Interhemispheric reactivity of the subthalamic nucleus sustains progressive dopamine neuron loss in asymmetrical parkinsonism.

Parkinson's disease (PD) is characterized by the progressive and asymmetrical degeneration of the nigrostriatal dopamine neurons and the unilateral presentation of the motor symptoms at onset, contralateral to the most impaired hemisphere. We previously developed a rat PD model that mimics these typical features, based on unilateral injection of a substrate inhibitor of excitatory amino acid transporters, L-trans-pyrrolidine-2,4-dicarboxylate (PDC), in the substantia nigra (SN). Here, we used this progressive model in a multilevel study (behavioral testing, in vivo 1H-magnetic resonance spectroscopy, slice electrophysiology, immunocytochemistry and in situ hybridization) to characterize the functional changes occurring in the cortico-basal ganglia-cortical network in an evolving asymmetrical neurodegeneration context and their possible contribution to the cell death progression. We focused on the corticostriatal input and the subthalamic nucleus (STN), two glutamate components with major implications in PD pathophysiology. In the striatum, glutamate and glutamine levels increased from presymptomatic stages in the PDC-injected hemisphere only, which also showed enhanced glutamatergic transmission and loss of plasticity at corticostriatal synapses assessed at symptomatic stage. Surprisingly, the contralateral STN showed earlier and stronger reactivity than the ipsilateral side (increased intraneuronal cytochrome oxidase subunit I mRNA levels; enhanced glutamate and glutamine concentrations). Moreover, its lesion at early presymptomatic stage halted the ongoing neurodegeneration in the PDC-injected SN and prevented the expression of motor asymmetry. These findings reveal the existence of endogenous interhemispheric processes linking the primary injured SN and the contralateral STN that could sustain progressive dopamine neuron loss, opening new perspectives for disease-modifying treatment of PD.

Motivational and cognitive predictors of apathy after subthalamic nucleus stimulation in Parkinson's disease.

Postoperative apathy is a frequent symptom in Parkinson's disease patients who have undergone bilateral deep brain stimulation of the subthalamic nucleus. Two main hypotheses for postoperative apathy have been suggested: (i) dopaminergic withdrawal syndrome relative to postoperative dopaminergic drug tapering; and (ii) direct effect of chronic stimulation of the subthalamic nucleus. The primary objective of our study was to describe preoperative and 1-year postoperative apathy in Parkinson's disease patients who underwent chronic bilateral deep brain stimulation of the subthalamic nucleus. We also aimed to identify factors associated with 1-year postoperative apathy considering: (i) preoperative clinical phenotype; (ii) dopaminergic drug management; and (iii) volume of tissue activated within the subthalamic nucleus and the surrounding structures. We investigated a prospective clinical cohort of 367 patients before and 1 year after chronic bilateral deep brain stimulation of the subthalamic nucleus. We assessed apathy using the Lille Apathy Rating Scale and carried out a systematic evaluation of motor, cognitive and behavioural signs. We modelled the volume of tissue activated in 161 patients using the Lead-DBS toolbox and analysed overlaps within motor, cognitive and limbic parts of the subthalamic nucleus. Of the 367 patients, 94 (25.6%) exhibited 1-year postoperative apathy: 67 (18.2%) with 'de novo apathy' and 27 (7.4%) with 'sustained apathy'. We observed disappearance of preoperative apathy in 22 (6.0%) patients, who were classified as having 'reversed apathy'. Lastly, 251 (68.4%) patients had neither preoperative nor postoperative apathy and were classified as having 'no apathy'. We identified preoperative apathy score [odds ratio (OR) 1.16; 95% confidence interval (CI) 1.10, 1.22; P < 0.001], preoperative episodic memory free recall score (OR 0.93; 95% CI 0.88, 0.97; P = 0.003) and 1-year postoperative motor responsiveness (OR 0.98; 95% CI 0.96, 0.99; P = 0.009) as the main factors associated with postoperative apathy. We showed that neither dopaminergic dose reduction nor subthalamic stimulation were associated with postoperative apathy. Patients with 'sustained apathy' had poorer preoperative fronto-striatal cognitive status and a higher preoperative action initiation apathy subscore. In these patients, apathy score and cognitive status worsened postoperatively despite significantly lower reduction in dopamine agonists (P = 0.023), suggesting cognitive dopa-resistant apathy. Patients with 'reversed apathy' benefited from the psychostimulant effect of chronic stimulation of the limbic part of the left subthalamic nucleus (P = 0.043), suggesting motivational apathy. Our results highlight the need for careful preoperative assessment of motivational and cognitive components of apathy as well as executive functions in order to better prevent or manage postoperative apathy.

