Noradrenergic alterations in Parkinson's disease: a combined 11C-yohimbine PET/neuromelanin MRI study.

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included.

Efficacy and safety of clonidine for the treatment of impulse control disorder in Parkinson's disease: a multicenter, parallel, randomised, double-blind, Phase 2b Clinical trial.

Background: Impulse control disorders (ICDs) are frequently encountered in Parkinson's disease (PD).

Objectives: We aimed to assess whether clonidine, an α2-adrenergic receptor agonist, would improve ICDs.

Methods: We conducted a multicentre trial in five movement disorder departments.

Distribution of α-Adrenergic Receptors in the Living Human Brain Using [C]yohimbine PET.

The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20-50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α-ARs) availability in the living human brain. The global map shows the highest [C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe.

Noradrenaline and Movement Initiation Disorders in Parkinson's Disease: A Pharmacological Functional MRI Study with Clonidine.

Slowness of movement initiation is a cardinal motor feature of Parkinson's disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols.

Modeling [C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region.

Unlabelled: Previous work introduced the [C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap.

The Human Basal Ganglia Mediate the Interplay between Reactive and Proactive Control of Response through Both Motor Inhibition and Sensory Modulation.

The basal ganglia (BG) have long been known for contributing to the regulation of motor behaviour by means of a complex interplay between tonic and phasic inhibitory mechanisms. However, after having focused for a long time on phasic reactive mechanisms, it is only recently that psychological research in healthy humans has modelled tonic proactive mechanisms of control. Mutual calibration between anatomo-functional and psychological models is still needed to better understand the unclear role of the BG in the interplay between proactive and reactive mechanisms of control.

Inhibitory control dysfunction in parkinsonian impulse control disorders.

Impulse control disorders (ICDs) in Parkinson's disease have been associated with dysfunctions in the control of value- or reward-based responding (choice impulsivity) and abnormalities in mesocorticolimbic circuits. The hypothesis that dysfunctions in the control of response inhibition (action impulsivity) also play a role in Parkinson's disease ICDs has recently been raised, but the underlying neural mechanisms have not been probed directly. We used high-resolution EEG recordings from 41 patients with Parkinson's disease with and without ICDs to track the spectral and dynamical signatures of different mechanisms involved in inhibitory control in a simple visuomotor task involving no selection between competing responses and no reward to avoid potential confounds with reward-based decision.

Resting state oscillations suggest a motor component of Parkinson's Impulse Control Disorders.

Objectives: Impulse control disorders (ICDs) in Parkinson's disease (PD) have been associated with cognitive impulsivity and dopaminergic dysfunction and treatment. The present study tests the neglected hypothesis that the neurofunctional networks involved in motor impulsivity might also be dysfunctional in PD-ICDs.

Methods: We performed blind spectral analyses of resting state electroencephalographic (EEG) data in PD patients with and without ICDs to probe the functional integrity of all cortical networks.

Odorants: a tool to provide nonpharmacological intervention to reduce anxiety during normal and pathological aging.

Anxiety disorders represent 1 of the most common classes of psychiatric disorders. In the aging population and for patients with age-related pathology, the percentage of people suffering of anxiety is significantly elevated. Furthermore, anxiety carries with it an increased risk for a variety of age-related medical conditions, including cardiovascular disease, stroke, cognitive decline, and increased severity of motor symptoms in Parkinson's disease.

Functional imaging studies of Impulse Control Disorders in Parkinson's disease need a stronger neurocognitive footing.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are associated with dopaminergic dysfunction and treatment, but have no satisfactory therapeutic solution. While studies assessing the neurofunctional bases of ICDs are important for advancing our understanding and management of ICDs, they remain sparse and inconsistent. Based on a systematic analysis of the neuroimaging literature, the present review pinpoints various abnormalities beyond the mesocorticolimbic circuit that supports reward processing, suggesting possible dysfunction at the sensorimotor, executive and affective levels.

Functional imaging correlates of akinesia in Parkinson's disease: Still open issues.

Akinesia is a major manifestation of Parkinson's disease (PD) related to difficulties or failures of willed movement to occur. Akinesia is still poorly understood and is not fully alleviated by standard therapeutic strategies. One reason is that the area of the clinical concept has blurred boundaries referring to confounded motor symptoms.

Removing deep brain stimulation artifacts from the electroencephalogram: Issues, recommendations and an open-source toolbox.

