Neuropsychological Changes in Isolated REM Sleep Behavior Disorder: A Systematic Review and Meta-analysis of Cross-sectional and Longitudinal Studies.

The aim of this meta-analysis is twofold: (a) to assess cognitive impairments in isolated rapid eye movement (REM) sleep behavior disorder (iRBD) patients compared to healthy controls (HC); (b) to quantitatively estimate the risk of developing a neurodegenerative disease in iRBD patients according to baseline cognitive assessment. To address the first aim, cross-sectional studies including polysomnography-confirmed iRBD patients, HC, and reporting neuropsychological testing were included. To address the second aim, longitudinal studies including polysomnography-confirmed iRBD patients, reporting baseline neuropsychological testing for converted and still isolated patients separately were included. The literature search was conducted based on PRISMA guidelines and the protocol was registered at PROSPERO (CRD42021253427). Cross-sectional and longitudinal studies were searched from PubMed, Web of Science, Scopus, and Embase databases. Publication bias and statistical heterogeneity were assessed respectively by funnel plot asymmetry and using I2. Finally, a random-effect model was performed to pool the included studies. 75 cross-sectional (2,398 HC and 2,460 iRBD patients) and 11 longitudinal (495 iRBD patients) studies were selected. Cross-sectional studies showed that iRBD patients performed significantly worse in cognitive screening scores (random-effects (RE) model = -0.69), memory (RE model = -0.64), and executive function (RE model = -0.50) domains compared to HC. The survival analyses conducted for longitudinal studies revealed that lower executive function and language performance, as well as the presence of mild cognitive impairment (MCI), at baseline were associated with an increased risk of conversion at follow-up. Our study underlines the importance of a comprehensive neuropsychological assessment in the context of iRBD.

Challenging subjective excessive daytime sleepiness as an insomnia symptom: a retrospective study.

Diagnostic manuals describe insomnia disorder (ID) characterised by fatigue and sleepiness as diurnal consequences of nocturnal symptoms. However, patients with ID do not frequently report sleepiness in the clinical setting. The present study aimed to investigate subjective sleepiness in ID measured through the Epworth Sleepiness Scale (ESS) and its independence towards daytime functioning and fatigue, and to evaluate cognitive behavioural therapy for insomnia (CBT-I) improvement in daytime consequences and their relationship to sleepiness and fatigue. We retrospectively collected the ESS evaluation in a large sample of 105 healthy controls (HCs), 671 patients with ID, and 602 patients with sleep disorders characterised by excessive daytime sleepiness (EDS). Moreover, we conducted a pre-post evaluation of the ESS in a sub-sample of patients with ID who underwent CBT-I. Component 2 of the Insomnia Severity Index and Profile of Mood States-Fatigue Inertia Scale was used to evaluate daytime functioning and fatigue. Patients with ID reported ESS levels comparable to that observed in HCs and significantly lower than the EDS group. No significant correlation arose between ESS and the diurnal impact of the disorder, suggesting the independence between daytime functioning and sleepiness in ID. Contrarily, insomnia severity and diurnal impact significantly correlated with fatigue. Data showed a statistically significant increase in sleepiness after CBT-I, despite significantly improving daytime consequences and fatigue. Although diagnostic manuals report sleepiness and fatigue as daytime consequences of sleep symptoms in patients with ID, these retrospective data indicate a dissociation between these entities. This evidence aligns with the core feature of ID: the hyperarousal status that pervades patients also during wakefulness.

The association between emotional dysregulation and REM sleep features in insomnia disorder.