Imbalanced motivated behaviors according to motor sign asymmetry in drug-naïve Parkinson's disease.

Few studies have considered the influence of motor sign asymmetry on motivated behaviors in de novo drug-naïve Parkinson's disease (PD). We tested whether motor sign asymmetry could be associated with different motivated behavior patterns in de novo drug-naïve PD. We performed a cross-sectional study in 128 de novo drug-naïve PD patients and used the Ardouin Scale of Behavior in Parkinson's disease (ASBPD) to assess a set of motivated behaviors. We assessed motor asymmetry based on (i) side of motor onset and (ii) MDS-UPDRS motor score, then we compared right hemibody Parkinson's disease to left hemibody Parkinson's disease. According to the MDS-UPDRS motor score, patients with de novo right hemibody PD had significantly lower frequency of approach behaviors (p = 0.031), including nocturnal hyperactivity (p = 0.040), eating behavior (p = 0.040), creativity (p = 0.040), and excess of motivation (p = 0.017) than patients with de novo left hemibody PD. Patients with de novo left hemibody PD did not significantly differ from those with de novo right hemibody PD regarding avoidance behaviors including apathy, anxiety and depression. Our findings suggest that motor sign asymmetry may be associated with an imbalance between motivated behaviors in de novo drug-naïve Parkinson's disease.

Trial of Botulinum Toxin for Isolated or Essential Head Tremor.

BACKGROUND: Local injections of botulinum toxin type A have been used to treat essential head tremor but have not been extensively studied in randomized trials. METHODS: In a multicenter, double-blind, randomized trial, we assigned, in a 1:1 ratio, adult patients with essential or isolated head tremor to receive botulinum toxin type A or placebo. Botulinum toxin or placebo was injected under electromyographic guidance into each splenius capitis muscle on the day of randomization (day 0) and during week 12. The primary outcome was improvement by at least 2 points on the Clinical Global Impression of Change (CGI) scale at week 6 after the second injection (week 18 after randomization). The CGI scale was used to record the patient's assessment of the degree of improvement or worsening of head tremor since baseline; scores range from 3 (very much improved) to -3 (very much worse). Secondary outcomes included changes in tremor characteristics from baseline to weeks 6, 12, and 24. RESULTS: A total of 120 patients were enrolled; 3 patients were excluded during screening, and 117 patients were randomly assigned to receive botulinum toxin (62 patients) or placebo (55 patients) and were included in the intention-to-treat analysis. Twelve patients in the botulinum toxin group and 2 patients in the placebo group did not receive injections during week 12. The primary outcome - improvement by at least 2 points on the CGI scale at week 18 - was met by 31% of the patients in the botulinum toxin group as compared with 9% of those in the placebo group (relative risk, 3.37; 95% confidence interval, 1.35 to 8.42; P = 0.009). Analyses of secondary outcomes at 6 and 12 weeks but not at 24 weeks were generally supportive of the primary-outcome analysis. Adverse events occurred in approximately half the patients in the botulinum toxin group and included head and neck pain, posterior cervical weakness, and dysphagia. CONCLUSIONS: Injection of botulinum toxin into each splenius capitis muscle on day 0 and during week 12 was more effective than placebo in reducing the severity of isolated or essential head tremor at 18 weeks but not at 24 weeks, when the effects of injection might be expected to wane, and was associated with adverse events. (Funded by the French Ministry of Health; Btx-HT ClinicalTrials.gov number, NCT02555982.).

