ON/OFF non-motor evaluation: a new way to evaluate non-motor fluctuations in Parkinson's disease.

BACKGROUND: NMF are currently poorly evaluated in therapeutic decisions. A quantification of their severity would facilitate their integration. The objective of this study was to validate an autoquestionnaire evaluating the severity of non-motor fluctuations (NMF) in Parkinson's disease (PD). METHODS: Patients with PD were included in presurgical situation for deep brain stimulation of subthalamic nuclei. They participated in the PREDISTIM cohort (a study evaluating the predictive factors for therapeutic response of subthalamic stimulation in PD) in 17 centres in France. Our questionnaire, resulting from previous phases of development, included 11 non-motor symptoms (NMS). Their severity ranged from 0 to 10 and was assessed in OFF and then ON-Dopa to study their fluctuations. RESULTS: 310 patients were included, of whom 98.8% had NMS and 98.0% had NMF. Each NMS was significantly improved by L-Dopa (decrease in severity score ranging from 43.1% to 69.9%). Fatigue was the most frequent and most severe NMS. NMS were considered more bothersome than motor symptoms by 37.5% of patients in OFF-Dopa and 34.9% in ON-Dopa. CONCLUSIONS: This is the first questionnaire allowing a real-time quantification of the severity of NMS and their fluctuation with levodopa. It was able to confirm and measure the effect of L-dopa and show differences according to the patients and the NMS. It differs from other questionnaires by its measurement at a precise moment of the severity of the NMS, allowing its use during pretherapeutic assessments.Our questionnaire has been validated to measure the severity of NMF. It will be able to quantify the non-motor effect of anti-parkinsonian treatments and could facilitate the integration of NMF in therapeutic decisions.

Results of a Randomized Clinical Trial of Speech After Early Neurostimulation in Parkinson's Disease.

BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deep Brain Stimulation-Withdrawal Syndrome in Parkinson's Disease: Risk Factors and Pathophysiological Hypotheses of a Life-Threatening Emergency.

BACKGROUND AND OBJECTIVES: Subthalamic nucleus deep brain stimulation (DBS) is the most common therapeutic surgical procedure for patients with Parkinson's disease with motor fluctuations, dyskinesia, or tremor. Routine follow-up of patients allows clinicians to anticipate replacement of the DBS battery reaching the end of its life. Patients who experience a sudden stop of the DBS battery experience a rapid worsening of symptoms unresponsive to high dose of levodopa, in a life-threatening phenomenon called "DBS-withdrawal syndrome." In the current context of the COVID-19 pandemic, in which many surgeries are being deprogrammed, it is of utmost importance to determine to what extent DBS battery replacement surgeries should be considered an emergency. In this study, we attempt to identify risk factors of DBS-withdrawal syndrome and provide new insights about pathophysiological hypotheses. We then elaborate on the optimal approach to avoid and manage such a situation. MATERIALS AND METHODS: We conducted a systematic review of the literature on the subject and reported the cases of 20 patients (including five from our experience) with DBS-withdrawal syndrome, comparing them with 15 undisturbed patients (including three from our experience), all having undergone neurostimulation discontinuation. RESULTS: A long disease duration at battery removal and many years of DBS therapy are the main potential identified risk factors (p < 0.005). In addition, a trend for older age at the event and higher Unified Parkinson's Disease Rating Scale motor score before initial DBS implantation (evaluated in OFF-drug condition) was found (p < 0.05). We discuss several hypotheses that might explain this phenomenon, including discontinued functioning of the thalamic-basal ganglia loop due to DBS-stimulation cessation in a context in which cortical-basal ganglia loop had lost its cortical input, and possible onset of a severe bradykinesia through the simultaneous occurrence of an alpha and high-beta synchronized state. CONCLUSIONS: The patients' clinical condition may deteriorate rapidly, be unresponsive to high dose of levodopa, and become life-threatening. Hospitalization is suggested for clinical monitoring. In the context of the current COVID-19 pandemic, it is important to widely communicate the replacement of DBS batteries reaching the end of their life. More importantly, in cases in which the battery has stopped, there should be no delay in performing replacement as an emergent surgery.