Rapid Eye Movement (REM) sleep is involved in nightly emotional processing; therefore, its disruption might be associated with an impaired ability of emotional regulation during daytime. Accordingly, the aim of the present study was to evaluate the presence of emotional dysregulation in insomnia patients and to test its correlation with REM sleep features. Forty-six subjects (23 insomnia patients and 23 healthy controls) were enrolled. All subjects underwent an assessment for the evaluation of emotion dysregulation (Difficulties in Emotion Regulation Scale, DERS), sleep quality, insomnia severity, excessive daytime sleepiness, worry, rumination, depressive and anxious symptomatology. Insomnia patients underwent a nocturnal polysomnographic recording to characterize sleep macrostructure and REM sleep microstructure variables. Insomnia patients reported increased values of emotional dysregulation. REM sleep percentage and REM sleep latency significantly correlated with DERS total score, and with the subscales "Lack of Confidence in Emotional Regulation Skills", "Difficulties in Behavioral Control" and "Difficulty in recognizing emotions". Furthermore, positive correlations between REM arousal index and emotion dysregulation were found, whereas REM density negatively correlated with DERS. Our results suggest the presence of a relationship between REM sleep and emotional regulation in insomnia patients.

Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa.

Pseudomonas aeruginosa (PA) is a major public health care issue due to its ability to develop antibiotic resistance mainly through adhesion and biofilm formation. Therefore, targeting the bacterial molecular arsenal involved in its adhesion and the formation of its biofilm appears as a promising tool against this pathogen. The galactose-binding LecA (or PA-IL) has been described as one of the PA virulence factors involved in these processes. Herein, the affinity of three tetravalent mannose-centered galactoclusters toward LecA was evaluated with five different bioanalytical methods: HIA, ELLA, SPR, ITC and DNA-based glycoarray. Inhibitory potential towards biofilms was then assessed for the two glycoclusters with highest affinity towards LecA (Kd values of 157 and 194 nM from ITC measurements). An inhibition of biofilm formation of 40% was found for these galactoclusters at 10 µM concentration. Applications of these macromolecules in anti-bacterial therapy are therefore possible through an anti-adhesive strategy.

The influence of the aromatic aglycon of galactoclusters on the binding of LecA: a case study with O-phenyl, S-phenyl, O-benzyl, S-benzyl, O-biphenyl and O-naphthyl aglycons.

A library of 24 new mannose-centered tetragalactoclusters with four different linkers (di- and triethyleneglycol with phosphodiester or phosphorothioate linkages) and six different aromatic aglycons (O-phenyl, S-phenyl, O-benzyl, S-benzyl, O-biphenyl and O-naphthyl) was synthesized. Their interactions with LecA were evaluated on a DNA Directed Immobilization (DDI) based glycocluster array allowing the determination of their IC50 against lactose and the evaluation of their dissociation constant (Kd). Finally, the docking simulations confirm the experimental results and demonstrated that the better affinity of O-biphenyl- and O-naphthyl-galactoside is due to a double interaction between the aromatic ring and the histidine 50 and proline 51 of LecA.

Neurophysiological Parameters Influencing Sleep-Wake Discrepancy in Insomnia Disorder: A Preliminary Analysis on Alpha Rhythm during Sleep Onset.

Sleep state misperception (SSM) is a common issue in insomnia disorder (ID), causing a discrepancy between objective and subjective sleep/wake time estimation and increased daytime impairments. In this context, the hyperarousal theory assumes that sustained central nervous system activation contributes to the SSM. This study investigates factors influencing SSM during sleep latency (SL) and total sleep time (TST). Objective polysomnographic sleep variables (the alpha density index, latency-to-sleep stages and the first K-complex, and Rapid Eye Movement (REM) arousal density) and subjective sleep indices, taken from sleep diaries, were analyzed in 16 ID patients. Correlation analyses revealed a positive association between the degree of SL misperception (SLm) and the percentage of epochs that contained a visually scored stereotyped alpha rhythm during objective SL. A regression analysis showed that the REM arousal density and alpha density index significantly predicted TST misperception (TSTm). Furthermore, the degree of SLm was associated with an increased probability of transitioning from stage 1 of non-REM sleep to wakefulness during subjective SL. These findings support the role of hyperarousal in SSM and highlight the importance of alpha activity in unravelling the heterogeneous underpinnings of SSM.

Periodic Leg Movements during Sleep Associated with REM Sleep Behavior Disorder: A Machine Learning Study.

