Targeting the adenosinergic system in restless legs syndrome: A pilot, "proof-of-concept" placebo-controlled TMS-based protocol.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative "pharmaco-TMS"-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), "TMS-guided", interventions.

A Next-Generation Sequencing Study in a Cohort of Sicilian Patients with Parkinson's Disease.

Parkinson's disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical-demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.

Repetitive transcranial magnetic stimulation in primary sleep disorders.

Repetitive transcranial magnetic stimulation (rTMS) is a widely used non-invasive neuromodulatory technique. When applied in sleep medicine, the main hypothesis explaining its effects concerns the modulation of synaptic plasticity and the strength of connections between the brain areas involved in sleep disorders. Recently, there has been a significant increase in the publication of rTMS studies in primary sleep disorders. A multi-database-based search converges on the evidence that rTMS is safe and feasible in chronic insomnia, obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and sleep deprivation-related cognitive deficits, whereas limited or no data are available for narcolepsy, sleep bruxism, and REM sleep behavior disorder. Regarding efficacy, the stimulation of the dorsolateral prefrontal cortex bilaterally, right parietal cortex, and dominant primary motor cortex (M1) in insomnia, as well as the stimulation of M1 leg area bilaterally, left primary somatosensory cortex, and left M1 in RLS reduced subjective symptoms and severity scale scores, with effects lasting for up to weeks; conversely, no relevant effect was observed in OSAS and narcolepsy. Nevertheless, several limitations especially regarding the stimulation protocols need to be considered. This review should be viewed as a step towards the further contribution of individually tailored neuromodulatory techniques for sleep disorders.

Reduced Intracortical Facilitation to TMS in Both Isolated REM Sleep Behavior Disorder (RBD) and Early Parkinson's Disease with RBD.

BACKGROUND: a reduced intracortical facilitation (ICF), a transcranial magnetic stimulation (TMS) measure largely mediated by glutamatergic neurotransmission, was observed in subjects affected by isolated REM sleep behavior disorder (iRBD). However, direct comparison between iRBD and Parkinson's disease (PD) with RBD is currently lacking. METHODS: resting motor threshold, contralateral cortical silent period, amplitude and latency of motor evoked potentials, short-interval intracortical inhibition, and intracortical facilitation (ICF) were recorded from 15 drug-naïve iRBD patients, 15 drug-naïve PD with RBD patients, and 15 healthy participants from the right First Dorsal Interosseous muscle. REM sleep atonia index (RAI), Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), and Epworth Sleepiness Scale (ESS) were assessed. RESULTS: Groups were similar for sex, age, education, and patients for RBD duration and RAI. Neurological examination, MMSE, ESS, and GDS were normal in iRBD patients and controls; ESS scored worse in PD patients, but with no difference between groups at post hoc analysis. Compared to controls, both patient groups exhibited a significantly decreased ICF, without difference between them. CONCLUSIONS: iRBD and PD with RBD shared a reduced ICF, thus suggesting the involvement of glutamatergic transmission both in subjects at risk for degeneration and in those with an overt α-synucleinopathy.

Post-stroke aphasia at the time of COVID-19 pandemic: a telerehabilitation perspective.

We report on our remote speech therapy experience in post-stroke aphasia. The aim was to test the feasibility and utility of telerehabilitation to support future randomized controlled trials. Post-stroke aphasia is a common and disabling speech disorder, which significantly affects patients' and caregivers' health and quality of life. Due to COVID-19 pandemic, most of the conventional speech therapy approaches had to stop or "switch" into telerehabilitation procedures to ensure the safety of patients and operators but, concomitantly, the best rehabilitation level possible. Here, we planned a 5-month telespeech therapy programme, twice per week, of a patient with non-fluent aphasia following an intracerebral haemorrhage. Overall, treatment adherence based on the operator's assessments was high, and incomplete adherence for technical problems occurred very rarely. In line with the patient's feedback, acceptability was also positive, since he was constantly motivated during the sessions and the exercises performed autonomously, as confirmed by the speech therapist and caregiver, respectively. Moreover, despite the sequelae from the cerebrovascular event, evident in some writing tests due to the motor deficits in his right arm and the disadvantages typical of all telepractices, more relevant results were achieved during the telerehabilitation period compared to those of the "face-to-face" therapy before the COVID-19 outbreak. The telespeech therapy performed can be considered successful and the patient was able to return to work. Concluding, we support it as a feasible approach offering patients and their families the opportunity to continue the speech and language rehabilitation pathway, even at the time of pandemic.