The Contribution of Subthalamic Nucleus Deep Brain Stimulation to the Improvement in Motor Functions and Quality of Life.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Early atypical signs and insula hypometabolism predict survival in multiple system atrophy.

OBJECTIVE: We aim to search for predictors of survival among clinical and brain 18F-FDG positron emission tomography (PET) metabolic features in our cohort of patients with multiple system atrophy (MSA). METHODS: We included patients with a 'probable' MSA diagnosis for whom a clinical evaluation and a brain PET were performed early in the course of the disease (median 3 years, IQR 2-5). A retrospective analysis was conducted using standardised data collection. Brain PET metabolism was characterised using the Automated Anatomical Labelling Atlas. A Cox model was applied to look for factors influencing survival. Kaplan-Meier method estimated the survival rate. We proposed to develop a predictive 'risk score', categorised into low-risk and high-risk groups, using significant variables entered in multivariate Cox regression analysis. RESULTS: Eighty-five patients were included. The overall median survival was 8 years (CI 6.64 to 9.36). Poor prognostic factors were orthostatic hypotension (HR=6.04 (CI 1.58 to 23.12), p=0.009), stridor (HR=3.41 (CI 1.31 to 8.87), p=0.012) and glucose PET hypometabolism in the left insula (HR=0.78 (CI 0.66 to 0.92), p=0.004). Good prognostic factors were time to diagnosis (HR=0.68 (CI 0.54 to 0.86), p=0.001) and use of selective serotonin reuptake inhibitor (SSRI) (HR=0.17 (CI 0.06 to 0.46), p<0.001). The risk score revealed a 5-year gap separating the median survival of the two groups obtained (5 years vs 10 years; HR=5.82 (CI 2.94 to 11.49), p<0.001). CONCLUSION: The clinical prognosis factors we have described support published studies. Here, we also suggest that brain PET is of interest for prognosis assessment and in particular in the search for left insula hypometabolism. Moreover, SSRIs are a potential drug candidate to slow the progression of the disease.

The Brain Connectome after Gamma Knife Radiosurgery of the Ventro-Intermediate Nucleus for Tremor: Marseille-Lausanne Radiobiology Study Protocol.

Essential tremor (ET) is the most common movement disorder. Deep brain stimulation is the current gold standard for drug-resistant tremor, followed by radiofrequency lesioning. Stereotactic radiosurgery by Gamma Knife (GK) is considered as a minimally invasive alternative. The majority of procedures aim at the same target, thalamic ventro-intermediate nucleus (Vim). The primary aim is to assess the clinical response in relationship to neuroimaging changes, both at structural and functional level. All GK treatments are uniformly performed in our center using Guiot's targeting and a radiation dose of 130 Gy. MR neuroimaging protocol includes structural imaging (T1-weighted and diffusion-weighted imaging [DWI]), resting-state functional MRI, and 18F-fluorodeoxyglucose-positron emission tomography. Neuroimaging changes are studied both at the level of the cerebello-thalamo-cortical tract (using the prior hypothesis based upon Vim's circuitry: motor cortex, ipsilateral Vim, and contralateral cerebellar dentate nucleus) and also at global brain level (no prior hypothesis). This protocol aims at using modern neuroimaging techniques for studying Vim GK radiobiology for tremor, in relationship to clinical effects, particularly in ET patients. In perspective, using such an approach, patient selection could be based upon a specific brain connectome profile.

Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease With Early Motor Complications.

BACKGROUND: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.

