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Transcranial magnetic stimulation-evoked electroencephalography potentials (TEPs) have been used to study motor cortical excitability in healthy subjects and several neurological conditions. However, optimal recording parameters for TEPs are still debated. Stimulation rates could affect TEP amplitude due to plasticity effects, thus confounding the assessment of cortical excitability. We tested whether short interpulse intervals (IPIs) affect TEP amplitude.

Abstract Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Abstract Increasing evidence suggests that the cerebellum may have a role in the pathophysiology of Parkinson’s disease (PD). Hence, the scope of this study was to investigate whether there are structural and functional alterations of the cerebellum and whether they correlate with motor and non-motor symptoms in early PD patients. Seventy-six patients with early PD and thirty-one age and sex-matched healthy subjects (HS) were enrolled and underwent a 3 T magnetic resonance imaging (MRI) protocol. The following MRI analyses were performed: (1) volumes of 5 cerebellar regions of interest (sensorimotor and cognitive cerebellum, dentate, interposed, and fastigial nuclei); (2) microstructural integrity of the cerebellar white matter connections (inferior, middle, and superior cerebellar peduncles); (3) functional connectivity at rest of the 5 regions of interest already described in point 1 with the rest of brain. Compared to controls, early PD patients showed a significant decrease in gray matter volume of the dentate, interposed and fastigial nuclei, bilaterally. They also showed abnormal, bilateral white matter microstructural integrity in all 3 cerebellar peduncles. Functional connectivity of the 5 cerebellar regions of interest with several areas in the midbrain, basal ganglia and cerebral cortex was altered. Finally, there was a positive correlation between abnormal functional connectivity of the fastigial nucleus with the volume of the nucleus itself and a negative correlation with axial symptoms severity. Our results showed that structural and functional alterations of the cerebellum are present in PD patients and these changes contribute to the pathophysiology of PD in the early phase.

Abstract This single-centre retrospective cohort study reports on the results of a descriptive (non-comparative) retrospective cohort study of early initiation of antivirals and combined monoclonal antibody therapy (mAbs) in 48 severely immunocompromised patients with COVID-19. The study assessed the outcomes and the duration of viral shedding. The patients started early combined therapy (ECT) a median of 2 days (interquartile range [IQR]: 1–3 days) after the diagnosis of SARS-CoV-2 infection. Except for 1 patient who died due COVID-19-related respiratory failure, patients had their first negative nasopharyngeal swab result after a median of 11 days (IQR: 6–17 days) after starting combined therapy. There were no reports of severe side effects. During a follow-up period of 512 days (interquartile range [IQR]: 413–575 days), 6 patients (12.5%) died and 16 (33.3%) were admitted to hospital. Moreover, 12 patients (25%) were diagnosed with SARS-CoV-2 reinfection a median of 245 days (IQR: 138–401 days) after starting combined treatment. No relapses were reported. Although there was no comparison group, these results compare favourably with the outcomes of severely immunocompromised patients with COVID-19 reported in the literature.

The search for reliable and easily accessible biomarkers in Parkinson’s disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson’s disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson’s disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson’s disease, has been the most investigated Parkinson’s disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson’s disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson’s disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson’s disease patients: total tau, phosphorylated tau, amyloid-β1–42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson’s disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson’s disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

Therapeutic communities face high drop-out rates and general distrust of their effectiveness among substance users. Actively involving users early in treatment promotes greater compliance with the treatment and is predictive of better outcomes. However, users often occupy a passive and subordinate role, exacerbated by the lack of research that explores their perspectives, beliefs, and experiences. This study examined the discourses of 57 consumers who were part of a community for less than 15 days, investigating the meanings attributed to service entry and treatment. A protocol of four written open-ended questions was employed and analysed through discourse analysis and positioning theory. The results indicate that participants configure the community as a place symbolically and spatially distinct from the rest of the world, where they isolate themselves to seek support during times of extreme difficulty. However, what they are seeking is a solution to acute distress caused by substance use, intertwined with social, economic, and relational issues. The concept of treatment is built on the image of the substance user as an individual making a weak request for help, attributing the problem solely to drugs and exhibiting reduced agency in addressing their issues. The collected texts provide a better understanding of the experiences of new users, highlighting the importance of co-constructing personalised projects that empower consumers to feel actively involved in their own change, exploring their theories and definitions of self to structure pathways based strictly on their needs.

Introduction Suicide is one of the leading causes of death worldwide and scientific community investigates suicide risk factors relentlessly. Among these, anxiety symptoms were strongly related to suicidal ideation in several studies. Moreover, sleep and its disturbances are closely connected to mental well-being and psychiatric disorders in a bidirectional pathway. Objectives The main purpose of the present study is to assess the relationship between anxiety symptoms and suicidal ideation in a sample of psychiatric patients and the mediational role of insomnia in this association. Methods Participants were 116 consecutive adult psychiatric inpatients (61 women and 55 men) enrolled to the psychiatric inpatient unit of Sant’Andrea Hospital in Rome. The measures used were a socio-anamnestic form, the Columbia Suicide Severity Rating Scale (C-SSRS), the Hamilton Anxiety Rating Scale (HAM-A), and the Insomnia Severity Index (ISI). Results Based on the results of statistical analysis, patients with suicidal ideation showed higher severity of insomnia and higher severity of anxiety symptoms than patients with no suicidal ideation. Moreover, the intensity of suicidal ideation was positively and significantly associated with the severity of anxiety symptoms and with the severity of insomnia. Finally, the mediation analysis showed that the effect of anxiety symptoms on suicidal ideation was completely mediated by insomnia severity. Conclusions The main result of the study indicates that patients who perceive more anxiety symptoms were more likely to experience higher suicidal ideation intensity through higher levels of insomnia. These findings implies that screening for sleep disturbances may help identify individuals at risk for suicide, and improving sleep quality through psychosocial and pharmacological treatments could mitigate the association between anxiety and suicidal ideation. Disclosure of Interest None Declared

