Levodopa Intake Research Articles

Motor-cognitive Functions in Parkinson’s Disease Patients across the Program of "Dry" Immersion: a Pilot Study

Motor-cognitive Functions in Parkinson’s Disease Patients across the Program of "Dry" Immersion: a Pilot Study

P 75 Movement-induced γ oscillations in the subthalamic nucleus are increased by dopamine and scaled by velocity in patients with Parkinson’s disease

Parkinson’s disease (PD) is a basal ganglia disorder that results in general slowness of movement and an effective treatment option consists in subthalamic deep brain stimulation (DBS). Postoperatively, DBS-electrodes are externalized which gives the unique opportunity of recording local field potentials (LFP). Previous studies have shown that there are disease specific oscillatory patterns at rest, most prominently an increased β synchronization (Kuhn, 2006) that correlates with clinical symptoms of PD such as rigidity and bradykinesia (Neumann, 2016). During movement, subthalamic oscillations show an increase of γ power that increases after L-Dopa intake (Androulidakis, 2007). In the motor cortex of healthy subjects (Cheyne, 2013) as well as in the internal pallidum of dystonia patients (Brucke, 2012) γ power is moreover scaled by kinematic parameters such as movement speed or force. Here we investigated whether γ oscillations in the human STN are related to scaling of movement and to what extent this modulation is influenced by dopamine and relates to symptom severity as assessed by the UPDRS-III motor score. To shed light on these questions, 16 PD patients (4 female, mean age 58.4 years ±2.8 SEM) undergoing electrode implantation in the STN for DBS were included in the study. Bipolar LFPs from 3 contact pairs were recorded while patients on their usual dopaminergic medication performed forearm pronation movements of three amplitudes (small, medium, large). 7 patients additionally performed the task after withdrawal of the dopaminergic replacement therapy, in the so called medical OFF state (>30% increase in UPDRS score). Signals were taken to the frequency domain using wavelet analysis, averaged and normalized to a pre-trial baseline period. Normalized time frequency plots were averaged across hemispheres and patients. Statistical analysis was conducted using FDR-corrected Monte Carlo permutation tests and correlations were calculated using Spearman’s Rho. Averaged Θ (2–8 Hz), β (13–30 Hz) and γ (40–90 Hz) power were compared across hemispheres, movement amplitudes and single trial velocities and correlated with the clinical symptom severity as measured by the UPDRS-ON score. We were able to reveal a neural signature of movement in the STN consisting in a synchronization in the Θ, a desynchronization in the β and a synchronization in the γ band compared to baseline. Our findings could be of special interest in the field of adaptive stimulation in order to monitor dopamine dependent subthalamic movement related activity in relation to current motor demand.

Toward an electrophysiological "sweet spot" for deep brain stimulation in the subthalamic nucleus.

Enhanced beta-band activity recorded in patients suffering from Parkinson's Disease (PD) has been described as a potential physiomarker for disease severity. Beta power is suppressed by Levodopa intake and STN deep brain stimulation (DBS) and correlates with disease severity across patients. The aim of the present study was to explore the promising signature of the physiomarker in the spatial domain. Based on local field potential data acquired from 54 patients undergoing STN-DBS, power values within alpha, beta, low beta, and high beta bands were calculated. Values were projected into common stereotactic space after DBS lead localization. Recorded beta power values were significantly higher at posterior and dorsal lead positions, as well as in active compared with inactive pairs. The peak of activity in the beta band was situated within the sensorimotor functional zone of the nucleus. In contrast, higher alpha activity was found in a more ventromedial region, potentially corresponding to associative or premotor functional zones of the STN. Beta- and alpha-power peaks were then used as seeds in a fiber tracking experiment. Here, the beta-site received more input from primary motor cortex whereas the alpha-site was more strongly connected to premotor and prefrontal areas. The results summarize predominant spatial locations of frequency signatures recorded in STN-DBS patients in a probabilistic fashion. The site of predominant beta-activity may serve as an electrophysiologically determined target for optimal outcome in STN-DBS for PD in the future. Hum Brain Mapp 38:3377-3390, 2017. © 2017 Wiley Periodicals, Inc.

