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. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease.

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. Patients with PD and ICDs (n = 41) were enrolled in an 8-week, randomised (1:1), double-blind, placebo-controlled study of clonidine (75 µg twice a day). Randomisation and allocation to the trial group were carried out by a central computer system. The primary outcome was the change at 8 weeks in symptom severity using the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) score. A reduction of the most elevated subscore of the QUIP-RS of more than 3 points without any increase in the other QUIP-RS dimension defined success. RESULTS: Between 15 May 2019 and 10 September 2021, 19 patients in the clonidine group and 20 patients in the placebo group were enrolled. The proportion difference of success in reducing QUIP-RS at 8 weeks, was 7% (one-sided upper 90% CI 27%) with 42.1% of success in the clonidine group and 35.0% in the placebo group. Compared to patients in the placebo group, patients in the clonidine group experienced a greater reduction in the total QUIP-RS score at 8 weeks (11.0 points vs. 3.6). DISCUSSION: Clonidine was well tolerated but our study was not enough powerful to demonstrate significant superiority compared to placebo in reducing ICDs despite a greater reduction of total QUIP score at 8 weeks. A phase 3 study should be conducted. TRIAL REGISTRATION: The study was registered (NCT03552068) on clinicaltrials.gov on June 11, 2018.

Distribution of α2-Adrenergic Receptors in the Living Human Brain Using [11C]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 [11C]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' (α2-ARs) availability in the living human brain. The global map shows the highest [11C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [11C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α2-ARs is suspected.

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. For that purpose, we administered 150 µg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson's disease.

Modeling [11C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region.

Previous work introduced the [11C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [11C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [11C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap. METHODS: Thirteen healthy humans underwent two [11C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested. RESULTS: We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTMCC (r2=0.94). Test-retest showed that the SRTMCC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTMCERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTMCC, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis. CONCLUSION: The results add experimental support for the suitability of [11C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.

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. Here, we implemented an event-related fMRI design allowing proper analysis of both the brain activity preceding the target-stimulus and the brain activity induced by the target-stimulus during a simple go/nogo task, with a particular interest in the ambiguous role of the basal ganglia. Post-stimulus activity was evoked in the left dorsal striatum, the subthalamus nucleus and internal globus pallidus by any stimulus when the situation was unpredictable, pinpointing its involvement in reactive, non-selective inhibitory mechanisms when action restraint is required. Pre-stimulus activity was detected in the ventral, not the dorsal, striatum, when the situation was unpredictable, and was associated with changes in functional connectivity with the early visual, not the motor, cortex. This suggests that the ventral striatum supports modulatory influence over sensory processing during proactive 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. Behaviourally, patients with Parkinson's disease with ICDs proved to be more impulsive than those without ICDs. This was associated with decreased beta activity in the precuneus and in a region of the medial frontal cortex centred on the supplementary motor area. The underlying dynamical patterns pinpointed dysfunction of proactive inhibitory control, an executive mechanism intended to gate motor responses in anticipation of stimulation in uncertain contexts. The alteration of the cortical drive of proactive response inhibition in Parkinson's disease ICDs pinpoints the neglected role the precuneus might play in higher order executive functions in coordination with the supplementary motor area, specifically for switching between executive settings. Clinical perspectives are discussed in the light of the non-dopaminergic basis of this function.

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. Analyses were performed directly at the source level after blind source separation. Discrete differences between groups were tested by comparing patients with and without ICDs. Gradual dysfunctions were assessed by means of correlations between power changes and clinical scores reflecting ICD severity (QUIP score). RESULTS: Spectral signatures of ICDs were found in the medial prefrontal cortex, the dorsal anterior cingulate and the supplementary motor area, in the beta and gamma bands. Beta power changes in the supplementary motor area were found to predict ICDs severity. CONCLUSION: ICDs are associated with abnormal activity within frequency bands and cortical circuits supporting the control of motor response inhibition. SIGNIFICANCE: These results bring to the forefront the need to consider, in addition to the classical interpretation based on aberrant mesocorticolimbic reward processing, the issue of motor impulsivity in PD-ICDs and its potential implications for PD therapy.

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. A variety of anxiolytic compounds are available but often carry with them disturbing side effects that impact quality of life. Among nonmedicinal approaches to reducing anxiety, odor diffusion and aromatherapy are the most popular. In this review, we highlight the emerging perspective that the use of odorants may reduce anxiety symptoms or at least potentiate the effect of other anxiolytic approaches and may serve as an alternative form of therapy to deal with anxiety symptoms. Such approaches may be particularly beneficial in aging populations with elevated risk for these disorders. We also discuss potential neural mechanisms underlying the anxiolytic effects of odorants based on work in animal models.

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. We advocate that: 1) Future studies should use more sophisticated psychological models and behavioral designs that take into account the potentially multifaceted aspect of ICDs; this would allow a more accurate assessment of the underlying neurocognitive processes, which are not all dependent on the dopaminergic system. 2) Future neuroimaging studies should rely more strongly on task-based, event-related analyses to disentangle the various mechanisms that can be dysfunctional in ICDs. We believe these guidelines constitute a prerequisite towards distinguishing causes, correlates and individual susceptibility factors of PD patients with ICDs.