Deep brain stimulation of the subthalamic nucleus in severe Parkinson's disease: relationships between dual-contact topographic setting and 1-year worsening of speech and gait.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) alleviates severe motor fluctuations and dyskinesia in Parkinson's disease, but may result in speech and gait disorders. Among the suspected or demonstrated causes of these adverse effects, we focused on the topography of contact balance (CB; individual, right and left relative dual positions), a scantly studied topic, analyzing the relationships between symmetric or non-symmetric settings, and the worsening of these signs. METHOD: An observational monocentric study was conducted on a series of 92 patients after ethical approval. CB was specified by longitudinal and transversal positions and relation to the STN (CB sub-aspects) and totalized at the patient level (patient CB). CB was deemed symmetric when the two contacts were at the same locations relative to the STN. CB was deemed asymmetric when at least one sub-aspect differed in the patient CB. Baseline and 1-year characteristics were routinely collected: (i) general, namely, Unified Parkinson's Disease Rating Scores (UPDRS), II, III motor and IV, daily levodopa equivalent doses, and Parkinson's Disease Questionnaire of Quality of Life (PDQ39) scores; (ii) specific, namely scores for speech (II-5 and III-18) and axial signs (II-14, III-28, III-29, and III-30). Only significant correlations were considered (p < 0.05). RESULTS: Baseline characteristics were comparable (symmetric versus asymmetric). CB settings were related to deteriorations of speech and axial signs: communication PDQ39 and UPDRS speech and gait scores worsened exclusively with symmetric settings; the most influential CB sub-aspect was symmetric longitudinal position. CONCLUSION: Our findings suggest that avoiding symmetric CB settings, whether by electrode positioning or shaping of electric fields, could reduce worsening of speech and gait.

Volumetric changes and clinical trajectories in Parkinson's disease: a prospective multicentric study.

BACKGROUND: Longitudinal measures of structural brain changes using MRI in relation to clinical features and progression patterns in PD have been assessed in previous studies, but few were conducted in well-defined and large cohorts, including prospective clinical assessments of both motor and non-motor symptoms. OBJECTIVE: We aimed to identify brain volumetric changes characterizing PD patients, and determine whether regional brain volumetric characteristics at baseline can predict motor, psycho-behavioral and cognitive evolution at one year in a prospective cohort of PD patients. METHODS: In this multicentric 1 year longitudinal study, PD patients and healthy controls from the MPI-R2* cohort were assessed for demographical, clinical and brain volumetric characteristics. Distinct subgroups of PD patients according to motor, cognitive and psycho-behavioral evolution were identified at the end of follow-up. RESULTS: One hundred and fifty PD patients and 73 control subjects were included in our analysis. Over one year, there was no significant difference in volume variations between PD and control subjects, regardless of the brain region considered. However, we observed a reduction in posterior cingulate cortex volume at baseline in PD patients with motor deterioration at one year (p = 0.017). We also observed a bilateral reduction of the volume of the amygdala (p = 0.015 and p = 0.041) and hippocampus (p = 0.015 and p = 0.053) at baseline in patients with psycho-behavioral deterioration, regardless of age, dopaminergic treatment and center. CONCLUSION: Brain volumetric characteristics at baseline may predict clinical trajectories at 1 year in PD as posterior cingulate cortex atrophy was associated with motor decline, while amygdala and hippocampus atrophy were associated with psycho-behavioral decline.

Correction: Association of Rare Genetic Variants in Opioid Receptors with Tourette Syndrome.

[This corrects the article DOI: 10.5334/tohm.464.].

Intrasubject subcortical quantitative referencing to boost MRI sensitivity to Parkinson's disease.