Levodopa response differs in Parkinson's motor subtypes: A task-based effective connectivity study.

Parkinson's disease (PD) is a circuit-level disorder with clinically-determined motor subtypes. Despite evidence suggesting each subtype may have different pathophysiology, few neuroimaging studies have examined levodopa-induced differences in neural activation between tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtype patients during a motor task. The goal of this functional MRI (fMRI) study was to examine task-induced activation and connectivity in the cortico-striatal-thalamo-cortical motor circuit in healthy controls, TD patients, and PIGD patients before and after levodopa administration. Fourteen TD and 12 PIGD cognitively-intact patients and 21 age- and sex-matched healthy controls completed a right-hand, paced tapping fMRI paradigm. Collectively, PD patients off medication (OFF) showed hypoactivation of the motor cortex relative to healthy controls, even when controlling for performance. After levodopa intake, the PIGD patients had significantly increased activation in the left putamen compared with TD patients and healthy controls. Psychophysiological interaction analysis revealed that levodopa increased effective connectivity between the posterior putamen and other areas of the motor circuit during tapping in TD patients, but not in PIGD patients. This novel, levodopa-induced difference in the neural responses between PD motor subtypes may have significant implications for elucidating the mechanisms underlying the distinct phenotypic manifestations and enabling the classification of motor subtypes objectively using fMRI.

Response of non-motor symptoms to levodopa in late-stage Parkinson's disease: Results of a levodopa challenge test

BackgroundNon-motor symptoms (NMS) are extremely common among late-stage Parkinson's disease (LSPD) patients. Levodopa (L-dopa) responsiveness seems to decrease with disease progression but its effect on NMS in LSPD still needs to be investigated. ObjectiveTo assess the response of blood pressure (BP), pain, fatigue and anxiety to L-dopa in LSPD patients. Methods20 LSPD patients, defined as Schwab and England ADL Scale <50 or Hoehn Yahr Stage >3 (MED ON) and 22 PD patients treated with subthalamic deep brain stimulation (advanced PD group) underwent an L-dopa challenge. BP and orthostatic hypotension (OH) assessment, a visual analogue scale (VAS) for pain and fatigue and the Strait Trait Anxiety (STAI) were evaluated before and after the L-dopa challenge. ResultsSystolic BP dropped significantly after L-dopa intake (p < 0.05) in LSPD patients, while there was no change in pain, fatigue or anxiety. L-dopa significantly improved (p < 0.05) pain and anxiety in the advanced PD group, whereas it had no effect on BP or fatigue. L-dopa-related adverse effects (AEs), namely OH and sleepiness, were more common among LSPD patients. 40% and 65% of LSPD patients were not able to fill out the VAS and the STAI, respectively, while measurement of orthostatic BP was not possible in four LSPD patients. ConclusionsThis exploratory study concludes that some non-motor variables in LSPD do not benefit from the acute action of L-dopa while it can still induce disabling AEs. There is a need for assessment tools of NMS adapted to these disabled LSPD patients.

