nocturia Quality of Life-NQoL questionnaire, at baseline and after two-months of Extended-Release L-dopa (L-dopa/carbidopa or L-dopa benserazide) treatment at bed-time. RESULTS: Statistical analysis showed significant improvement on both total IPSS, item 7and NQoL scores following two-months ER L-dopa-treatment. ΔIPSS score inversely correlated with disease duration. CONCLUSIONS: This results support previous evidence of pathophysiological involvement of dopaminergic transmission on bladder dysfunction in PD.

Does fatigue in Parkinson's disease correlate with autonomic nervous system dysfunction?

BACKGROUND: Despite its negative impact on quality of life, fatigue in Parkinson's disease (PD) remains an under-recognized issue and the underlying pathology is undetermined. OBJECTIVE: To contribute at understanding the pathogenesis of fatigue in a naturalistic cohort of cognitively intact PD patients. METHODS: In a Caucasian population of PD patients (n = 27), we evaluated to what extent fatigue (quantified as PFS-16 score) is associated with PD duration and with autonomic dysfunction, studied by both MIBG scintigraphy and autonomic nervous system testing. The latter included the head-up tilt test, Valsalva maneuver, deep breathing, and handgrip tests. RESULTS: PFS-16 score correlated with disease duration (R = 0.57, p = 0.002). Fatigue showed a clear correlation with deep breathing test (R = - 0.53, p = 0.004) but not with the MIBG H/M ratios. CONCLUSIONS: Our data are consistent with a multifactorial pathogenesis of fatigue and with effects of dopamine depletion in PD-related fatigue; on the other hand, our findings do not support a role for sympathetic denervation in PD-related fatigue.

Dysfunctional inhibitory control in Parkinson's disease patients with levodopa-induced dyskinesias.

INTRODUCTION: Chronic dopamine replacement therapies in Parkinson's disease can induce side effects, such as levodopa-induced dyskinesias and impulse control disorders. A dysfunction of inhibitory brain networks has been related to both disorders; however, there is no clear behavioral evidence supporting this hypothesis. We aimed to determine whether PD patients with levodopa-induced dyskinesias show features of increased impulsivity in parallel with altered motor inhibition. METHODS: Two matched samples of Parkinson's disease patients with (n = 14) or without (n = 14) levodopa-induced dyskinesias and a control group (n = 10) participated in the study. All groups were evaluated by the Barratt Impulsiveness Scale-11 to assess impulsivity traits. Furthermore, participants performed a stop signal task to evaluate reactive-motor inhibition and a Go/NoGo task to evaluate proactive-inhibitory control. PD patients were tested both in OFF and ON levodopa medication. RESULTS: Parkinson's disease patients with levodopa-induced dyskinesias showed higher impulsivity scores than PD patients without levodopa-induced dyskinesias. Dyskinetic patients presented also delayed stop signal reaction times indicating a worse performance in reactive inhibition. The slowness in inhibiting a motor command correlated with the impulsiveness scores. Furthermore, in the dyskinetic group, a positive correlation was found between stop reaction times and the severity of involuntary movements. Under the effect of levodopa, all patients were faster but dyskinetic patients were significantly less accurate in proactive inhibition. CONCLUSION: Inhibitory control is compromised in dyskinetic patients in parallel with increased impulsivity, revealing an impairment of motor and behavioral inhibitory control in Parkinson's disease patients with levodopa-induced dyskinesias.

Is there a correlation between urological and cardiovascular dysfunction in Parkinson's disease?

It is well established that non-motor symptoms are a core feature of Parkinson's disease (PD). A dysregulation of the autonomic nervous system seems to be present in PD, supporting the coexistence of urological and cardiovascular non-motor features. We evaluated whether bladder dysfunctions in patients with PD are linked to blood pressure dysregulation. Twenty-eight mild PD patients, previously submitted to a urodynamic evaluation, underwent 24-hour ambulatory blood pressure and heart rate monitoring to allow assessment of their circadian blood pressure profile; the occurrence of postprandial hypotension and orthostatic hypotension was also investigated. No significant differences in blood pressure control were detected between bladder hyperreflexic and normoreflexic subjects. Our findings support different origins of urological and cardiovascular impairments in PD.

Impaired intracortical transmission in G2019S leucine rich-repeat kinase Parkinson patients.