Increased Serum Prolactin and Excessive Daytime Sleepiness: An Attempt of Proof-of-Concept Study.

The objectives of this study were: (1) to identify subjects with hyperprolactinemia in a clinical sample of patients; (2) to compare the neurologic, psychiatric, and sleep conditions found in patients subgrouped by excessive daytime sleepiness (EDS) and hyperprolactinemia; and (3) to identify patients with hyperprolactinemia and EDS not supported by the presence of any other neurologic, psychiatric, or sleep disorder, or substance/medication use. A retrospective chart review of inpatients was carried out in order to identify all patients in whom the prolactin (PRL) serum levels were determined. A total of 130 subjects were retrieved: 55 had increased levels of PRL, while the remaining 75 participants had normal PRL levels. EDS was reported by 32 (58.2%) participants with increased PRL and 34 (45.3%) with normal PRL. Obstructive sleep apnea or other sleep or neurologic/psychiatric conditions could explain EDS in all participants with normal PRL. Among subjects with increased PRL, eight had no other neurologic/psychiatric or sleep disorder (or drug) potentially causing EDS; these participants, at polysomnography, had time in bed, sleep period time, and total sleep time longer than those with EDS associated to another condition. These findings can be considered as a preliminary indication of a role of hyperprolactinemia in EDS and represent a basis for future controlled studies able to test this hypothesis in a reliable, objective, and methodologically more appropriate way.

Cognitive Impairment in Inpatients with Prurigo Nodularis and Psychiatric Comorbidities.

BACKGROUND: Prurigo nodularis (PN) is a chronic refractory itchy dermatosis. Although psychiatric comorbidity is known, research in cognitive impairment is lacking. We evaluated the occurrence and types of cognitive impairment in a series of inpatients with PN. METHODS: This was a retrospective chart review of all the patients with PN admitted to a referral neurological institute from September 2018 to March 2021. Any neurological and psychiatric disorder, along with neuroactive drugs taken, were concomitantly assessed. RESULTS: A total of 16 patients with PN (median age: 70 years, two males) were selected from a total of 1806 hospital admissions. Most of them had a neurodegenerative cognitive disorder, from mild cognitive impairment (8) to Alzheimer's disease (1), followed by mixed disorder (degenerative and vascular) in six and vascular dementia in one. Comorbid psychiatric diseases (anxiety and depression) were more common than either individual condition, followed by bipolar disorder, whereas two patients did not show psychiatric manifestations. Most patients were on combined treatment with benzodiazepines and antidepressants. CONCLUSION: Cognitive impairment can be observed in PN. In addition to screening for psychiatric comorbidity and initiating appropriate treatment or referral, clinicians may also consider the presence of cognitive impairment in PN of both degenerative and vascular origin.

A Customized Next-Generation Sequencing-Based Panel to Identify Novel Genetic Variants in Dementing Disorders: A Pilot Study.

Purpose: The advancements in the next-generation sequencing (NGS) techniques have allowed for rapid, efficient, and cost-time-effective genetic variant detection. However, in both clinical practice and research setting, sequencing is still often limited to the use of gene panels clinically targeted on the genes underlying the disease of interest. Methods: We performed a neurogenetic study through an ad hoc NGS-based custom sequencing gene panel in order to screen 16 genes in 8 patients with different types of degenerative cognitive disorders (Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and dementia associated with Parkinson's disease). The study protocol was based on previous evidence showing a high sensitivity and specificity of the technique even when the panel is limited to some hotspot exons. Results: We found variants of the TREM2 and APP genes in three patients; these have been previously identified as pathogenic or likely pathogenic and, therefore, considered "disease causing." In the remaining subjects, the pathogenicity was evaluated according to the guidelines of the American College of Medical Genetics (ACMG). In one patient, the p.R205W variant in the CHMP2B gene was found to be likely pathogenic of the disease. A variant in the CSF1R and SERPINI1 genes found in two patients was classified as benign, whereas the other two (in the GRN and APP genes) were classified as likely pathogenic according to the ACMG. Conclusions: Notwithstanding the preliminary value of this study, some rare genetic variants with a probable disease association were detected. Although future application of NGS-based sensors and further replication of these experimental data are needed, this approach seems to offer promising translational perspectives in the diagnosis and management of a wide range of neurodegenerative disorders.