Several postmortem studies have shown iron accumulation in the substantia nigra of Parkinson's disease patients. Iron concentration can be estimated via MRI-R2∗ mapping. To assess the changes in R2∗ occurring in Parkinson's disease patients compared to controls, a multicentre transversal study was carried out on a large cohort of Parkinson's disease patients (n = 163) with matched controls (n = 82). In this study, 44 patients and 11 controls were removed due to motion artefacts, 21 patient and 6 controls to preserve matching. Thus, 98 patients and 65 age and sex-matched healthy subjects were selected with enough image quality. The study was conducted on patients with early to late stage Parkinson's disease. The images were acquired at 3Tesla in 12 clinical centres. R2∗ values were measured in subcortical regions of interest (substantia nigra, red nucleus, striatum, globus pallidus externus and globus pallidus internus) contralateral (dominant side) and ipsilateral (non dominant side) to the most clinically affected hemibody. As the observed inter-subject R2∗ variability was significantly higher than the disease effect, an original strategy (intrasubject subcortical quantitative referencing, ISQR) was developed using the measurement of R2∗ in the red nucleus as an intra-subject reference. R2∗ values significantly increased in Parkinson's disease patients when compared with controls; in the substantia nigra (SN) in the dominant side (D) and in the non dominant side (ND), respectively (PSN_D and PSN_ND < 0.0001). After stratification into four subgroups according to the disease duration, no significant R2∗ difference was found in all regions of interest when comparing Parkinson's disease subgroups. By applying our ISQR strategy, R2(ISQR)∗ values significantly increased in the substantia nigra (PSN_D and PSN_ND < 0.0001) when comparing all Parkinson's disease patients to controls. R2(ISQR)∗ values in the substantia nigra significantly increased with the disease duration (PSN_D = 0.01; PSN_ND = 0.03) as well as the severity of the disease (Hoehn & Yahr scale <2 and ≥ 2, PSN_D = 0.02). Additionally, correlations between R2(ISQR)∗ and clinical features, mainly related to the severity of the disease, were found. Our results support the use of ISQR to reduce variations not directly related to Parkinson's disease, supporting the concept that ISQR strategy is useful for the evaluation of Parkinson's disease.

Can Dopamine Responsiveness Be Predicted in Parkinson's Disease Without an Acute Administration Test?

BACKGROUND: Dopamine responsiveness (dopa-sensitivity) is an important parameter in the management of patients with Parkinson's disease (PD). For quantification of this parameter, patients undergo a challenge test with acute Levodopa administration after drug withdrawal, which may lead to patient discomfort and use of significant resources. OBJECTIVE: Our objective was to develop a predictive model combining clinical scores and imaging. METHODS: 350 patients, recruited by 13 specialist French centers and considered for deep brain stimulation, underwent an acute L-dopa challenge (dopa-sensitivity > 30%), full assessment, and MRI investigations, including T1w and R2* images. Data were randomly divided into a learning base from 10 centers and data from the remaining centers for testing. A machine selection approach was applied to choose the optimal variables and these were then used in regression modeling. Complexity of the modelling was incremental, while the first model considered only clinical variables, the subsequent included imaging features. The performances were evaluated by comparing the estimated values and actual valuesResults:Whatever the model, the variables age, sex, disease duration, and motor scores were selected as contributors. The first model used them and the coefficients of determination (R2) was 0.60 for the testing set and 0.69 in the learning set (p < 0.001). The models that added imaging features enhanced the performances: with T1w (R2 = 0.65 and 0.76, p < 0.001) and with R2* (R2 = 0.60 and 0.72, p < 0.001). CONCLUSION: These results suggest that modeling is potentially a simple way to estimate dopa-sensitivity, but requires confirmation in a larger population, including patients with dopa-sensitivity < 30.

Naltrexone promotes mechanical allodynia in humans and rats.

Mechanical allodynia has been studied in chronic naltrexone-treated people (N.T.P.) and rats (N.T.R.). After persistent naltrexone administration, patients acquired static and dynamic mechanical allodynia, as measured by von Frey filament (vFf) and brush stimulations. Pregabalin and levodopa administrations in N.T.P. significantly reduced allodynic behaviour, albeit these molecules did not completely stop it. As evidenced by the deployment of the vFf, subchronic treatment with Naltrexone delivered peripherally or intrathecally induced allodynic behaviour in rats. Increased expressions of two pain markers, pERK1/2 and PKCγ, in the spinal dorsal horn laminae were associated with naltrexone-induced allodynic behaviour. After vFf stimulation, pERK1/2 expression was substantially higher (p < 0.001) in superficial spinal dorsal horn laminae than in non-stimulated or naive non-stimulated rats. In addition, when compared to control rats, N.T.R. showed a substantial (p < 0.001) increase in PKCγ expression. PKCγ expression was found to be strong in lamina IIi and laminae III-IV. A cellular mechanism is proposed for the naltrexone effect. In both people and rats, Naltrexone induces static mechanical allodynia, according to this study.