OBJECTIVES: A mutation in leucine-rich repeat kinase 2 is the most common cause of hereditary Parkinson's disease (PD), yet the neural mechanisms and the circuitry potentially involved are poorly understood. METHODS: We used different transcranial magnetic stimulation protocols to explore in the primary motor cortex the activity of intracortical circuits and cortical plasticity (long-term potentiation) in patients with the G2019S leucine-rich repeat kinase 2 gene mutation when compared with idiopathic PD patients and age-matched healthy subjects. Paired pulse transcranial magnetic stimulation was used to investigate short intracortical inhibition and facilitation and short afferent inhibition. Intermittent theta burst stimulation, a form of repetitive transcranial magnetic stimulation, was used to test long-term potentiation-like cortical plasticity. Leucine-rich repeat kinase 2 and idiopathic PD were tested both in ON and in OFF l-dopa therapy. RESULTS: When compared with idiopathic PD and healthy subjects, leucine-rich repeat kinase 2 PD patients showed a remarkable reduction of short intracortical inhibition in both ON and in OFF l-dopa therapy. This reduction was paralleled by an increase of intracortical facilitation in OFF l-dopa therapy. Leucine-rich repeat kinase 2 PD showed abnormal long-term potentiation-like cortical plasticity in ON l-dopa therapy. DISCUSSION: The motor cortex in leucine-rich repeat kinase 2 mutated PD patients is strongly disinhibited and hyperexcitable. These abnormalities could be a result of an impairment of inhibitory (gamma-Aminobutyric acid) transmission eventually related to altered neurotransmitter release. © 2017 International Parkinson and Movement Disorder Society.

Genetic analysis of CHCHD2 and CHCHD10 in Italian patients with Parkinson's disease.

In recent years, CHCHD2 and CHCHD10 mutations were reported to be associated with a broad spectrum of neurodegenerative diseases, including Parkinson's disease (PD), although with conflicting results in different populations. The present study aimed to evaluate CHCHD2 and CHCHD10 coding variants in Italian patients with PD. All the coding regions and flanking intronic splice sites of CHCHD2 and CHCHD10 were sequenced. None of our 119 PD cases carried CHCHD2 mutations, whereas 1 sporadic PD patient showed the Pro34Ser substitution in CHCHD10. Our data suggest that CHCHD2 and CHCDH10 mutations are not a relevant cause of PD in Italian population.

Rotigotine Effects on Bladder Function in Patients with Parkinson's Disease.

BACKGROUND: The objective of this study was to assess the effect of rotigotine treatment on bladder function in patients with Parkinson's disease (PD) who have urinary urgency. METHODS: in total, 20 patients with PD underwent urodynamic evaluation and completed International Prostate Symptoms questionnaires in off-rotigotine condition and after 3 months of rotigotine patch monotherapy administration. In both sessions, clinical motor condition was evaluated with the Unified Parkinson Disease Rating Scale, Part III (motor part). RESULTS: Rotigotine administration significantly ameliorated the first sensation of bladder filling, the neurogenic detrusor overactive contractions threshold and bladder capacity compared with the off-treatment condition. Moreover, the total score on the International Prostate Symptoms questionnaire revealed a decrease of filling (irritative) symptoms after rotigotine treatment compared with the off-treatment condition. CONCLUSION: The positive effects of rotigotine may be due to its balanced agonism to D1 and D2 receptors and in particular to its stimulation of D1 receptors in the anterior cingulate cortex and insula, which are known as areas involved in bladder-inhibitory functions.

Subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson's patients.

BACKGROUND: The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. OBJECTIVES: By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. METHODS: PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. RESULTS: STN-DBS enhanced early global TMS-evoked activity (∼45-80ms) and high-alpha TMS-evoked oscillations (11-13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80-130ms) and beta TMS-evoked oscillations (13-30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values. CONCLUSIONS: Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.

Altered inhibitory interaction among inferior frontal and motor cortex in l-dopa-induced dyskinesias.

BACKGROUND: Levodopa-induced dyskinesias are associated with thalamo-cortical disinhibition and frontal area overactivation. Neuroimaging and transcranial magnetic stimulation studies have highlighted the involvement of the right inferior frontal cortex in levodopa-induced dyskinesias. METHODS: Using transcranial magnetic stimulation, we tested connectivity between the inferior frontal and contralateral motor cortex in Parkinson's disease patients with and without levodopa-induced dyskinesias compared with age-matched controls. Furthermore, in dyskinetic patients, connectivity between the inferior frontal and contralateral motor cortex was assessed before and after a single session of continuous theta-burst stimulation applied over the inferior frontal cortex. RESULTS: Dyskinetic patients showed abnormal facilitatory connectivity between the inferior frontal and motor cortex when compared with the nondyskinetic group. Continuous theta-burst stimulation over the inferior frontal cortex eliminated such facilitatory connectivity and decreased the levodopa-induced dyskinesias that was induced by a supramaximal dose of levodopa. CONCLUSION: In dyskinetic patients, a weaker inhibitory cortico-cortical interaction between the inferior frontal and contralateral motor cortex could be involved in levodopa-induced dyskinesias and restored by continuous theta-burst stimulation over the inferior frontal cortex. © 2016 Movement Disorder Society.