Most patients with idiopathic REM sleep behavior disorder (iRBD) present peculiar repetitive leg jerks during sleep in their clinical spectrum, called periodic leg movements (PLMS). The clinical differentiation of iRBD patients with and without PLMS is challenging, without polysomnographic confirmation. The aim of this study is to develop a new Machine Learning (ML) approach to distinguish between iRBD phenotypes. Heart rate variability (HRV) data were acquired from forty-two consecutive iRBD patients (23 with PLMS and 19 without PLMS). All participants underwent video-polysomnography to confirm the clinical diagnosis. ML models based on Logistic Regression (LR), Support Vector Machine (SVM), Random Forest (RF), and eXtreme Gradient Boosting (XGBoost) were trained on HRV data, and classification performances were assessed using Leave-One-Out cross-validation. No significant clinical differences emerged between the two groups. The RF model showed the best performance in differentiating between iRBD phenotypes with excellent accuracy (86%), sensitivity (96%), and specificity (74%); SVM and XGBoost had good accuracy (81% and 78%, respectively), sensitivity (83% for both), and specificity (79% and 72%, respectively). In contrast, LR had low performances (accuracy 71%). Our results demonstrate that ML algorithms accurately differentiate iRBD patients from those without PLMS, encouraging the use of Artificial Intelligence to support the diagnosis of clinically indistinguishable iRBD phenotypes.

Boosting obstructive sleep apnea therapy by non-pharmacological approaches: A network meta-analysis.

INTRODUCTION: Obstructive sleep apnea (OSA) is the most common breathing-related sleep disorder with a considerable economic burden, low diagnosis and treatment rates. Continuous positive airway pressure (CPAP/PAP) is the principal therapy for OSA treatment; nevertheless, effectiveness is often limited by suboptimal adherence. The present network meta-analysis aims to systematically summarize and quantify different interventions' effects on CPAP/PAP adherence (such as mean usage CPAP or PAP in hours per night) in OSA patients, comparing Behavioral, Educational, Supportive and Mixed interventions in Randomized Control Trials (RCT). METHODS: We conducted a computer-based search using the electronic databases of Pubmed, Psycinfo, Scopus, Embase, Chinal and Medline until August 2022, selecting 50 RCT. RESULTS: By means of a random effect model network meta-analysis, results suggested that the most effective treatment in improving CPAP/PAP adherence was the Supportive approach followed by Behavioral Therapy focused on OSA treatment adherence. CONCLUSION: This network meta-analysis might encourage the most experienced clinicians and researchers in the field to collaborate and implement treatments for improving CPAP/PAP treatment adherence. Moreover, these results support the importance of multidisciplinary approaches for OSA treatment, which should be framed within a biopsychological model.

A case of Wernicke encephalopathy combined with disulfiram intoxication.

There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings.

Cognitive Reserve in Isolated Rapid Eye-Movement Sleep Behavior Disorder.

Isolated rapid-eye-movement sleep behaviour disorder (RBD) is considered the prodromal stage of α-synucleinopathies (e.g., Parkinson's disease and dementia with Lewy bodies); however, iRBD patients show a wide variety in the progression timing (5-15 years). The model of cognitive reserve (CR) might contribute to explaining this phenomenon. Our exploratory study aimed to evaluate, for the first time, the impact of CR level on cognitive performance in polysomnography-confirmed iRBD patients. Fifty-five iRBD patients (mean age ± SD: 66.38 ± 7.51; M/F 44/11) underwent clinical and neuropsychological evaluations at the time of diagnosis. The CR Index questionnaire was part of the clinical assessment. We found that iRBD patients with high levels of CR showed: (i) the lowest percentage of mild cognitive impairment (10%), and (ii) the best performance in visuo-constructive and verbal memory functions (i.e., the recall of the Rey-Osterrieth complex figure test). Our results suggest that CR might help iRBD patients better cope with the cognitive decline related to the neurodegenerative process, providing the first preliminary findings supporting CR as a possible protective factor in this condition. This might pave the way for future longitudinal studies to evaluate the role of CR as a modulating factor in the timing of iRBD conversion and cognitive deterioration development.

A data-driven approach to neuropsychological features in isolated REM behaviour disorder: A latent class analysis.