DOPAMINE DYSREGULATION SYNDROME IN PARKINSON’S DISEASE AND APPROACHES TO ITS CORRECTION WITH DRUGS

The objective is to describe a clinical case of dopamine dysregulation syndrome (DDS) with compulsive intake of large doses of levodopa in a patient with Parkinson’s disease (PD). Materials and methods. Male patient R., born in 1956, has had PD since 2004 when he noticed changes in his handwriting, difficulties to perform small movements with the right hand. Therapy with levodopa/benserazide was started at 300 mg/day. With time symptoms of the disease escalated: gait impairment and motor fluctuations started. Action duration after administration of levodopa/benserazide sin gle dose shortened to 2 hours, peak dose dyskinesia developed, as well as instability with frequent falls. In 2012, clinical picture of the disease included symptoms of DDS. The patient independently increased the drug dose, decreased time between doses, didn’t follow the doctor’s recommendations. Relatives noticed a state of euphoria in the patient after taking a dose of levodopa/benserazide. At the time of visiting the Department of Neurology of the Russian Medical Academy of Continuous Professional Education in the beginning of 2016, the daily equivalent levodopa dose was 2000 mg, and 800 mg of it were taken at night. Results. The patient was transferred to a three-component modern levodopa drug Stalevo (levodopa + carbidopa + entacapone) 150 mg + levodopa/benserazide 50 mg 6 times a day (daily dose 1200 mg). Decreased levodopa daily dose achieved by transferring the patient to a three-component drug with better bioavailability lead to significant reduction of motor and non-motor symptoms, significant increase in effect duration after a single dose of levodopa. In a year of follow-up, DDS symptoms gradually regressed, time between drug administration increased, the patient stopped taking the drug at night, fluctuations and drug-induced dyskinesias significantly decreased. Conclusion. In this clinical case, manifestations of DDS caused by long-term compulsive levodopa intake at doses significantly exceeding daily dose (necessary for control of motor symptoms) are described. One of the approaches to reduction of high doses of levodopa and control of motor fluctuations is prescription of Stalevo which stabilizes levodopa level in plasma and provides a more continuous stimulation of dopamine receptors in the striatum.

LONG-TERM DOPAMINERGIC THERAPY OF PARKINSON DISEASE

The use of dopaminergic tools, particularly levodopa and dopamine receptors agonists (DRA), for many years allowed to effectively control the major motor symptoms of Parkinson disease, supporting mobility and daily activity, and eventually increasing the survivability of patients. However, a few years after the start of the Levodopa intake the vast majority of patients have motor fluctuations and dyskinesias. The Levodopa action is ensured not only by the short-term but also by the so-called long-term effect of Levodopa, which is developing when the drug is taken regularly. The long-term response provides at least half of the total response to dopaminergic drugs, particularly, Levodopa. As the disease progresses, the long-term response tends to decrease, with a more precise «pulse» of a short-term reaction that does not affect its parameters. It is believed that this is related to the development of the phenomenon of «dose-end exhaustion» and then to «turn on-off». Thus, the task of delaying the occurrence of motor fluctuations must be to keep the long-term dopaminergic effect as long as possible. Dopaminergic receptors agonists (DRA) are capable of direct stimulating of dopamine receptors on striatal neurons, bypassing degeneration nigrostriatal cells, thus simulating operation of an endogenous mediator. Agonists of D2-receptors can induce long-term reactions. It is shown that in six weeks after the Ropinirol intake, the subsequent discontinuation of its application results in a slow rise in the motor symptoms during a week. The effectiveness of Ropinirol with the prolonged release at various stages of the PD is confirmed in several placebo-controlled studies. The role of a slow release dosage of Ropinirol in maintaining a long-term response requires special study.

Abnormal premotor-motor interaction in heterozygous Parkin- and Pink1 mutation carriers.

Mutations in the Parkin and PINK1 gene account for the majority of autosomal recessive early-onset Parkinson cases. There is increasing evidence that clinically asymptomatic subjects with single heterozygous mutations have a latent nigrostriatal dopaminergic deficit and could be taken as in vivo model of pre-symptomatic phase of Parkinsonism. We charted premotor-motor excitability changes as compensatory mechanisms for subcortical dopamine depletions using transcranial magnetic stimulation by applying magnetic resonance-navigated premotor-motor cortex conditioning in 15 asymptomatic, heterozygous Parkin and PINK1 mutation carriers (2 female; mean age 53±8years) and 16 age- and sex-matched controls (5 female; mean age 57±9years). Participants were examined at baseline and after acute l-dopa challenge. There were l-dopa and group specific effects during premotor-motor conditioning at an interstimulus interval of 6ms indicating a normalisation of premotor-motor interactions in heterozygous Parkin and PINK1 mutation carriers after l-dopa intake. Non-physiologically high conditioned MEP amplitudes at this interval in mutation carriers decreased after l-dopa intake but increased in controls. Premotor-motor excitability changes are part of the cortical reorganization in asymptomatic heterozygous Parkin- and PINK1 mutation carriers. These subjects offer opportunities to delineate motor network adaptation in pre-symptomatic Parkinsonism.