Facilitatory/inhibitory intracortical imbalance in REM sleep behavior disorder: early electrophysiological marker of neurodegeneration?

STUDY OBJECTIVES: Previous studies found an early impairment of the short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) to transcranial magnetic stimulation (TMS) in Parkinson's disease. However, very little is known on the TMS correlates of rapid eye movement (REM) sleep behavior disorder (RBD), which can precede the onset of a α-synucleinopathy. METHODS: The following TMS measures were obtained from 14 de novo patients with isolated RBD and 14 age-matched healthy controls: resting motor threshold, cortical silent period, latency and amplitude of the motor evoked potentials, SICI, and ICF. A cognitive screening and a quantification of subjective sleepiness (Epworth Sleepiness Scale [ESS]) and depressive symptoms were also performed. RESULTS: Neurological examination, global cognitive functioning, and mood status were normal in all participants. ESS score was higher in patients, although not suggestive of diurnal sleepiness. Compared to controls, patients exhibited a significant decrease of ICF (median 0.8, range 0.5-1.4 vs. 1.9, range 1.4-2.3; p < 0.01) and a clear trend, though not significant, towards a reduction of SICI (median 0.55, range 0.1-1.4 vs. 0.25, range 0.1-0.3), with a large effect size (Cohen's d: -0.848). REM Sleep Atonia Index significantly correlated with SICI. CONCLUSIONS: In still asymptomatic patients for a parkinsonian syndrome or neurodegenerative disorder, changes of ICF and, to a lesser extent, SICI (which are largely mediated by glutamatergic and GABAergic transmission, respectively) might precede the onset of a future neurodegeneration. SICI was correlated with the muscle tone alteration, possibly supporting the proposed RBD model of retrograde influence on the cortex from the brainstem.

Subclinical abnormal EMG activation of the gastrocnemii during gait analysis in restless legs syndrome: a preliminary report in 13 patients.

OBJECTIVE: The purpose of this study was to detect the eventual presence of a minor voluntary motor involvement in restless legs syndrome (RLS), not detectable clinically, which might be observed by means of a sophisticated instrumental analysis of movement, such as gait analysis. SUBJECTS AND METHODS: Gait analysis was performed and surface EMG activity was recorded in 13 RLS patients and 8 normal controls from 8 muscles: tibialis anterior, gastrocnemius lateralis, gastrocnemius medialis, and soleus in both legs. RESULTS: Ten out of the 13 RLS patients and none of the normal control group showed a mild abnormality of the EMG activation of the gastrocnemius muscles during gait which, however, had no detectable effects on its kinematics. CONCLUSIONS: These preliminary results might be interpreted as the effect of an impaired supraspinal dopaminergic control with possible action on spinal structures involved in the control of gait. If confirmed in future studies, this mild EMG abnormality might constitute an additional supportive feature for the diagnosis of RLS in difficult cases.

The APOE epsilon4 allele increases the risk of impaired spatial working memory in obstructive sleep apnea.

BACKGROUND: Contradictory data have been published on the influence of Apolipoprotein E (APOE) epsilon4 allele on obstructive sleep apnea (OSA). The aims of this study were to confirm the presence of specific neuropsychological changes in OSA patients carrying the APOE epsilon4 allele and to clarify if these changes are due to the sole presence of this allele or to its interactions with OSA pathology. METHODS: The APOE genotype was examined in 123 patients with OSA and in 121 controls, together with a series of neuropsychological tests. RESULTS: OSA and control subjects had similar APOE genotype and allele distribution, but when neuropsychological tests were considered, OSA patients showed significantly lower values for verbal long-term (delayed free recall at the Rey auditory-verbal learning test) and working memory (bisyllabic words). Moreover, spatial span was found to be lower in OSA epsilon4 allele carriers than in non-carriers; this difference was not observed in controls. CONCLUSIONS: This study confirms the presence of a verbal memory impairment in OSA patients and provides evidence for a significant interaction of APOE epsilon4 allele and OSA on frontal lobe function in adults, possibly mediated by the presence of specific frontal lobe neuroanatomical changes in these patients.

The neurophysiology of the alternating leg muscle activation (ALMA) during sleep: study of one patient before and after treatment with pramipexole.