An investigation of hearing impairment in de-novo Parkinson's disease patients: A preliminary study.

OBJECTIVE: To investigate the peripheral auditory pathway in Parkinson's disease (PD) by using objective, quantitative and non-invasive audiological techniques, transient-evoked (TEOAE) and distortion product (DPOAE) otoacoustic emissions, in order to detect subclinical alterations of cochlear functioning and possible changes after dopaminergic stimulation. METHODS: We enrolled 11 untreated de-novo PD patients and 11 age and sex-matched healthy controls. Subjects underwent a routine audiological evaluation and otoacoustic emission recordings. The patients were then slowly-titrated to a stable dose of 100 mg levodopa four times in a day. A post-treatment assessment was made in order to detect significant changes in audiological responses. Finally, possible associations between clinical data and hearing results were also evaluated. RESULTS: At pure-tone audiometry, higher auditory threshold levels were observed in PD when compared to the controls. Moreover, DPOAE responses in PD patients were found low at almost all tested frequencies, suggesting subclinical cochlear damage. Interestingly, after dopaminergic treatment, a significant increase in DPOAE responses was detected. Notably, DPOAE dysfunction correlated with clinical severity, whereas high hearing thresholds appeared positively related with more prolonged disease duration. CONCLUSIONS: Our findings demonstrate that otoacoustic emission recording and pure-tone audiometry reveal levodopa-sensitive cochlear dysfunction and hearing loss in PD. A parallel improvement in subjective motor symptoms and DPOAE objective responses could help clinicians in monitoring therapeutic responses and dynamic changes during the course of the disease.

A network centred on the inferior frontal cortex is critically involved in levodopa-induced dyskinesias.

Levodopa-induced dyskinesias are disabling motor complications of long-term dopamine replacement in patients with Parkinson's disease. In recent years, several alternative models have been proposed to explain the pathophysiological mechanisms underlying this hyperkinetic motor disorder. In particular, our group has shed new light on the role of the prefrontal cortex as a key site of interest, demonstrating that, among other areas, the inferior frontal cortex is particularly characterized by altered patterns of anatomical and functional changes. However, how neural activity varies depending on levodopa treatment in patients with dyskinesias and whether the reported prefrontal abnormalities may have a critical role in dyskinesias is debated. To answer these questions we performed independent functional magnetic resonance imaging and repetitive transcranial magnetic stimulation studies. In the first experiment we applied resting state functional magnetic resonance imaging on 12 patients with Parkinson's disease with levodopa-induced dyskinesias and 12 clinically matched patients without dyskinesias, before and after administration of levodopa. Functional connectivity of brain networks in the resting state was assessed in both groups. We chose the right inferior frontal cortex as the seed region given the evidence highlighting the role of this region in motor control. In a second experiment, we applied different forms of repetitive transcranial magnetic stimulation over the right inferior frontal cortex in a new group of dyskinetic patients who were taking a supramaximal dose of levodopa, to verify the clinical relevance of this area in controlling the development of hyperkinetic movements. The resting state functional imaging analysis revealed that in patients with levodopa-induced dyskinesias connectivity of the right inferior frontal cortex was decreased with the left motor cortex and increased with the right putamen when compared to patients without levodopa-induced dyskinesias. This abnormal pattern of connectivity was evident only during the ON phase of levodopa treatment and the degree of such alteration correlated with motor disability. The repetitive TMS experiments showed that a session of continuous but not intermittent or sham theta burst stimulation applied over the inferior frontal cortex was able to reduce the amount of dyskinesias induced by a supramaximal single dose of levodopa, suggesting that this area may play a key role in controlling the development of dyskinesias. Our combined resting state functional magnetic resonance and transcranial magnetic stimulation studies demonstrate that pathophysiological mechanisms underlying levodopa-induced dyskinesias may extend beyond the 'classical' basal ganglia dysfunctions model, including the modulation performed by the neural network centred on the inferior frontal cortex.