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

BackgroundThe 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. ObjectivesBy 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. MethodsPD 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. ResultsSTN-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. ConclusionsOur 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.

Parkinsonian Rest Tremor Is Associated With Modulations of Subthalamic High-Frequency Oscillations.

High frequency oscillations (>200 Hz) have been observed in the basal ganglia of PD patients and were shown to be modulated by the administration of levodopa and voluntary movement. The objective of this study was to test whether the power of high-frequency oscillations in the STN is associated with spontaneous manifestation of parkinsonian rest tremor. The electromyogram of both forearms and local field potentials from the STN were recorded in 11 PD patients (10 men, age 58 [9.4] years, disease duration 9.2 [6.3] years). Patients were recorded at rest and while performing repetitive hand movements before and after levodopa intake. High-frequency oscillation power was compared across epochs containing rest tremor, tremor-free rest, or voluntary movement and related to the tremor cycle. We observed prominent slow (200-300 Hz) and fast (300-400 Hz) high-frequency oscillations. The ratio between slow and fast high-frequency oscillation power increased when tremor became manifest. This increase was consistent across nuclei (94%) and occurred in medication ON and OFF. The ratio outperformed other potential markers of tremor, such as power at individual tremor frequency, beta power, or low gamma power. For voluntary movement, we did not observe a significant difference when compared with rest or rest tremor. Finally, rhythmic modulations of high-frequency oscillation power occurred within the tremor cycle. Subthalamic high-frequency oscillation power is closely linked to the occurrence of parkinsonian rest tremor. The balance between slow and fast high-frequency oscillation power combines information on motor and medication state. © 2016 International Parkinson and Movement Disorder Society.

Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost.

Dopamine is known to be involved in regulating effort investment in relation to reward, and the disruption of this mechanism is thought to be central in some pathological situations such as Parkinson's disease, addiction, and depression. According to an influential model, dopamine plays this role by encoding the opportunity cost, i.e., the average value of forfeited actions, which is an important parameter to take into account when making decisions about which action to undertake and how fast to execute it. We tested this hypothesis by asking healthy human participants to perform two effort-based decision-making tasks, following either placebo or levodopa intake in a double blind within-subject protocol. In the effort-constrained task, there was a trade-off between the amount of force exerted and the time spent in executing the task, such that investing more effort decreased the opportunity cost. In the time-constrained task, the effort duration was constant, but exerting more force allowed the subject to earn more substantial reward instead of saving time. Contrary to the model predictions, we found that levodopa caused an increase in the force exerted only in the time-constrained task, in which there was no trade-off between effort and opportunity cost. In addition, a computational model showed that dopamine manipulation left the opportunity cost factor unaffected but altered the ratio between the effort cost and reinforcement value. These findings suggest that dopamine does not represent the opportunity cost but rather modulates how much effort a given reward is worth. Dopamine has been proposed in a prevalent theory to signal the average reward rate, used to estimate the cost of investing time in an action, also referred to as opportunity cost. We contrasted the effect of dopamine manipulation in healthy participants in two tasks, in which increasing response vigor (i.e., the amount of effort invested in an action) allowed either to save time or to earn more reward. We found that levodopa-a synthetic precursor of dopamine-increases response vigor only in the latter situation, demonstrating that, rather than the opportunity cost, dopamine is involved in computing the expected value of effort.

