[Usefulness of repetitive transcranial magnetic stimulation in psychiatric disorders].

International audienceMental disorders represent a concern for the public health because of their prevalence in the general population. Despite progress in psychopharmacology, 20-30 % of the patients suffering of depressive disorders are responding only partially to different pharmacological and psychological therapeutic strategies. Until recently, the therapeutic alternative in refractory depression was the electroconvulsive therapy. New therapeutic approaches should be therefore explored. In October 2008 repetitive transcranial magnetic stimulation was approved as an antidepressive monotherapy by the FDA, opening the way to a routine application of this technique, which will supplement the body of our therapeutic armamentarium for mood disorders. We review this new therapeutic approach, which is rapidly developing for treating depression and schizophrenia

Psychostimulant effect of levodopa: reversing sensitisation is possible

Levodopa therapy in Parkinson's disease (PD) is associated with non-motor complications resulting from sensitisation of the ventral striatum system. Recent studies showed an improvement in non-motor complications in PD patients with subthalamic stimulation. We hypothesised that ventral striatum desensitisation might contribute to this improvement

Long-term independence and quality of life after subthalamic stimulation in Parkinson's disease.

BACKGROUND Studies on long-term non-motor outcomes of subthalamic nucleus stimulation in Parkinson's disease are scarce. This study reports on very-long term non-motor and motor outcomes in one of the largest cohorts of people with advanced Parkinson's disease, treated for more than ten years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non-motor and motor outcomes. METHODS Patients were studied preoperatively, at one year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non-motor and neuropsychological assessments. RESULTS Eighty-five people with PD were included. Independence scores in the off-medication condition (measured with the Schwab & England activities of daily living scale), as well as quality of life (measured with the PDQ37) remained improved at longest follow-up compared to preoperatively (respectively p < 0.001, p = 0.015). Cognitive scores, measured with the MDRS, significantly worsened compared to before and one-year after surgery (p < 0.001), without significant change in depression, measured with the BDI. Motor fluctuations, dyskinesias and off dystonia remained improved at longest follow-up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001). CONCLUSIONS This study highlights the long-term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa-resistant symptoms

Serotonergic and Dopaminergic Lesions Underlying Parkinsonian Neuropsychiatric Signs.

BACKGROUND Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. METHODS To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. RESULTS The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. CONCLUSIONS Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society

Limbic Serotonergic Plasticity Contributes to the Compensation of Apathy in Early Parkinson's Disease.

BACKGROUND De novo Parkinson's disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown. OBJECTIVES To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis. METHODS Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [11 C]PE2I for dopamine transporter and [11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis. RESULTS After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy. CONCLUSION Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society

Axial impairment and falls in Parkinson's disease: 15 years of subthalamic deep brain stimulation

In this retrospective study, we longitudinally analyzed axial impairment and falls in people with Parkinson's disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS). Axial scores and falling frequency were examined at baseline, and 1, 10, and 15 years after surgery. Preoperative demographic and clinical data, including PD duration and severity, phenotype, motor and cognitive scales, medications, and vascular changes on neuroimaging were examined as possible risk factors through Kaplan-Meier and Cox regression analyses. Of 302 individuals examined before and at 1 year after surgery, 102 and 57 were available also at 10 and 15 years of follow-up, respectively. Axial scores were similar at baseline and at 1 year but worsened at 10 and 15 years. The prevalence rate of frequent fallers progressively increased from baseline to 15 years. Preoperative axial scores, frontal dysfunction and age at PD onset were risk factors for axial impairment progression after surgery. Axial scores, akinetic/rigid phenotype, age at disease onset and disease duration at surgery predicted frequent falls. Overall, axial signs progressively worsened over the long-term period following STN-DBS, likely related to the progression of PD, especially in a subgroup of subjects with specific risk factors

[Behavioral disorders in Parkinson's disease: from pathophysiology to the mastery of dopaminergic treatment].

International audienceINTRODUCTION: Behavioral changes in Parkinson's disease are complex and their pathophysiology is not yet fully understood. The dopaminergic system seems to play a major role and most of the behavioral disorders in Parkinson's disease can be classified into either hypodopaminergic if related to the disease itself or hyperdopaminergic if related to dopaminergic treatment. STATE OF THE ART: Subthalamic stimulation, which enables withdrawal of dopaminergic medication at an advanced stage in the disease, provides a model for the study of certain nonmotor, dopamine-sensitive symptoms. Such a study has shown that apathy, which is the most frequent behavioral problem in Parkinson's disease, is part of a much broader hypodopaminergic behavioral syndrome which also includes anxiety and depression. Nonmotor fluctuations--essential fluctuations in the patient's psychological state--are an expression of mesolimbic denervation, as shown in positron emission tomography. Drug-induced sensitization of the denervated mesolimbic system accounts for hyperdopaminergic behavioral problems that encompass impulse control disorders that can be alternatively classified as behavioral addictions. The association of impulse control disorders and addiction to the dopaminergic medication has been called dopamine dysregulation syndrome. While L-dopa is the most effective treatment for motor symptoms, dopamine agonists are more effective in improving the nonmotor levodopa-sensitive symptoms. On the other hand, L-dopa induces more motor complications and dopamine agonist more behavioral side effects. There is increasing data and awareness that patients' quality of life appears to be dictated by hypo- and hyperdopaminergic psychological symptoms stemming from mesolimbic denervation and dopaminergic treatment rather than by motor symptoms and motor complications related to nigrostriatal denervation and dopaminergic treatment. PERSPECTIVES: Better management requires knowledge of the clinical syndromes of hyper- and hypodopaminergic behaviors and nonmotor fluctuations, a better understanding of their underlying mechanisms and the development of new evaluation tools for these nonmotor symptoms. CONCLUSIONS: The neurologist who strives to gain mastery of dopaminergic treatment needs to fine tune the dosage of levodopa and dopamine agonists on an individual basis, depending on the presence of motor and nonmotor signs respectively

Pathological gambling in Parkinson's disease improves on chronic subthalamic nucleus stimulation.

International audiencePathological gambling (PG) related to dopaminergic treatment in Parkinson's disease (PD) is part of a spectrum of behavioral disorders called the dopamine dysregulation syndrome (DDS). We describe a series of PD patients with preoperative active PG due to dopaminergic treatment from a total of 598 patients who have undergone surgery for subthalamic nucleus stimulation for disabling motor fluctuations. The patients had systematic open assessment of behavioral symptoms and standardized assessments of motor symptoms, mood, and apathy. Seven patients (6 men, 1 woman; age, 54 +/- 9 years; levodopa equivalent dose, 1,390 +/- 350 mg/day) had preoperative PG over a mean of 7 years, intolerant to reduction in medication. Six had nonmotor fluctuations and four had other behavioral symptoms consistent with a diagnosis of the DDS. After surgery, motor symptoms improved, allowing for 74% reduction of dopaminergic treatment, below the dosage of gambling onset. In all patients, PG resolved postoperatively after 18 months on average (range, 0-48), although transient worsening occurred in two. Improvement paralleled the time course and degree of reduction in dopaminergic treatment. Nonmotor fluctuations, off period dysphoria, and other symptoms of the DDS improved. Two patients developed persistent apathy. In conclusion, PG and other symptoms of the DDS-associated dopaminergic treatment improved in our patients following surgery. Dopaminergic dysregulation commonly attributed to pulsatile overstimulation of the limbic dopaminergic system may be subject to desensitization on chronic subthalamic stimulation, which has a relative motor selectivity and allows for decrease in dopaminergic treatment