Early Parkinson's Disease Phenotypes Tailored by Personality, Behavior, and Motor Symptoms.

BACKGROUND: Previous studies described a parkinsonian personality characterized as rigid, introverted, and cautious; however, little is known about personality traits in de novo Parkinson's disease (PD) patients and their relationships with motor and neuropsychiatric symptoms. OBJECTIVE: To investigate personality in de novo PD and explore its relationship with PD symptoms. METHODS: Using Cloninger's biosocial model, we assessed personality in 193 de novo PD patients. Motor and non-motor symptoms were measured using several validated scales. Cluster analysis was conducted to investigate the interrelationship of personality traits, motor, and non-motor symptoms. RESULTS: PD patients showed low novelty seeking, high harm avoidance, and normal reward dependence and persistence scores. Harm avoidance was positively correlated with the severity of depression, anxiety, and apathy (rs = [0.435, 0.676], p < 0.001) and negatively correlated with quality of life (rs = -0.492, p < 0.001). Novelty seeking, reward dependence, and persistence were negatively correlated with apathy (rs = [-0.274, -0.375], p < 0.001). Classification of patients according to personality and PD symptoms revealed 3 distinct clusters: i) neuropsychiatric phenotype (with high harm avoidance and low novelty seeking, hypodopaminergic neuropsychiatric symptoms and higher impulsivity), ii) motor phenotype (with low novelty seeking and higher motor severity), iii) benign phenotype (with low harm avoidance and high novelty seeking, reward dependence, and persistence traits clustered with lower symptoms severity and low impulsivity). CONCLUSION: Personality in early PD patients allows us to recognize 3 patients' phenotypes. Identification of such subgroups may help to better understand their natural history. Their longitudinal follow-up will allow confirming whether some personality features might influence disease evolution and treatment.

Glutamate cycle changes in the putamen of patients with de novo Parkinson's disease using 1H MRS.

INTRODUCTION: To investigate glutamatergic metabolism changes in the putamen of patients with de novo Parkinson's Disease (PD) and test the hypothesis that glutamate (Glu) levels are abnormally elevated in the putamen contralateral to where the motor clinical signs predominate as expected from observations in animal models. METHODS: 1H NMR spectra from 17 healthy control volunteers were compared with spectra from 17 de novo PD patients of who 14 were evaluated again after 2-3 years of disease progression. Statistical analysis used random-effects models. RESULTS: The only significant difference between PD patients and controls was a higher glutamine (Gln) concentration in the putamen ipsilateral to the hemibody with predominant motor signs (Visit 1: 6.0 ± 0.4 mM vs. 5.2 ± 0.2 mM, p < 0.05; Visit 2: 6.2 ± 0.3 mM vs. 5.2 ± 0.2 mM, p < 0.05). At Visit 1, PD patients had higher Glu and Gln levels in the putamen ipsilateral versus contralateral to dominant clinical signs (Glu: 12.2 ± 0.6 mM vs. 10.4 ± 0.6 mM, p < 0.05; Gln: 6.0 ± 0.4 mM vs. 4.8 ± 0.4 mM, p < 0.05; Glu and Gln pool (Glx): 17.9 ± 0.8 mM vs. 14.7 ± 1.1 mM, p < 0.05). At Visit 2, the sum of the two metabolites remained significantly higher in the ipsilateral versus contralateral putamen (Glx: 18.3 ± 0.6 mM vs. 16.1 ± 0.9 mM, p < 0.05). CONCLUSION: In de novo PD patients, the putamen ipsilateral to the more affected hemibody showed elevated Gln versus controls and elevated Glu and Gln concentrations versus the contralateral side. Abnormalities in Glu metabolism therefore occur early in PD but unexpectedly in the putamen contralateral to the more damaged hemisphere, suggesting they are not dependent solely on dopamine loss.