Recent evidence demonstrated that neuropsychological assessment may be considered a valid marker of neurodegeneration in idiopathic REM sleep behaviour disorder (iRBD). However, little is known about the possible neuropsychological heterogeneity within the iRBD population. This retrospective study aimed to identify and describe different neuropsychological phenotypes in iRBD patients by means of a data-driven approach using latent class analysis. A total of 289 iRBD patients underwent a neuropsychological assessment evaluating cognitive domains: global cognition, language, short- and long-term memory, executive functions and visuospatial abilities. The presence of mild cognitive impairment (MCI) was also assessed. Latent class analysis was carried out to identify iRBD subtypes according to neuropsychological scores. The most parsimonious model identified three latent classes. Groups were labelled as follows: Class 2 "severely impaired" (n = 83/289): mean pathological scores in different tests, a high percentage of MCI multiple-domain and impairment in all neuropsychological domains. Class 1 "moderately impaired" (n = 44/289): mean neuropsychological score within the normal value, a high percentage of MCI (high risk to phenoconversion) and great impairment in the visuospatial domain. Class 3 "slightly impaired" (n = 162/289): no deficit worthy of attention except for short- and long-term memory. Our results suggest three different clinical phenotypes within the iRBD population. These findings may be relevant in the future for predicting the clinical trajectories of phenoconversion in iRBD.

Electronegative LDL Is Associated with Plaque Vulnerability in Patients with Ischemic Stroke and Carotid Atherosclerosis.

Owing to the high risk of recurrence, identifying indicators of carotid plaque vulnerability in atherothrombotic ischemic stroke is essential. In this study, we aimed to identify modified LDLs and antioxidant enzymes associated with plaque vulnerability in plasma from patients with a recent ischemic stroke and carotid atherosclerosis. Patients underwent an ultrasound, a CT-angiography, and an 18F-FDG PET. A blood sample was obtained from patients (n = 64, 57.8% with stenosis ≥50%) and healthy controls (n = 24). Compared to the controls, patients showed lower levels of total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein B (apoB), apoA-I, apoA-II, and apoE, and higher levels of apoJ. Patients showed lower platelet-activating factor acetylhydrolase (PAF-AH) and paraoxonase-1 (PON-1) enzymatic activities in HDL, and higher plasma levels of oxidized LDL (oxLDL) and electronegative LDL (LDL(-)). The only difference between patients with stenosis ≥50% and <50% was the proportion of LDL(-). In a multivariable logistic regression analysis, the levels of LDL(-), but not of oxLDL, were independently associated with the degree of carotid stenosis (OR: 5.40, CI: 1.15-25.44, p < 0.033), the presence of hypoechoic plaque (OR: 7.52, CI: 1.26-44.83, p < 0.027), and of diffuse neovessels (OR: 10.77, CI: 1.21-95.93, p < 0.033), indicating that an increased proportion of LDL(-) is associated with vulnerable atherosclerotic plaque.

The effects of alcohol on cognition in the elderly: from protection to neurodegeneration.

The effects of chronic alcohol abuse on cognition are well known. Memory and executive functions appear to be the cognitive domains primarily impaired, and prefrontal and frontal damage is reported on neuroimaging studies both at micro- and macrostructural levels. Abstinence can partially reverse these alterations through mechanisms of neuroplasticity. Alcohol acts in a dose-dependent fashion, and a light-to-moderate consumption indeed has protective effects on cardiovascular risk factors and promotes anti-inflammatory and anti-oxidative processes. In the elderly on such a regimen, several epidemiological studies have reported a decreased risk of both coronary and cerebrovascular disease and of dementia. However, because of data heterogeneity and the presence of several confounding variables, further studies are needed to clarify these findings. In addition, the complexity of alcohol neurobiology (interaction of alcohol effects with genetic predisposition and environmental factors) and the occurrence of age-related changes should also be taken into account. As dementia, stroke and cardiovascular disease are the leading causes of mortality in older people in developed countries, a better knowledge of the mechanisms underlying the effects of alcohol intake may be helpful from the perspective not only of medical management but also of social health policy.