BACKGROUND AND PURPOSES: To report the neurophysiological features of a patient with alternating leg muscle activation (ALMA) during sleep, a quickly alternating pattern of anterior tibialis activation which might represent transient facilitation of a spinal central pattern generator for locomotion, perhaps due to the serotonergic effects of antidepressant medication. PATIENT AND METHODS: A 33-year-old male patient with ALMA. The patient underwent a complete and detailed study of his neurophysiological parameters during sleep, before and after treatment with pramipexole. RESULTS: The treatment with pramipexole was followed by a significant reduction in the rate of occurrence of ALMA, in reported insomnia, and in daytime sleepiness. The ALMA generally were preceded by cyclic alternating pattern A phases and increased heart rate in most instances. Visual scoring and spectral analyses suggested that after pramipexole more intense arousal was required to trigger ALMA. CONCLUSION: The evident beneficial effect induced by the treatment with pramipexole indicates that the spinal networks involved in the generation of ALMA might also be under the inhibitory control of dopaminergic networks. We suggest that ALMA can be seen even in the absence of other factors such as antidepressant therapy, sleep apnea or periodic leg movements during sleep, and might be considered as an additional phenomenon influenced by sleep instability. Our patient seems to indicate also that treatment with dopamine agonists can be useful in such patients because the treatment can be followed by a good clinical response.

Agrypnia excitata in a patient with progeroid short stature and pigmented Nevi (Mulvihill-Smith syndrome).

We report the video-polysomnographic sleep characteristics of a 25-year-old woman with the Mulvihill-Smith syndrome, a rare clinical condition characterized by progeria-like aspect, peculiar multiple pigmented nevi, low stature, and cognitive impairment. Among the various exams, two overnight video-polysomnographic recordings were carried out; moreover, cerebral MRI and molecular analysis of the prion protein gene (PRNP) were also performed. The video-polysomnographic recordings showed the absence of clear sleep episodes but the presence of periods during which the patient had poor contact with the environment, stereotyped afinalistic movements of the upper limbs and hands, irregular or periodic breathing (with central apnea episodes), heart rate arrhythmia, and rapid eye movements. Cerebral MRI showed only diffuse mild enlargement of the cortical sulci and the molecular genetics analysis of the PRNP was normal. Our clinical and neurophysiological study seems to indicate that a particular condition of severe sleep disruption, similar to some extent to that reported in the fatal familial insomnia and in the Morvan fibrillary chorea, which has been indicated as Agrypnia Excitata in recent literature, might be associated with the Mulvihill-Smith syndrome. The inclusion of a detailed study on the sleep characteristics of eventual additional patients will certainly help our understanding of this rare condition.

Heart rate variability during sleep in children with partial epilepsy.

Alterations in autonomic control of cardiac activity in epileptic patients have been reported by several studies in the past, and both ictal and interictal modifications of heart rate regulation have been described. Alterations of autonomic control of cardiac activity can play an important role in sudden unexplained death in patients with epilepsy (SUDEP). However, the presence of specific changes in heart rate variability (HRV) during sleep, not correlated with seizures, has not been assessed in children with epilepsy; for this reason, we evaluated features of cardiac autonomic function during sleep without ictal epileptiform electroencephalogram (EEG) activity in a group of children with partial epilepsy. Eleven patients (five males and six females; mean age 11.5 years, SD: 3.65 years) affected by partial epilepsy were admitted to this study; 11 normal subjects (five males and six females; mean age 12.9 years, SD: 2.72 years) served as a control group. All subjects slept in the laboratory for two consecutive nights. The data were analyzed during the second night. Sleep was polygraphically recorded [including one electrocardiography (ECG) channel] and signals were digitally stored. A series of 5-min ECG epochs were chosen from each sleep stage, during periods without evident ictal epileptiform activity in the EEG. Electrocardiography signals were analyzed for automatic detection of R-waves and, subsequently, a series of time- and frequency-domain measures were calculated. Epileptic subjects tended to show an overall lower HRV in both time- and frequency-domain parameters, principally during rapid eye movement (REM) sleep and, to a lesser extent, during sleep stage 2. Among the different bands, this decrease was most evident for the high-frequency band (HF) absolute power. For this reason, the ratio between the low-frequency band (LF) and HF was always higher in epileptic patients than in normal controls and the difference was statistically significant during sleep stages 3 and/or 4 and REM sleep. Our results indicate that during sleep, a particular condition of basal modification in autonomic characteristics occurs (mostly during REM sleep) in partial epilepsy patients. This finding might represent an important factor contributing to the complex mechanism of SUDEP which takes place most often during sleep and supports the need of studying HRV specifically during this state in subjects with seizures.