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. Here, we review neuroimaging studies which, by providing access to finer-grained mechanisms, have the potential to reveal the dysfunctional brain processes that account for akinesia. It comes out that no clear common denominator could be identified across studies that are too heterogeneous with respect to the clinical/theoretical concepts and methods used. Results reveal, however, that various abnormalities within but also outside the motor and dopaminergic pathways might be associated with akinesia in PD patients. Notably, numerous yet poorly reproducible neural correlates were found in different brain regions supporting executive control by means of resting-state or task-based studies. This includes for instance the dorsolateral prefrontal cortex, the inferior frontal cortex, the supplementary motor area, the medial prefrontal cortex, the anterior cingulate cortex or the precuneus. This observation raises the issue of the multidimensional nature of akinesia. Yet, other open issues should be considered conjointly to drive future investigations. Above all, a unified terminology is needed to allow appropriate association of behavioral symptoms with brain mechanisms across studies. We adhere to a use of the term akinesia restricted to dysfunctions of movement initiation, ranging from delayed response to freezing or even total abolition of movement. We also call for targeting more specific neural mechanisms of movement preparation and action triggering with more sophisticated behavioral designs/event-related neurofunctional analyses. More work is needed to provide reliable evidence, but answering these still open issues might open up new prospects, beyond dopaminergic therapy, for managing this disabling symptom.

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. These include simple techniques such as oversampling, antialiasing analog filtering and digital low-pass filtering, which are necessary but typically not sufficient to fully remove DBS artifacts when each is used in isolation. We also cover more advanced methods, including techniques tracking outliers in the frequency-domain, which can be effective, but are rarely used. The reason for that is twofold: First, it requires advanced skills in signal processing since no user friendly tool for removing DBS artifacts is currently available. Second, it involves fine-tuning to avoid over-aggressive filtering. We highlight an open-source toolbox incorporating most artifact removal methods, allowing users to combine different strategies.

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. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.

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. Consequently, different psychological and anatomo-functional models coexist, which often appear in conflict with each other even though they are not necessarily mutually exclusive. The standard model of response inhibition in go/no-go tasks assumes that inhibitory processes are reactively and selectively triggered by the stimulus that participants must refrain from reacting to. Recent alternative models suggest that action restraint could instead rely on reactive but non-selective mechanisms (all automatic responses are automatically inhibited in uncertain contexts) or on proactive and non-selective mechanisms (a gating function by which reaction to any stimulus is prevented in anticipation of stimulation when the situation is unpredictable). Here, we assessed the physiological plausibility of these different models by testing their respective predictions regarding event-related BOLD modulations (forward inference using fMRI). We set up a single fMRI design which allowed for us to record simultaneously the different possible forms of inhibition while limiting confounds between response inhibition and parallel cognitive processes. We found BOLD dynamics consistent with non-selective models. These results provide new theoretical and methodological lines of inquiry for the study of basic functions involved in behavioural control and related disorders.

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. Herein, we provide an overview of molecular imaging advances and how these approaches help us to understand PD and atypical parkinsonisms. © 2016 International Parkinson and Movement Disorder Society.

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. RESULTS: For all subjects, the level of activation of SMA was found to predict RT on a trial-by-trial basis. The increase in movement initiation latency observed in PD patients with regard to controls was associated with pre-stimulus BOLD increases within several nodes of the proactive inhibitory network (caudate nucleus, precuneus, thalamus). CONCLUSIONS: These results provide physiological data consistent with impaired control of proactive inhibition over motor initiation in PD. Patients would be locked into a mode of control maintaining anticipated inhibition over willed movements even when the situation does not require action restraint. The functional and neurochemical bases of brain activity associated with executive settings need to be addressed thoroughly in future studies to better understand disabling symptoms that have few therapeutic options like akinesia.

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

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. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([(18)F]DOPA), dopamine D2/D3 receptors ([(11)C]raclopride), and serotonin transporter (11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB) and serotonin 1A receptor ([(18)F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [(18)F]DOPA uptake in the anterior putamen, [(11)C]raclopride binding in the posterior striatum, and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine [(18)F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [(11)C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [(18)F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD. SIGNIFICANCE STATEMENT: The present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.

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. A total of 132 insular foci were selected from 96 published experiments comprising the five functional categories: cognition, affective/behavioral symptoms, bodily awareness/autonomic function, sensorimotor function, and nonspecific resting functional changes associated with the disease. We found a significant convergence of activation maxima related to PD in different insular regions including anterior and posterior regions bilaterally. This study provides evidence of an important functional distribution of different domains within the insular cortex in PD, particularly in relation to nonmotor aspects, with an influence of medication effect.

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. Unexpectedly, this injury had no impact on tremor or on bradykinesia, but altered rigidity. It abolished the l-DOPA-induced dyskinesia and neuropsychiatric-like behaviours, without altering the anti-parkinsonian response. These data demonstrate that 5-HT fibres play a critical role in the expression of both motor and non-motor symptoms in Parkinson's disease, and highlight that an imbalance between the 5-HT and dopaminergic innervating systems is involved in specific basal ganglia territories for different symptoms.

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). OBJECTIVE: To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. METHODS: Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 µg oral dose of clonidine (ON- or OFF-DBS). RESULTS: In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. CONCLUSIONS: Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.