Propriospinal Myoclonus.

Propriospinal myoclonus (PSM) consists of paroxysmal and sudden jerks involving axial flexion trunk and hip muscles, conditioning sudden myoclonias of the trunk and arms/limbs, both spontaneous and triggered by sensory stimulations, emerging in relaxed wakefulness typically during the transition between wake and sleep. Generally, PSM originates from a thoracic myelomere and spreads caudally and rostrally, provoking flexion and/or extension movements, leading to jumps or trunk jerks. They appear triggered by the lying-down position and disappear when the subject stands up. The main consequences are the difficulties in sleep start and the reappearance during the period of wakefulness after sleep onset.

Depressive and stress symptoms in insomnia patients predict group cognitive-behavioral therapy for insomnia long-term effectiveness: A data-driven analysis.

BACKGROUND: Insomnia Disorder is characterized by high degree of phenotypic heterogeneity, that might influence treatment response. METHODS: 123 of 294 insomnia patients initially recruited (66.7% females, age=40.59±11.89) were assessed before and after group Cognitive-Behavioral Therapy for Insomnia (CBT-I), as well as at follow-up (7.8±1.6 years after the end-of-treatment). By use of latent class analysis (LCA) we identified insomnia subtypes according with baseline scores of insomnia severity and features, anxiety, depression, stress and sleepiness symptoms, circadian rhythm, and treatment effectiveness (Delta score of Insomnia Severity Index-ISI between baseline and end-of-treatment). RESULTS: By LCA we revealed three classes: "PURE INSOMNIA", "INSOMNIA+ANXIETY+DEPRESSION+STRESS", and "INSOMNIA+ANXIETY". The improvements in insomnia severity was maintained up to 10 years after the end-of-treatment, but with differences between classes (p<0.05). Class "INSOMNIA+ANXIETY+DEPRESSION+STRESS" showed at the end-of-treatment the largest percentage of responders (63.5% = Insomnia Severity Index decrease ≥8). However, at follow up the effect was less and 48.1% had a moderate or severe insomnia (Insomnia Severity Index >14). LIMITATIONS: The lack of a control group and the absence of a complete clinical assessment at the follow-up limit the interpretability of our results. CONCLUSIONS: Our data driven analysis suggest insomnia heterogeneity can be categorized into sub-classes by depression, anxiety, and stress symptoms. In addition, insomnia patients with stress and depression symptoms maintained highest percentage of clinical depression at the end-of-treatment and insomnia at follow-up, in comparison with others classes. Stress and depression symptoms should be considered risk factors that play an important role in the long-term outcome of CBT-I.

Exploring the functional role and neural correlates of K-complexes in isolated rapid eye movement sleep behavior disorder.

Underlying neural mechanisms and cognitive implications of non-Rapid Eye Movement (NREM) sleep in isolated Rapid Eye Movement (REM) sleep behavior disorder (iRBD) are not yet fully elucidated. This study aims to evaluate brain metabolic connectivity of the anterior default mode network (ADMN) underlying a waveform that is an hallmark of NREM sleep, namely K-complex (KC) and their implication for neuropsychological functioning in iRBD patients. Combining polysomnographic and multivariate molecular imaging (FDG-PET) approaches may provide crucial insights regarding KCs role in the prodromal stages of synucleinopathies. We applied a seed-based interregional correlation analysis on FDG-PET data. iRBD patients with cognitive decline displayed a reduced KC density (KCd) in comparison to patients without cognitive impairments. KCd showed a significant positive correlation with global cognitive functioning, specifically with visuo-spatial and executive performances, two cognitive domains known to be relevant in predicting conversion into neurodegenerative disorders. Increased KCd was associated with a more preserved ADMN connectivity. Our study underlines the importance of NREM sleep in prodromal stages of synucleinopathies, and future investigations might clarify its role in iRBD.

Therapy for Insomnia and Circadian Rhythm Disorder in Alzheimer Disease.