Two-year longitudinal follow-up of visual illusions and hallucinations in Parkinson's disease.

BACKGROUND: Previous longitudinal studies assessing visual hallucinations in Parkinson's disease (PD) have not specifically considered the respective evolution of visual illusions (VI) and visual hallucinations (VH), neither did they assess the role of ocular pathology on the evolution of those manifestations. OBJECTIVE: We aimed to determine whether VI evolve towards VH along the time in PD, and whether ophthalmological treatment may have a positive effect on the prognosis of those visuo-perceptive manifestations. METHODS: PD patients from a previous cohort [PD with VI (n = 26), PD with VH (n = 28), and PD without VI or VH (n = 28)] were contacted by phone 2 years later and questioned regarding the current presence of VI or VH, any current visual complaints, and the occurrence of any ophthalmological or antipsychotic treatment during the 2-year period, as well as any dopatherapy adjustment. RESULTS: Among PD-VI patients, 43% normalized, 48% remained PD-VI, 9% evolved towards coexisting VI and VH, and none converted to pure VH. Among PD-VH patients, 42% normalized, 32% remained PD-VH, 21% evolved towards coexisting VI and VH, and only 5% converted to pure VI. At follow-up, visual complaints remained greater among PD-VI and PD-VH compared to controls (p = 0.005). Among PD-VI and PD-VH who became control at follow-up, 35% received ophthalmologic treatment, 29% antipsychotic treatment, and 23% a dopatherapy reduction. CONCLUSION: PD Patients with VI do not necessarily evolve towards VH over time, and ophthalmological treatment may have a positive effect on the prognosis of those visuo-perceptive manifestations in PD similar to antipsychotic treatment and dopatherapy adjustment. TRIAL REGISTRATION: clinicaltrials.gov number NCT01114321.

Quantification of Head Tremors in Medical Conditions: A Comparison of Analyses Using a 2D Video Camera and a 3D Wireless Inertial Motion Unit.

This study compares two methods to quantify the amplitude and frequency of head movements in patients with head tremor: one based on video-based motion analysis, and the other using a miniature wireless inertial magnetic motion unit (IMMU). Concomitant with the clinical assessment of head tremor severity, head linear displacements in the frontal plane and head angular displacements in three dimensions were obtained simultaneously in forty-nine patients using one video camera and an IMMU in three experimental conditions while sitting (at rest, counting backward, and with arms extended). Head tremor amplitude was quantified along/around each axis, and head tremor frequency was analyzed in the frequency and time-frequency domains. Correlation analysis investigated the association between the clinical severity of head tremor and head linear and angular displacements. Our results showed better sensitivity of the IMMU compared to a 2D video camera to detect changes of tremor amplitude according to examination conditions, and better agreement with clinical measures. The frequency of head tremor calculated from video data in the frequency domain was higher than that obtained using time-frequency analysis and those calculated from the IMMU data. This study provides strong experimental evidence in favor of using an IMMU to quantify the amplitude and time-frequency oscillatory features of head tremor, especially in medical conditions.

Fatigue in de novo Parkinson's Disease: Expanding the Neuropsychiatric Triad?

BACKGROUND: Fatigue is a frequent and troublesome symptom present from the early stages of Parkinson's disease (PD). OBJECTIVE: To examine the relationship between fatigue and the neuropsychiatric triad, which includes apathy, depression, and anxiety, in de novo PD. METHODS: We performed a cross-sectional study including 197 patients with de novo PD and assessed fatigue using the Parkinson's Disease Fatigue Scale (PDFS-16). We evaluated motor status using the Unified Parkinson's Disease Rating Scale (UPDRS) part III score and evaluated neuropsychiatric status using the Ardouin Scale of Behavior in Parkinson's Disease (ASBPD). We carried out univariate and multivariate analyses to model association between motor signs, non-motor signs, and fatigue risk. RESULTS: Frequency of fatigue (28.9%) was of the same order of magnitude as that of apathy. PD patients with fatigue reported a lower quality of life than patients without fatigue (p < 0.0001). The ASBPD showed that patients with fatigue had higher scores for depressed mood (p < 0.0001), anxiety (p < 0.0001), and apathy (p < 0.0001). In the univariate analysis, fatigue score was positively correlated with apathy, depression, anxiety, and the neuropsychiatric triad as a whole, and to a lesser extent with female sex, hyperemotivity, and the UPDRS part III score. In the multivariate analysis, after adjusting for sex and motor status, the fatigue score remained significantly correlated with apathy (OR = 11.17 [4.33-28.78], p < 0.0001) and depression (OR = 4.28 [1.39-13.12], p = 0.01), but not with anxiety (OR = 0.94 [0.34-2.58], p = 0.9). CONCLUSION: We propose that the neuropsychiatric triad could be expanded to include fatigue.

