A fundamental function of the motor system is to gather key information from the environment in order to implement behavioral strategies appropriate to the context. Although several lines of evidence ...indicate that Parkinson's disease affects the ability to modify behavior according to task requirements, it is currently unknown whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects context-related planning. To explore this issue, we asked 12 Parkinson's patients with bilateral STN DBS and 13 healthy subjects to execute similar arm reaching movements in two different paradigms: go-only and countermanding tasks. In the former task patients had to perform speeded reaching movements to a peripheral target. In contrast, in the countermanding task participants had to perform the same reaches unless an infrequent and unpredictable stop-signal was shown during the reaction time (RT) indicating that they should withhold the ongoing action. We compared the performance of Parkinson's patients in different DBS conditions. We found that patients with both DBS-ON behaved similarly to healthy subjects, in that RTs of no-stop trial increased while movement times (MTs) decreased with respect to those of go-only-trials. However, when both DBS were off, both RTs and MTs were longer in no-stop trials than in go-only trials. These findings indicate that bilateral DBS of STN can partially restore the appropriate motor strategy according to the given cognitive contexts.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
ALS is a devastating neurodegenerative disorder with no effective treatment. In the present study, we found that daily doses of lithium, leading to plasma levels ranging from 0.4 to 0.8 mEq/liter, ...delay disease progression in human patients affected by ALS. None of the patients treated with lithium died during the 15 months of the follow-up, and disease progression was markedly attenuated when compared with age-, disease duration-, and sex-matched control patients treated with riluzole for the same amount of time. In a parallel study on a genetic ALS animal model, the G93A mouse, we found a marked neuroprotection by lithium, which delayed disease onset and duration and augmented the life span. These effects were concomitant with activation of autophagy and an increase in the number of the mitochondria in motor neurons and suppressed reactive astrogliosis. Again, lithium reduced the slow necrosis characterized by mitochondrial vacuolization and increased the number of neurons counted in lamina VII that were severely affected in saline-treated G93A mice. After lithium administration in G93A mice, the number of these neurons was higher even when compared with saline-treated WT. All these mechanisms may contribute to the effects of lithium, and these results offer a promising perspective for the treatment of human patients affected by ALS.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Oral levodopa remains the mainstay of treatment for Parkinson's disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and ...patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson's Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD.
PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10-15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0)
patient chart review/interview.
Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2-3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%).
This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.
Neurological disorders such as stroke, Parkinson's disease (PD), and severe traumatic brain injury (sTBI) are leading global causes of disability and mortality. This study aimed to assess the ability ...to walk of patients with sTBI, stroke, and PD, identifying the differences in dynamic postural stability, symmetry, and smoothness during various dynamic motor tasks. Sixty people with neurological disorders and 20 healthy participants were recruited. Inertial measurement unit (IMU) sensors were employed to measure spatiotemporal parameters and gait quality indices during different motor tasks. The Mini-BESTest, Berg Balance Scale, and Dynamic Gait Index Scoring were also used to evaluate balance and gait. People with stroke exhibited the most compromised biomechanical patterns, with lower walking speed, increased stride duration, and decreased stride frequency. They also showed higher upper body instability and greater variability in gait stability indices, as well as less gait symmetry and smoothness. PD and sTBI patients displayed significantly different temporal parameters and differences in stability parameters only at the pelvis level and in the smoothness index during both linear and curved paths. This study provides a biomechanical characterization of dynamic stability, symmetry, and smoothness in people with stroke, sTBI, and PD using an IMU-based ecological assessment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Despite the relevance of inhibitory control in shaping our behavior its neural substrates are still hotly debated. In this regard, it has been suggested that inhibitory control relies upon a ...right-lateralized network which involves the right subthalamic nucleus (STN). To assess the role of STN, we took advantage of a relatively rare model, i.e., advanced Parkinson's patients who received unilateral deep-brain stimulation (DBS) of the STN either of the left (
= 10) or of the right (
= 10) hemisphere. We gave them a stop-signal reaching task, and we compared patients' performance in two experimental conditions, DBS-ON and DBS-OFF. In addition, we also tested 22 age-matched healthy participants. As expected, we found that inhibitory control is impaired in Parkinson's patients with respect to healthy participants. However, neither reactive nor proactive inhibition is improved when either the right or the left DBS is active. We interpreted these findings in light of the fact that previous studies, exploiting exactly the same task, have shown that only bilateral STN DBS restores a near-normal inhibitory control. Thus, although null results have to be interpreted with caution, our current findings confirm that the right STN does not play a key role in suppressing pending actions. However, on the ground of previous studies, it is very likely that this subcortical structure is part of the brain network subserving inhibition but to implement this executive function both subthalamic nuclei must be simultaneously active. Our findings are of significance to other researchers studying the effects of STN DBS on key executive functions, such as impulsivity and inhibition and they are also of clinical relevance for determining the therapeutic benefits of STN DBS as they suggest that, at least as far as inhibitory control is concerned, it is better to implant DBS bilaterally than unilaterally.