PURPOSE OF THE REVIEW: There is strong evidence for a bidirectional association between sleep disorders and Alzheimer's disease (AD). In particular, insomnia may be a potentially modifiable risk factor for AD. The present review summarizes recent advances in treatment of sleep disorders in AD. RECENT FINDINGS: Some studies investigated the efficacy and safety of hypnotic agents as ramelteon and mirtazapine to treat sleep disorders in AD but no significant therapeutic effects have been observed. Benzodiazepines are the most frequently used medication for treatment of insomnia but they may cause significant side effects in old subjects. Suvorexant, an orexin receptor antagonist, showed a positive effect on AD insomnia. Recent report suggests an association between trazodone use and delayed cognitive decline in AD. With respect to circadian rhythm disorders, non-pharmacological treatments, especially bright light therapy, could be useful and safe options for treatment in AD. Some pharmacological and non-pharmacological treatments might have benefits in AD patients with sleep disturbances, but further well-designed controlled trials are needed.

COVID-19 and Sleep in Medical Staff: Reflections, Clinical Evidences, and Perspectives.

PURPOSE OF THE REVIEW: There is evidence that, before the coronavirus pandemic 2019 (COVID-19), healthcare workers did not experience good sleep quality with relevant consequences on health. By contrast, little is known about the sleep quality of medical staff during the COVID-19 pandemic. In this review, we aimed to contribute with a review of the literature, sharing our clinical experience supported by actigraphic evaluation and by proposing future strategies. RECENT FINDINGS: Sleep disorders, in particular insomnia, have been commonly reported in frontline medical workers, in hospitals during the COVID-19 pandemic and are often accompanied by depressive and anxiety symptoms. Sleep quality, however, has been mainly assessed by the use of self-reported measures, thus limiting clinical usefulness. SUMMARY: Poor sleep quality among the medical staff is prevalent, and our experience supports that this has increased during the COVID-19 pandemic. A longitudinal investigation assessing whether and for how long sleep remains altered in medical staff could be of interest to evaluate the temporal effect of the pandemic on health.

DBS in restless legs syndrome: a new therapeutic approach?

OBJECTIVE: Restless legs syndrome (RLS) is a sleep disorder characterized by an urge to move legs or arms, with a typical circadian rhythm. RLS can be treated with pharmacological and non-pharmacological therapies. Nevertheless, in some patients RLS can be refractory to all medical and non-medical treatments. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been reported to improve RLS symptoms in Parkinson's disease (PD) patients with RLS. We describe the case of a patient suffering from refractory idiopathic RLS implanted with bilateral GPi DBS. METHOD: The patient underwent DBS targeting the bilateral GPi. Follow up for three years involved clinical evaluation and polysomnography (PSG). RESULTS: The patient reported subjective improvement, with reduction in the IRLS score. Furthermore, the polysomnography (PSG) showed an objective improvement of polysomnographic parameters, which remained stable during the follow-up. CONCLUSION: DBS for RLS can be a new therapeutic approach for severe RLS, but further studies are needed.

D3 receptor agonist efficacy in restless legs syndrome.

Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a sleep related movement disorder characterized by an irresistible urge to move the limbs frequently associated with uncomfortable sensations that usually begin or worsen during inactivity and may be relieved by movement. The pathophysiology of the disorder involves several biological system; in particular, dopaminergic pathway and iron physiology have been extensively studied. Being a chronic condition, long-term treatments are required for an adequate management and strong evidence support the employment of dopamine agonists. D3 receptor agonists are of particular interest, because they act on receptors that are widely expressed in the spinal cord with an inhibitory action on sensory system. Pramipexole, rotigotine and ropinirole act on D3 receptors, even if not selectively, and are effective in reducing sensorimotor symptoms and improving sleep quality. However, despite an initial amelioration patients frequently experience augmentation, i.e., a worsening of symptoms induced by dopamine agonists. This can be explained by the activity of D1 receptor and by the non-selectiveness of D3 agonist drugs. Higher dopamine concentrations tend to activate the excitatory D1-like receptor that are associated with increased motor activity. The development of drugs that selectively target D3 receptors will be fundamental to provide alternative therapeutic strategies and to reduce the occurrence of augmentation.