A major question for deep brain stimulation (DBS) research is understanding how DBS of one target area modulates activity in different parts of the brain. EEG gives privileged access to brain dynamics, but its use with implanted patients is limited since DBS adds significant high-amplitude electrical artifacts that can completely obscure neural activity measured using EEG. Here, we systematically review and discuss the methods available for removing DBS artifacts.

Clonidine modulates the activity of the subthalamic-supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients.

Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine.

Testing the physiological plausibility of conflicting psychological models of response inhibition: A forward inference fMRI study.

The neural mechanisms underlying response inhibition and related disorders are unclear and controversial for several reasons. First, it is a major challenge to assess the psychological bases of behaviour, and ultimately brain-behaviour relationships, of a function which is precisely intended to suppress overt measurable behaviours. Second, response inhibition is difficult to disentangle from other parallel processes involved in more general aspects of cognitive control.

Molecular imaging to track Parkinson's disease and atypical parkinsonisms: New imaging frontiers.

Molecular imaging has proven to be a powerful tool for investigation of parkinsonian disorders. One current challenge is to identify biomarkers of early changes that may predict the clinical trajectory of parkinsonian disorders. Exciting new tracer developments hold the potential for in vivo markers of underlying pathology.

Slowness in Movement Initiation is Associated with Proactive Inhibitory Network Dysfunction in Parkinson's Disease.

Background: Impairment in initiating movements in PD might be related to executive dysfunction associated with abnormal proactive inhibitory control, a pivotal mechanism consisting in gating movement initiation in uncertain contexts.

Objective: Testing this hypothesis on the basis of direct neural-based evidence.

Methods: Twelve PD patients on antiparkinsonian medication and fifteen matched healthy controls performed a simple reaction time task during event-related functional MRI scanning.

Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms.

Unlabelled: It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET.

Contribution of insula in Parkinson's disease: A quantitative meta-analysis study.

The insula region is known to be an integrating hub interacting with multiple brain networks involved in cognitive, affective, sensory, and autonomic processes. There is growing evidence suggesting that this region may have an important role in Parkinson's disease (PD). Thus, to investigate the functional organization of the insular cortex and its potential role in parkinsonian features, we used a coordinate-based quantitative meta-analysis approach, the activation likelihood estimation.

Behavioural impact of a double dopaminergic and serotonergic lesion in the non-human primate.

Serotonergic (5-HT) neurons degenerate in Parkinson's disease. To determine the role of this 5-HT injury-besides the dopaminergic one in the parkinsonian symptomatology-we developed a new monkey model exhibiting a double dopaminergic/serotonergic lesion by sequentially using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 3,4-methylenedioxy-N-methamphetamine (MDMA, better known as ecstasy). By positron emission tomography imaging and immunohistochemistry, we demonstrated that MDMA injured 5-HT nerve terminals in the brain of MPTP monkeys.

Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease.

Background: Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic).

A functional magnetic resonance imaging study of pathophysiological changes responsible for mirror movements in Parkinson's disease.

Mirror movements correspond to involuntary movements observed in the limb contralateral to the one performing voluntary movement. They can be observed in Parkinson's disease (PD) but their pathophysiology remains unclear. The present study aims at identifying their neural correlates in PD using functional magnetic resonance imaging.

A multi-atlas based method for automated anatomical Macaca fascicularis brain MRI segmentation and PET kinetic extraction.

Unlabelled: MRI templates and digital atlases are needed for automated and reproducible quantitative analysis of non-human primate PET studies. Segmenting brain images via multiple atlases outperforms single-atlas labelling in humans. We present a set of atlases manually delineated on brain MRI scans of the monkey Macaca fascicularis.

Deep brain stimulation of the subthalamic nucleus, but not dopaminergic medication, improves proactive inhibitory control of movement initiation in Parkinson's disease.

Slowness in movement initiation is a cardinal feature of Parkinson's disease (PD) that is still poorly understood and unsuccessfully alleviated by standard therapies. Here, we raise this major clinical issue within the framework of a novel theoretical model that allows a better understanding of the basic mechanisms involved in movement initiation. This model assumes that movement triggering is inhibited by default to prevent automatic responses to unpredictable events.

Effects of dopamine and serotonin antagonist injections into the striatopallidal complex of asymptomatic MPTP-treated monkeys.

The cardinal symptoms of Parkinson's disease (PD), akinesia, rigidity and tremor, are only observed when the striatal level of dopamine (DA) is decreased by 60-80%. It is likely that compensatory mechanisms during the early phase of DA depletion delay the appearance of motor symptoms. In a previous study, we proposed a new PD monkey model with progressive MPTP intoxication.