Effects of subthalamic nucleus stimulation and levodopa on decision-making in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is frequently associated with behavioral disorders, particularly within the spectrum of motivated behaviors such as apathy or impulsivity. Both pharmacological and neurosurgical treatments have an impact on these impairments. However, there still is controversy as to whether subthalamic nucleus deep brain stimulation (STN-DBS) can cause or reduce impulsive behaviors. OBJECTIVES: We aimed to identify the influence of functional surgery on decision-making processes in PD. METHODS: We studied 13 PD patients and 13 healthy controls. The experimental task involved squeezing a dynamometer with variable force to obtain rewards of various values under four conditions: without treatment, with l-dopa or subthalamic stimulation alone, and with both l-dopa and subthalamic stimulation. Statistical analyses consisted of generalized linear mixed models including treatment condition, reward value, level of effort, and their interactions. We analyzed acceptance rate (the percentage of accepted trials), decision time, and force applied. RESULTS: Comparatively to controls, patients without treatment exhibited lower acceptance rate and force applied. Patients under l-dopa alone did not exhibit increased acceptance rate. With subthalamic stimulation, either with or without added l-dopa, all measures were improved so that patients' behaviors were undistinguishable from healthy controls'. CONCLUSIONS: Our study shows that l-dopa administration does not fully restore cost-benefit decision-making processes, whereas STN-DBS fully normalizes patients' behaviors. These findings suggest that dopamine is partly involved in cost-benefit valuation, and that STN-DBS can have a beneficial effect on motivated behaviors in PD and may improve certain forms of impulsive behaviors. © 2019 International Parkinson and Movement Disorder Society.

Deep brain stimulation does not enhance neuroinflammation in multiple system atrophy.

Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.

Beta burst coupling across the motor circuit in Parkinson's disease.

Exaggerated activity in the beta band (13-35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.

Brain PET substrate of impulse control disorders in Parkinson's disease: A metabolic connectivity study.

Impulse control disorders (ICDs) have received increased attention in Parkinson's disease (PD) because of potentially dramatic consequences. Their physiopathology, however, remains incompletely understood. An overstimulation of the mesocorticolimbic system has been reported, while a larger network has recently been suggested. The aim of this study is to specifically describe the metabolic PET substrate and related connectivity changes in PD patients with ICDs. Eighteen PD patients with ICDs and 18 PD patients without ICDs were evaluated using cerebral 18F-fluorodeoxyglucose positron emission tomography. SPM-T maps comparisons were performed between groups and metabolic connectivity was evaluated by interregional correlation analysis (IRCA; p < .005, uncorrected; k > 130) and by graph theory (p < .05). PD patients with ICDs had relative increased metabolism in the right middle and inferior temporal gyri compared to those without ICDs. The connectivity of this area was increased mostly with the mesocorticolimbic system, positively with the orbitofrontal region, and negatively with both the right parahippocampus and the left caudate (IRCA). Moreover, the betweenness centrality of this area with the mesocorticolimbic system was lost in patients with ICDs (graph analysis). ICDs are associated in PD with the dysfunction of a network exceeding the mesocorticolimbic system, and especially the caudate, the parahippocampus, and the orbitofrontal cortex, remotely including the right middle and inferior temporal gyri. This latest area loses its central place with the mesocorticolimbic system through a connectivity dysregulation.

Clinical response to Vim's thalamic stereotactic radiosurgery for essential tremor is associated with distinctive functional connectivity patterns.

INTRODUCTION: Essential tremor (ET) is the most common movement disorder. Drug-resistant ET can benefit from standard surgical stereotactic procedures (deep brain stimulation, thalamotomy) or minimally invasive high-intensity focused ultrasound (HIFU) or stereotactic radiosurgical thalamotomy (SRS-T). Resting-state fMRI (rs-fMRI) is a non-invasive imaging method acquired in absence of a task. We examined whether rs-fMRI correlates with tremor score on the treated hand (TSTH) improvement 1 year after SRS-T. METHODS: We included 17 consecutive patients treated with left unilateral SRS-T in Marseille, France. Tremor score evaluation and rs-fMRI were acquired at baseline and 1 year after SRS-T. Resting-state data (34 scans) were analyzed without a priori hypothesis, in Lausanne, Switzerland. Based on degree of improvement in TSTH, to consider SRS-T at least as effective as medication, we separated two groups: 1, ≤ 50% (n = 6, 35.3%); 2, > 50% (n = 11, 64.7%). They did not differ statistically by age (p = 0.86), duration of symptoms (p = 0.41), or lesion volume at 1 year (p = 0.06). RESULTS: We report TSTH improvement correlated with interconnectivity strength between salience network with the left claustrum and putamen, as well as between bilateral motor cortices, frontal eye fields and left cerebellum lobule VI with right visual association area (the former also with lesion volume). Longitudinal changes showed additional associations in interconnectivity strength between right dorsal attention network with ventro-lateral prefrontal cortex and a reminiscent salience network with fusiform gyrus. CONCLUSIONS: Brain connectivity measured by resting-state fMRI relates to clinical response after SRS-T. Relevant networks are visual, motor, and attention. Interconnectivity between visual and motor areas is a novel finding, revealing implication in movement sensory guidance.