EP 38. Subthalamic nucleus Deep Brain Stimulation (STN-DBS) reduces freezing of gait in Parkinson’s disease in the VANTAGE prospective, multi-center trial

Background Deep Brain Stimulation (DBS) is effective for Parkinson’s disease (PD) symptom relief; however, improvement of freezing of gait (FOG) remains under debate. Some studies indicate STN-DBS alleviates FOG, while others suggest an association of STN-DBS with worsening of gait and balance or even induction of FOG. The VANTAGE study assesses motor improvement in moderate-to-severe PD following bilateral STN-DBS using a new, implantable, rechargeable, multiple-source, 16-output (supporting two 8-contact leads), constant-current, CE-marked DBS System. We report the effects of STN-DBS on FOG in this cohort of PD subjects. Methods VANTAGE is a monitored, prospective, multi-center, non-randomized, open-label interventional trial, sponsored by Boston Scientific Corporation. FOG was characterized with UPDRS-II item 14, the freezing of gait questionnaire (FOGQ) and a walking test known to provoke FOG pre and post-surgery. Data collection included FOGQ at Baseline and 26 weeks post-implantation, and the walking test at Baseline, 12, 26, and 52 weeks post-implantation. The walking test was videotaped and rated remotely by an independent rater (CS), blinded to the subject’s implantation status. Results Thirty-eight subjects, of the forty implanted, were analyzed with FOGQ data. The FOGQ showed significant improvement at 26 week follow up versus baseline derived from UPDRS-III item 29 and UPDRS II item 14. FOGQ (item 3) data at 26 weeks versus baseline indicated 12 freezers remained freezers, 15 freezers turned to non-freezers, 10 non-freezers remained non-freezers, and one non-freezer turned to a freezer. The walking test was performed by 29 of 38 subjects at baseline during medication off. Thirteen subjects showed FOG-episodes off medication at baseline and improved after L-Dopa intake. Postoperatively, the total walking time, FOG episode occurrences, and total time spent frozen were reduced at week 12, 26, and 52 compared to baseline during medication off. Conclusions FOGQ and walking test data demonstrate that STN-DBS can reduce FOG occurrence and severity at 26 weeks postoperatively with constant effects at week 52. Follow-up data will help to understand if improvement on FOG persists long term.

Plantar cutaneous function in Parkinson’s disease patients ON and OFF L-dopa

While Parkinson’s disease (PD) is traditionally viewed as a motor disorder, there is mounting evidence that somatosensory function becomes affected as well. However, conflicting reports exist regarding whether plantar sensitivity is reduced in early-onset PD patients. Plantar sensitivity was assessed using monofilaments and a gold-standard, two-interval two-alternative forced choice vibrotactile detection task at both 30 and 250Hz. Lower-limb cutaneous reflexes were assessed by delivering continuous, sinusoidal vibration at 30 and 250Hz while recording muscle activity in Tibialis Anterior. We found no evidence of elevated plantar thresholds or dysfunctional lower-limb cutaneous reflexes in PD patients ON medication. We also found no acute effect of ceasing L-dopa intake on either plantar sensitivity or cutaneous reflexes. Our finding of intact cutaneous function in PD supports the further exploration of therapeutics that enhance plantar sensitivity to minimize postural instability, a source of considerable morbidity in this clinical population.

Motor fluctuations due to interaction between dietary protein and levodopa in Parkinson's disease.

BackgroundThe modulation of levodopa transport across the blood brain barrier by large neutral amino acids is well documented. Protein limitation and protein redistribution diets may improve motor fluctuations in patients with Parkinson’s disease but the pharmacokinetics and pharmacodynamics of levodopa and amino acids are highly variable.MethodsClinical records of 1037 Parkinson’s disease patients were analyzed to determine the proportion of patients with motor fluctuations related to protein interaction with levodopa. Motor fluctuations due to protein interaction with levodopa were defined as dietary protein being associated with (i) longer time to levodopa effectiveness, (ii) reduced benefit or duration of benefit, (iii) dose failures or (iv) earlier wearing off from a previously effective dose. Dose failures, sudden, painful or behavioral wearing-off periods, gait freezing, nausea, hallucinations, orthostasis, and dyskinesias were taken as markers of motor fluctuations, disease severity, and levodopa side effects potentially influenced by protein.Results5.9 % of Parkinson’s disease patients on levodopa, and 12.4 % with motor fluctuations on levodopa correlated their fluctuations with the relative timing of levodopa and protein intake. These patients were younger at disease onset, had worse motor fluctuations and had a higher incidence of family members with Parkinson’s disease. Early wearing off or decreased dose efficacy were most commonly associated with protein interaction. 60 % of patients who modified their diets had weight loss.ConclusionsThis study suggests that clinically significant protein interaction with levodopa may occur mostly in a subset of Parkinson’s disease patients with earlier disease onset and those with familial disease.