Decision making under uncertainty in Parkinson's disease with Rem sleep behavior disorder.

BACKGROUND: REM sleep behavior disorder (RBD) is associated with an increased risk to develop Impulse control disorders (ICDs) in Parkinson's disease (PD), however the mechanisms underlying this putative association are still poorly understood. Decision-making impairment, one major neuro-psychological dimension that may lead to ICDs, has been reported in idiopathic RBD, but has never been assessed in RBD associated with PD. OBJECTIVE: We aimed to assess decision-making abilities under ambiguous situations associated with the presence of RBD in PD patients. METHODS: In this cross-sectional study, 60 non-demented PD patients with (PD-RBD, n = 40) and without (PD-nRBD, n = 20) video polysomnography-confirmed RBD, and 20 healthy controls matched for gender and age were included. All subjects underwent neurological and neuropsychological examination, including Iowa Gambling task designed to asses decision-making under uncertainty. RESULTS: IGT total score did not differ between groups (p = 0.851), however PD-RBD presented, more disadvantageous choices for the last blocks of IGT compared to PD-nRBD (p = 0.001) and to HC (p = 0.012). Progression of scores did not differ between HC and PD-nRBD. Multivariate analyses taking into account the value of scores at baseline, as well as the duration of PD, the duration of treatment, the presence of ICDs and MMSE confirmed those results. CONCLUSION: Decision making under uncertainty is impaired in PD-RBD compared to PD-nRBD and healthy controls, regardless to the duration of disease, treatment, cognitive status and the presence of ICDs. This could reflect an inability to learn from punishment or reward in PD-RBD, and could explain the increased risk to develop ICDs reported in those patients.

Structural and Functional Correlates of Hallucinations and Illusions in Parkinson's Disease.

BACKGROUND: Visual illusions (VI) in Parkinson's disease (PD) are generally considered as an early feature of the psychosis spectrum leading to fully formed visual hallucinations (VH), although this sequential relationship has not been clearly demonstrated. OBJECTIVE: We aimed to determine whether there are any overlapping, potentially graded patterns of structural and functional connectivity abnormalities in PD with VI and with VH. Such a finding would argue for a continuum between these entities, whereas distinct imaging features would suggest different neural underpinnings for the phenomena. METHODS: In this case control study, we compared structural and resting state functional MRI brain patterns of PD patients with VH (PD-H, n = 20), with VI (PD-I, n = 19), and without VH or VI (PD-C, n = 23). RESULTS: 1) PD-H had hypo-connectivity between the ILO and anterior cingulate precuneus and parahippocampal gyrus compared to PD-C and PD-I; 2) In contrast, PD-I had hyper-connectivity between the inferior frontal gyrus and the postcentral gyrus compared to PD-C and PD-H. Moreover, PD-I had higher levels of functional connectivity between the amygdala, hippocampus, insula, and fronto-temporal regions compared to PD-H, together with divergent patterns toward the cingulate. 3) Both PD-I and PD-H had functional hypo-connectivity between the lingual gyrus and the parahippocampal region vs. PD-C, and no significant grey matter volume differences was observed between PD-I and PD-H. CONCLUSION: Distinct patterns of functional connectivity characterized VI and VH in PD, suggesting that these two perceptual experiences, while probably linked and driven by at least some similar mechanisms, could reflect differing neural dysfunction.

Behavioral, Cellular and Molecular Responses to Cold and Mechanical Stimuli in Rats with Bilateral Dopamine Depletion in the Mesencephalic Dopaminergic Neurons.