Right Brodmann area 18 predicts tremor arrest after Vim radiosurgery: a voxel-based morphometry study.

INTRODUCTION: Drug-resistant essential tremor (ET) can benefit from open standard stereotactic procedures, such as deep-brain stimulation or radiofrequency thalamotomy. Non-surgical candidates can be offered either high-focused ultrasound (HIFU) or radiosurgery (RS). All procedures aim to target the same thalamic site, the ventro-intermediate nucleus (e.g., Vim). The mechanisms by which tremor stops after Vim RS or HIFU remain unknown. We used voxel-based morphometry (VBM) on pretherapeutic neuroimaging data and assessed which anatomical site would best correlate with tremor arrest 1 year after Vim RS. METHODS: Fifty-two patients (30 male, 22 female; mean age 71.6 years, range 49-82) with right-sided ET benefited from left unilateral Vim RS in Marseille, France. Targeting was performed in a uniform manner, using 130 Gy and a single 4-mm collimator. Neurological (pretherapeutic and 1 year after) and neuroimaging (baseline) assessments were completed. Tremor score on the treated hand (TSTH) at 1 year after Vim RS was included in a statistical parametric mapping analysis of variance (ANOVA) model as a continuous variable with pretherapeutic neuroimaging data. Pretherapeutic gray matter density (GMD) was further correlated with TSTH improvement. No a priori hypothesis was used in the statistical model. RESULTS: The only statistically significant region was right Brodmann area (BA) 18 (visual association area V2, p = 0.05, cluster size Kc = 71). Higher baseline GMD correlated with better TSTH improvement at 1 year after Vim RS (Spearman's rank correlation coefficient = 0.002). CONCLUSIONS: Routine baseline structural neuroimaging predicts TSTH improvement 1 year after Vim RS. The relevant anatomical area is the right visual association cortex (BA 18, V2). The question whether visual areas should be included in the targeting remains open.

The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making.

Adaptive behaviour entails the capacity to select actions as a function of their energy cost and expected value and the disruption of this faculty is now viewed as a possible cause of the symptoms of Parkinson's disease. Indirect evidence points to the involvement of the subthalamic nucleus-the most common target for deep brain stimulation in Parkinson's disease-in cost-benefit computation. However, this putative function appears at odds with the current view that the subthalamic nucleus is important for adjusting behaviour to conflict. Here we tested these contrasting hypotheses by recording the neuronal activity of the subthalamic nucleus of patients with Parkinson's disease during an effort-based decision task. Local field potentials were recorded from the subthalamic nucleus of 12 patients with advanced Parkinson's disease (mean age 63.8 years ± 6.8; mean disease duration 9.4 years ± 2.5) both OFF and ON levodopa while they had to decide whether to engage in an effort task based on the level of effort required and the value of the reward promised in return. The data were analysed using generalized linear mixed models and cluster-based permutation methods. Behaviourally, the probability of trial acceptance increased with the reward value and decreased with the required effort level. Dopamine replacement therapy increased the rate of acceptance for efforts associated with low rewards. When recording the subthalamic nucleus activity, we found a clear neural response to both reward and effort cues in the 1-10 Hz range. In addition these responses were informative of the subjective value of reward and level of effort rather than their actual quantities, such that they were predictive of the participant's decisions. OFF levodopa, this link with acceptance was weakened. Finally, we found that these responses did not index conflict, as they did not vary as a function of the distance from indifference in the acceptance decision. These findings show that low-frequency neuronal activity in the subthalamic nucleus may encode the information required to make cost-benefit comparisons, rather than signal conflict. The link between these neural responses and behaviour was stronger under dopamine replacement therapy. Our findings are consistent with the view that Parkinson's disease symptoms may be caused by a disruption of the processes involved in balancing the value of actions with their associated effort cost.