The single intake of levodopa modulates implicit learning in drug naïve, de novo patients with idiopathic Parkinson's disease.

Although dopamine is known to aggravate implicit learning, the exact impact on behaviour when feedback is unavailable remains unclear. Previous studies revealed that non-rewarded learning habits are affected in long-term dopaminergic treated patients with Parkinson's disease (PD). We studied the influence of a onetime levodopa intake on implicit learning in de novo, untreated PD patients. De novo PD patients (n=22) before and after the single intake of levodopa and control subjects (n=23) took part in a Go/NoGo paradigm. One stimulus was defined as target, which was first consistently preceded by one of three non-target stimuli (conditioning). This coupling was dissolved thereafter (deconditioning). In the 'Go version' subjects were asked to respond to the target by pressing a key, whereas in the 'NoGo version' response had to be inhibited. PD patients and controls (n=14/n=19) with an initial learning effect due to the target were included for further statistical analysis. Within the subgroup incorrect responses upon NoGo stimuli increased during the deconditioning phase. In contrast, the same patients failed to show any change after receiving 200mg of levodopa. During the Go version, no change of the overall error rate between conditioning and deconditioning was detectable over all groups. Learning behaviour in untreated PD patients and healthy controls was indistinguishable. In contrast, the same patients varied in their implicit learning after one-time intake of levodopa, when actions had to be inhibited. Hence, the single intake of levodopa appears to modulate implicit learning behaviour in de novo PD patients.

Levodopa and neuropathy risk in patients with Parkinson disease: Effect of COMT inhibition

ObjectiveOur purpose was to determine whether the use of catechol-O-methyltransferase-inhibitors (ICOMT) can reduce the risk of developing levodopa (LD)-induced neuropathy in Parkinson's disease (PD) patients. MethodsA multicentre study of 197 PD patients was performed. 144 were exposed to LD for more than three years (LELD group); 53 simultaneously assumed Entacapone for at least eighteen months (LELD_ICOMT group). ResultsThe prevalence of neuropathy in LELD patients was 19.4% whereas it was 5.7% in LELD_ICOMT group with a significant difference (p = 0.025). In LELD_ICOMT cohort the daily LD dose and serum VB12 levels were significantly higher (p < 0.0001), the serum Hcy levels were significantly lower (p = 0.001) compared to LELD group. ConclusionOur results suggest that ICOMT could have a protective effect on the development of LD-induced neuropathy. Their action probably occurs through the metabolic rebalancing of the one-carbon-pathway cycle and is independent of the PD duration and severity and the duration of LD intake.

Gender and non motor fluctuations in Parkinson's disease: A prospective study

IntroductionIn Parkinson's disease (PD), non motor symptoms can fluctuate either along or irrespective to motor on/off phenomena. Prospective studies suggest that higher motor scores and levodopa dosage, younger age at onset and female gender represent risk factors for motor fluctuations' development. Yet, the predictors of development of non motor fluctuations (NMF) are less clear.In this prospective study, we aimed to assess the relationship between NMF and gender along with other potential risk factors. MethodsForty-seven (16 women/31 men) de novo, drug-naïve PD patients have been followed for 4 years since diagnosis. Motor and non motor fluctuations were evaluated with the 19-item Wearing off Questionnaire (WOQ-19). The association between gender and NMF was explored with multivariable regression models adjusted for age at onset, motor and non motor symptoms at diagnosis and levodopa intake at follow up. ResultsFemale gender was more likely associated with a diagnosis of NMF (adjusted odds ratio, AOR = 5.33,95%CI = 1.21–23.4, p = 0.027), but not with a diagnosis of generic wearing off at follow up (OR = 3.66, 95%CI = 0.8–16.8, p = 0.097). Women had greater likelihood of developing higher WOQ-19 Non motor scores (AOR = 4.58, 95%CI = 1.23–17.03, p = 0.023), but not higher WOQ-19 Total scores (AOR = 2.88, 95%CI = 0.86–9.71, p = 0.087) compared to men. Notwithstanding, no gender differences were detected in medication intake. ConclusionsWe showed that female gender represents a major risk factor for the development of NMF. There were no gender differences in medication intake, thus NMF in women remain mostly underestimated and not properly treated. From a practical standpoint, clinicians should take into account the role of gender in the management of NMF in PD.

