Multi-facetted impulsivity following nigral degeneration and dopamine replacement therapy.

Impulse control disorders (ICDs) are debilitating side effects of dopamine replacement therapy (DRT) in Parkinson's disease (PD) that severely affect the quality of life of patients. While DRT, the pattern and extent of neurodegeneration, and prodromic factors of vulnerability (e.g. impulsivity) have all been hypothesized to play a role in the development of ICDs, their respective, and potentially interacting, contributions remain to be established. High impulsive (HI), Intermediate (Int) or low impulsive (LI) rats were identified based on their performance in both a differential reinforcement of low rate of responding (DRL) and a fixed consecutive number (FCN) schedules, that operationalize two independent facets of impulsivity, waiting and action inhibition (motor impulsivity). We investigated whether high impulsivity trait influenced the progressive development of a parkinsonian state induced by viral-mediated overexpression of α-synuclein, and whether impulsivity trait and nigrostriatal neurodegeneration independently or jointly influenced the effects of DRT on impulse control. α-synuclein-induced nigrostriatal neurodegeneration increased both waiting and motor impulsivity. The D2/D3 dopamine receptor agonist pramipexole exacerbated motor impulsivity more than waiting. However, the pramipexole-induced increase in waiting impulsivity observed in both sham and lesioned rats, was more pronounced in HI lesioned rats, which displayed a restricted α-synuclein-induced dopaminergic neurodegeneration. Thus, a PD-like nigrostriatal lesion increases both motor and waiting impulsivity, but its interaction with a pre-existing impulsivity trait, which, at the cellular level, confers resilience to dopaminergic neurodegeneration, worsens the detrimental effects of D2/D3 dopamine receptor agonists on inhibitory control.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S0028390816302118

A phenomenological approach to the neurobiological substrates of the relationship between impulsivity and compulsive disorders

L'impulsivité, un trait multidimensionnel, détermine la sévérité d'affections comportant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson, troubles obsessionnels compulsifs), mais la nature de la relation impulsivité / compulsivité reste méconnue. L'intérêt du présent travail est d'identifier les substrats neurobiologiques de la balance impulsivité / compulsivité, dans une approche transnosographique, en s'aidant au plan préclinique, de manipulations causales et au plan clinique, d'une approche corrélationnelle. Ainsi, nous démontrons pour la première fois en dehors du champ de l'addiction, non seulement que l'impulsivité motrice, endophénotype de vulnérabilité à la compulsivité, prédit, sous l'influence de la transmission noradrénergique, la transition vers la compulsivité, mais aussi que (dans le modèle de la maladie de Parkinson) la dénervation de la voie nigrostriée et les traitements substitutifs dopaminergiques amplifient l'état impulsif. D'où l'interaction complexe entre le trait impulsif, les traitements et le processus dégénératif. Enfin, nous démontrons le bénéfice thérapeutique de la stimulation de la portion antérieure du pallidum interne dans les formes sévères de tics et suggérons dans un modèle préclinique d'une grande valeur heuristique, que le trait impulsif prédit l'efficacité de la stimulation du core du noyau accumbens. Nos résultats démontrent l'intérêt de mieux caractériser le trait impulsif des patients présentant des désordres compulsifs (syndrome de Gilles de la Tourette, maladie de Parkinson) et ouvrent ainsi de nouvelles perspectives thérapeutiques, tant pour la prévention de la transition de l'impulsivité à la compulsivité, que dans le traitement de ceux-ci.Impulsivity, a multidimensional trait, determines the severity of compulsive disorders (Tourette's syndrome, Parkinson's disease, obsessive compulsive disorders), but the impulsive / compulsive relation remains unclear. The aim of this work is to identify the neurobiological substrates of impulsive / compulsive balance, using causal manipulations in rats and correlational studies in patients. The results demonstrate - for the first time beside the field of addiction - that, not only high impulsive trait is a transnosological endophenotype of increased vulnerability to develop compulsive disorders, but also that the transition from impulsivity toward compulsivity depends upon the noradrenergic transmission. Furthermore, we also show that, in a Parkinson's disease preclinical model, both the nigrostriatal denervation and dopaminergic treatments increase impulsive state, thereby indicating the contribution of a complex interaction between impulsive trait, medications and neurodegenerative process to the impulsive/compulsive balance. Finally, we show the therapeutic benefit of anterior globus pallidus interna in severe forms of tics and suggest in a preclinical model, with great heuristic value, that impulsive trait predicts the efficacy of nucleus accumbens core stimulation. Together, our results demonstrate the need to address the impulsive/compulsive balance in compulsive disorders and show promise for developing new pathophysiological-based therapeutic strategies that will treat both impulsivity and compulsivity

Revisiting the Robustness of PET-Based Textural Features in the Context of Multi-Centric Trials.

This study aimed to investigate the variability of textural features (TF) as a function of acquisition and reconstruction parameters within the context of multi-centric trials.The robustness of 15 selected TFs were studied as a function of the number of iterations, the post-filtering level, input data noise, the reconstruction algorithm and the matrix size. A combination of several reconstruction and acquisition settings was devised to mimic multi-centric conditions. We retrospectively studied data from 26 patients enrolled in a diagnostic study that aimed to evaluate the performance of PET/CT 68Ga-DOTANOC in gastro-entero-pancreatic neuroendocrine tumors. Forty-one tumors were extracted and served as the database. The coefficient of variation (COV) or the absolute deviation (for the noise study) was derived and compared statistically with SUVmax and SUVmean results.The majority of investigated TFs can be used in a multi-centric context when each parameter is considered individually. The impact of voxel size and noise in the input data were predominant as only 4 TFs presented a high/intermediate robustness against SUV-based metrics (Entropy, Homogeneity, RP and ZP). When combining several reconstruction settings to mimic multi-centric conditions, most of the investigated TFs were robust enough against SUVmax except Correlation, Contrast, LGRE, LGZE and LZLGE.Considering previously published results on either reproducibility or sensitivity against delineation approach and our findings, it is feasible to consider Homogeneity, Entropy, Dissimilarity, HGRE, HGZE and ZP as relevant for being used in multi-centric trials

Robustness for multi-centric conditions.

Variation of the COV for each TF when pooling different reconstructions detailed in Table 1 in order to mimic multi-centric conditions.</p

Tumor illustration.

Illustration of a tumor (axial slice) reconstructed using different reconstruction settings. Two different images are presented for each reconstruction algorithm studied (AW, OP, PSF and PSF-TOF) corresponding to the minimum and maximum value of the parameters investigated (number of iterations, level of post-filtering and acquisition time). Upper row: variation of the number of iterations (2 and 6 iterations). Middle row: variation of the post-filtering level (0 mm or 5 mm FWHM). Bottom row: variation of the acquisition time for a surrogate of noise in the input data (60 s or 180 s). The grey scale level is identical for each image.</p