Assessing the clinical outcome of Vim radiosurgery with voxel-based morphometry: visual areas are linked with tremor arrest!

INTRODUCTION: Radiosurgery (RS) is an alternative to open standard stereotactic procedures (deep-brain stimulation or radiofrequency thalamotomy) for drug-resistant essential tremor (ET), aiming at the same target (ventro-intermediate nucleus, Vim). We investigated the Vim RS outcome using voxel-based morphometry by evaluating the interaction between clinical response and time. METHODS: Thirty-eight patients with right-sided ET benefited from left unilateral Vim RS. Targeting was performed using 130 Gy and a single 4-mm collimator. Neurological and neuroimaging assessment was completed at baseline and 1 year. Clinical responders were considered those with at least 50% improvement in tremor score on the treated hand (TSTH). RESULTS: Interaction between clinical response and time showed the left temporal pole and occipital cortex (Brodmann area 19, including V4, V5 and the parahippocampal place area) as statistically significant. A decrease in gray matter density (GMD) 1 year after Vim RS correlated with higher TSTH improvement (Spearman = 0.01) for both anatomical areas. Higher baseline GMD within the left temporal pole correlated with better TSTH improvement (Spearman = 0.004). CONCLUSIONS: Statistically significant structural changes in the relationship to clinical response after Vim RS are present in remote areas, advocating a distant neurobiological effect. The former regions are mainly involved in locomotor monitoring toward the local and distant environment, suggesting the recruiting requirement in targeting of the specific visuomotor networks.

A preoperative metabolic marker of parkinsonian apathy following subthalamic nucleus stimulation.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD) has been associated with the development of postoperative apathy. Debate on the causes of postoperative apathy continues, and the dominant hypothesis is that stimulation or dopaminergic drug reductions are causal in its development. We hypothesized that a preoperative predisposition to apathy also could exist. To this end, we sought to identify a preoperative metabolic pattern using [(18)]Fluorodeoxyglucose Positron Emission Tomography (PET), which could be associated with the occurrence of postoperative apathy after STN-DBS for PD. METHODS: Thirty-four patients with PD, not clinically apathetic, underwent an [(18)]Fluorodeoxyglucose-PET scan before surgery of STN-DBS, and were tested for the occurrence of apathy 1 y after surgery. Whole-brain voxel-based PET intergroup comparison (P < 0.005; corrected for the cluster) was evaluated between patients who developed apathy at 1 y and those who did not. RESULTS: Eight patients (23.5%) became apathetic after surgery. Motor improvement and decrease in dopaminergic treatment were similar in both postoperative apathy and non-apathy groups. We found a cluster of significantly greater metabolism in the postoperative apathy group within the cerebellum, brainstem (in particular ventral tegmental area), temporal lobe, insula, amygdala, lentiform nucleus, subgenual anterior cingulate, and inferior frontal gyrus. A metabolic value above 68 could discriminate patients who would develop postoperative apathy with 100% sensitivity and 88.5% specificity. CONCLUSIONS: We describe a preoperative metabolic pattern associated with the development of apathy after STN-DBS in PD. This suggests the existence of a predisposition to apathy, which may further be triggered by perioperative drug modifications.

Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial.

BACKGROUND: Even with optimal dopaminergic treatments, many patients with Parkinson's disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine's ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. METHODS: We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. FINDING: 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from -11.5 (-15/-7) at baseline to -20 (-25/-12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: -0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. INTERPRETATION: Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. REGISTRATION: Clinicaltrials.gov reference: NCT00767091.