Resting-state connectivity predicts levodopa-induced dyskinesias in Parkinson's disease.

ABSTRACTBackgroundLevodopa‐induced dyskinesias are a common side effect of dopaminergic therapy in PD, but their neural correlates remain poorly understood.ObjectivesThis study examines whether dyskinesias are associated with abnormal dopaminergic modulation of resting‐state cortico‐striatal connectivity.MethodsTwelve PD patients with peak‐of‐dose dyskinesias and 12 patients without dyskinesias were withdrawn from dopaminergic medication. All patients received a single dose of fast‐acting soluble levodopa and then underwent resting‐state functional magnetic resonance imaging before any dyskinesias emerged. Levodopa‐induced modulation of cortico‐striatal resting‐state connectivity was assessed between the putamen and the following 3 cortical regions of interest: supplementary motor area, primary sensorimotor cortex, and right inferior frontal gyrus. These functional connectivity measures were entered into a linear support vector classifier to predict whether an individual patient would develop dyskinesias after levodopa intake. Linear regression analysis was applied to test which connectivity measures would predict dyskinesia severity.ResultsDopaminergic modulation of resting‐state connectivity between the putamen and primary sensorimotor cortex in the most affected hemisphere predicted whether patients would develop dyskinesias with a specificity of 100% and a sensitivity of 91% (P < .0001). Modulation of resting‐state connectivity between the supplementary motor area and putamen predicted interindividual differences in dyskinesia severity (R 2 = 0.627, P = .004). Resting‐state connectivity between the right inferior frontal gyrus and putamen neither predicted dyskinesia status nor dyskinesia severity.ConclusionsThe results corroborate the notion that altered dopaminergic modulation of cortico‐striatal connectivity plays a key role in the pathophysiology of dyskinesias in PD. © 2016 International Parkinson and Movement Disorder Society

Alpha and beta power decrease during enhanced cognitive effort in the basal ganglia: An intracerebral recording study

Purpose Cognitive adverse effects may accompany deep brain stimulation (DBS) treatment, as the basal ganglia have influence on widespread neocortical networks. The aim of this study was to investigate how complex motor-cognitive activities are processed in the subthalamic nucleus (STN) and internal globus pallidum (GPi). Methods Dystonia patients implanted with GPi-DBS electrodes ( n = 5), and individuals with Parkinson’s disease (PD) ( n = 4) or essential tremor ( n = 1) with STN-DBS electrodes performed two tasks involving the writing of single letters: 1. copying letters from a monitor; and 2. writing of any letter other than that appearing on the monitor. The cognitive load of the second task was increased relative to the first. Intracranial recordings of task-related oscillatory changes were assessed and compared. Results Local event-related alpha and beta desynchronization (ERD) were more expressed during the second task while the lower gamma synchronization (ERS) decreased regardless of the basal ganglia structure from which recordings were obtained or the clinical diagnosis. Task-related ERD differences recorded from the language-dominant left hemisphere correlated with a behavioural (RT) measure of cognitive effort. ERD changes declined after levodopa intake in PD patients. Conclusions The STN and Gpi participate in cognitive networks. Alpha and beta ERD seems to be essential during processing complex motor-cognitive tasks and increase with enhanced cognitive effort.

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16hour daily infusion of LCIG for 12months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37±11%, mean daily “off” period reduced from 6.3±2 to 1.9±2hours, total daily “on” time increased from 10.2±3 to 13.7±2hours, “on” period without dyskinesia increased from 4.5±3 to 7.5±5hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5±35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12±B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily “on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.