In this study we asked whether subthalamic nucleus deep brain stimulation (STN-DBS) alone, or in combination with l-dopa, modifies voluntary, spontaneous and reflex blinking in patients with ...Parkinson's disease (PD). Sixteen PD patients who underwent STN-DBS were studied in four experimental conditions: without STN-DBS and without l-dopa, STN-DBS alone, l-dopa alone and STN-DBS plus l-dopa. The results were compared with those obtained in 15 healthy controls. Voluntary blinking was assessed by asking participants to blink as fast as possible; spontaneous blinking was recorded during two 60s rest periods; reflex blinking was evoked by electrical stimulation of the supraorbital nerve. Blinking were recorded and analysed with the SMART motion system. STN-DBS increased the peak velocity and amplitude for both the closing and opening voluntary blink phases, but prolonged the inter-phase pause duration. l-dopa had no effects on voluntary blinking but reversed the increased inter-phase pause duration seen during STN-DBS. Spontaneous blink rate increased after either STN-DBS or l-dopa. Reflex blinking kinematics were not modified by STN-DBS or l-dopa. The STN-DBS effects on voluntary blinking kinematics and spontaneous blinking rate may occur as results of changes of cortico-basal ganglia activity. The prolonged pause duration of voluntary blinking indicates that STN-DBS has detrimental effects on the cranial region. These results also shed light on the pathophysiology of eyelids opening apraxia following STN-DBS.
► STN-DBS modifies voluntary and spontaneous blinking but not reflex blinking. ► The STN-DBS effects on voluntary blinking may be detrimental. ► The STN-DBS effects on blinking reflect changes of cortico-basal ganglia activity. ► Our results shed lights on the eyelids opening apraxia following STN-DBS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Introduction Recent studies have suggested that the cerebellum may be involved in the pathophysiology of resting tremor in patients with Parkinson's disease (PD). The aim of the study was to ...investigate the effects of cerebellar continuous theta burst stimulation (cTBS) on cerebello-thalamo-cortical connectivity and resting tremor in PD patients. Methods Thirteen PD patients and ten healthy subjects underwent two experimental sessions: (i) ‘real’ cTBS, delivered over the cerebellar hemisphere and (ii) ‘sham’ cerebellar cTBS, delivered over the neck muscles. The two sessions were performed at least one week apart. The effects of ‘real’ and ‘sham’ cerebellar cTBS were quantified as excitability changes in the contralateral primary motor cortex or as possible changes in resting tremor in the ipsilateral hand. Primary motor cortex excitability was assessed by recording the input/output curve of the motor-evoked potentials from the contralateral first dorsal interosseous muscle. Results Resting tremor was rated clinically and objectively assessed by means of kinematic techniques. ‘Real’ cerebellar cTBS, though not ‘sham’ cerebellar cTBS, reduced the excitability in the contralateral primary motor cortex both in healthy subjects and in patients with PD. There was no significant change in rest tremor severity, as assessed by a clinical examination or kinematic techniques, after either ‘real’ or ‘sham’ cerebellar cTBS in patients. Lastly, there was no correlation between individual changes in M1 excitability and clinical or kinematic measures of resting tremor in patients. Conclusion The cerebello-thalamo-cortical connectivity, as tested by cTBS, is not predominantly involved in the generation of resting tremor in PD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Levodopa (L-Dopa), representing the therapeutic gold standard for the treatment of Parkinson disease (PD), is associated with side effects like L-Dopa induced dyskinesia (LID). Although several ...non-genetic and genetic factors have been investigated for association with LID risk, contrasting results were reported and its genetic basis remain largely unexplored.
In an Italian PD cohort (N = 460), we first performed stepwise multivariable Cox Proportional Hazard regressions modeling LID risk as a function of gender, PD familiarity, clinical subtype, weight, age-at-onset (AAO) and years-of-disease (YOD), L-Dopa dosage, severity scores, and scales assessing motor (UPDRS-III), cognitive (MoCA), and non-motor symptoms (NMS). Then we enriched the resulting model testing two variants-rs356219 and D4S3481-increasing the expression of the
gene, previously suggested as a potential mechanism of LID onset. To account for more complex (non-linear) relations of these variables with LID risk, we built a survival random forest (SRF) algorithm including all the covariates mentioned above.
Among tested variables (N = 460 case-complete, 211 LID events; total follow-up 31,361 person-months, median 61 months), disease duration showed significant association (
< 0.005), with 6 (3-8)% decrease of LID risk per additional YOD. Other nominally significant associations were observed for gender-with women showing a 39 (5-82)% higher risk of LID-and AAO, with 2 (0.3-3)% decrease of risk for each year increase of PD onset. The SRF algorithm confirmed YOD as the most prominent feature influencing LID risk, with a variable importance of about 8% in the model. In genetic models, no statistically significant effects on incident LID risk was observed.
This evidence supports a protective effect of late PD onset and gender (men) against LID risk and suggests a new independent protective factor, YOD. Moreover, it underlines the importance of personalized therapeutic protocols for PD patients in the future.
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.
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