Pain is the major non-motor symptom in Parkinson's disease (PD). Preclinical studies have mostly investigated mechanical pain by considering the decrease in a nociceptive threshold. Only a few studies have focused on thermal pain in animal models of PD. Therefore, the goal of this study was to assess the thermal nociceptive behavior of rats subjected to 6-hydroxydopamine (6-OHDA) administration, which constitutes an animal model of PD. Thermal plate investigation demonstrated significant thermal sensitivity to cold temperatures of 10 °C and 15 °C, and not to higher temperatures, in 6-OHDA-lesioned rats when compared with sham. 6-OHDA-lesioned rats also showed cold allodynia as demonstrated by a significant difference in the number of flinches, latency and reaction time to acetone stimulus. Ropinirole administration, a dopamine receptor 2 (D2R) agonist, blocked the acetone-induced cold allodynia in 6-OHDA-lesioned rats. In addition, mechanical hypersensitivity and static allodynia, as demonstrated by a significant difference in the vocalization threshold and pain score respectively, were noticed in 6-OHDA-lesioned rats. Acetone stimulus induced a significant increase in extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, a pain process molecular marker, in the spinal dorsal horn (SDH), the insular and cingulate cortices in 6-OHDA-lesioned rats when compared to sham. In 6-OHDA-lesioned rats, there was a significant augmentation in the expression of both protein kinase C gamma (PKCγ) and glutamate decarboxylase 67 (GAD67) in the SDH. This highlighted an increase in excitation and a decrease in inhibition in the SDH. Overall, the present study demonstrated a clear cold thermal hypersensitivity, in addition to a mechanical one, in 6-OHDA-lesioned rats.

Preoperative REM Sleep Behavior Disorder and Subthalamic Nucleus Deep Brain Stimulation Outcome in Parkinson Disease 1 Year After Surgery.

BACKGROUND AND OBJECTIVES: To determine whether patients with Parkinson disease (PD) eligible for subthalamic nucleus deep brain stimulation (STN-DBS) with probable REM sleep behavior disorder (RBD) preoperatively could be more at risk of poorer motor, nonmotor, and quality of life outcomes 12 months after surgery compared to those without RBD. METHODS: We analyzed the preoperative clinical profile of 448 patients with PD from a French multicentric prospective study (PREDISTIM) according to the presence or absence of probable RBD based on the RBD Single Question and RBD Screening Questionnaire. Among the 215 patients with PD with 12 months of follow-up after STN-DBS, we compared motor, cognitive, psycho-behavioral profile, and quality of life outcomes in patients with (pre-opRBD+) or without (pre-opRBD-) probable RBD preoperatively. RESULTS: At preoperative evaluation, pre-opRBD+ patients were older (61 ± 7.2 vs 59.5 ± 7.7 years; p = 0.02), had less motor impairment (Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] III "off": 38.7 ± 16.2 vs 43.4 ± 7.1; p = 0.03) but more nonmotor symptoms on daily living activities (MDS-UPDRS I: 12.6 ± 5.5 vs 10.7 ± 5.3; p < 0.001), had more psychobehavioral manifestations (Ardouin Scale of Behavior in Parkinson's Disease total: 7.7 ± 5.1 vs 5.1 ± 0.4; p = 0.003), and had worse quality of life (Parkinson's Disease Questionnaire-39: 33 ± 12 vs 29 ± 12; p = 0.03), as compared to pre-opRBD- patients. Both pre-opRBD+ and pre-opRBD- patients had significant MDS-UPDRS IV score decrease (-37% and -33%, respectively), MDS-UPDRS III "med 'off'/stim 'on'" score decrease (-52% and -54%), and dopaminergic treatment decrease (-52% and -49%) after surgery, with no between-group difference. There was no between-group difference for cognitive and global quality of life outcomes. CONCLUSIONS: In patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with a different clinical outcome 1 year after neurosurgery. TRIAL REGISTRATION INFORMATION: NCT02360683. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with PD eligible for STN-DBS, the presence of probable RBD preoperatively is not associated with poorer outcomes 1 year post surgery.