Introduction Suicide is a multifactorial phenomenon characterized by many biological, psychological, and social-cultural factors. The study of this phenomenon in migrants is complex, with no theoretical framework that can describe the available heterogeneous data. Although Italy has the fourth largest migrant population of EU, only few studies have assessed suicidal risk in migrants. Objectives The aim of his study is to assess suicide risk factors (hopelessness; interpersonal needs; traumatic experiences) in a sample of migrant patients, and to evaluate the possible application of the Interpersonal Theory of Suicide (ITS). Moreover, suicidal ideation and attempts were compared between migrants and natives. Lastly, a wider psychometric assessment has been conducted (depressive and anxiety symptoms; autistic traits). Methods In this case-control study, we included 50 migrants vs. 50 natives. Data were collected during the same period by gender, age, and diagnosis. We collected sociodemographic and clinical characteristics. We administered the following tests: Columbia Suicide Severity Rating Scale, Interpersonal Needs Questionnaire, Beck Hopelessness Scale, Beck Depression Inventory-II, Hamilton Anxiety Scale, Childhood Trauma Questionnaire, and Adult Autism Subthreshold Spectrum. Results There were no differences in sociodemographic characteristics, except for ethnicity. Otherwise, there were significative differences between diagnosis (p:0.013), with native reporting more Mood Disorders, and migrants reporting more Anxiety, Obsessive-Compulsive, Trauma-Related, Eating, and Substance Use Disorders. Migrants were more prone to be on treatment with Mood Stabilizers (p:0.000). There were significative differences for interpersonal needs, trauma, anxiety, and autistic traits. Migrants show more perceived burdensomeness (p:0.05), more physical neglect (p:0.004), physical abuse (p:0.002), and sexual abuse (p:0.016), more anxiety symptoms (p:0.046), and more empathy alterations (p:0.014). No differences were found for suicidal ideation and attempts, hopelessness, and depressive symptoms. Conclusions Despite there were no differences in suicide risk, migrants showed higher rates of perceived burdensomeness (PB) and childhood traumatic experiences (CTE). Both PB and CTE represent cardinal constructs of the ITS. No differences were found for hopelessness and depressive symptoms. Migrants showed higher rates of anxiety symptoms and empathy alterations. Even if suicide rates between migrants and natives were similar, accurate assessment of suicidal risk in migrants is crucial in improving suicide prevention strategies. Suicide risk evaluation in migrants should consider the application of ITS. For an appropriate clinical evaluation of the migrant patients, anxiety dimensions and autistic traits should be investigated. Disclosure of Interest None Declared

Introduction In patients affected by Schizophrenia and Bipolar Disorder disorders the use of antipsychotic drugs is essential in preventing the exacerbation of symptoms. The use of long-acting injectable (LAI) antipsychotics is considered an important treatment option. The aim of this study was to evaluate the incidence and predictors of relapse during antipsychotic treatment with LAIs in a sample of psychiatric outpatients up to a year after the start of long-acting therapy. Objectives The study included 103 adult patients admitted to the psychiatric unit of Sant’Andrea University Hospital in Rome. Methods We evaluated duration of untreated illness, previous treatments, substance abuse, suicidal status, LAI dose, and use of other medicines for association with new episodes of illness or of symptomatic worsening as well as hospitalization, using bivariate and multivariate analyses. Results Seventy-three patients were diagnosed with schizophrenia spectrum and 30 with bipolar disorders. Age at study entry averaged 36.7 years (SD= 11.55). 40.8% of patients were women. The mean age at onset were 23.11 (SD= 7.0). All the other information were reported in Table 1. On 103 patients undergoing with LAI treatment for a year only 9 (8.7%) patients had a relapse during the study period. The two groups differed according to the presence of hospitalization during the 12 months before the LAI treatment (p = .022), in particular patients with relapse were more hospitalized than patients with no relapse (62.5% vs. 21.7%). Moreover, group with relapse were more at risk of suicide during the 12 months before the LAI treatment than the other group, for both suicidal ideation (11.1% vs. 4.3%; p= .015) and attempt (25.0% vs. 3.2%; p= .049). Finally, the two groups differed according to the side effects reported during the year of LAI treatment (χ² =38.48; p< .001). Specifically, patients’ group with relapse reported more side effects caused by parkinsonism (25.0% vs. 1.1%) and tremor (25.0% vs. 0%). No differences were found for the other variables (See table 1). Image: Conclusions In conclusion, our observations confirm the importance of LAI therapy in real word. However, our results indicate that these drugs might not prevent subsequent exacerbations for a proportion of individuals whose illness is stabilised on continuous antipsychotic treatment. Extra pyramidal symptoms in particular might have pathophysiological implications for relapse. Disclosure of Interest None Declared

BackgroundAging clocks tag the actual underlying age of an organism and its discrepancy with chronological age and have been reported to predict incident disease risk in the general population. However, the relationship with neurodegenerative risk and in particular with Parkinson’s Disease (PD) remains unclear, with few discordant findings reporting associations with both incident and prevalent PD risk.ObjectiveTo clarify this relationship, we computed a common aging clock based on blood markers and tested the resulting discrepancy with chronological age (ΔPhenoAge) for association with both incident and prevalent PD risk.MethodsIn a large Italian population cohort - the Moli-sani study (N=23,437; age ≥ 35 years; 52% women) - we carried out both Cox Proportional Hazards regressions modelling ΔPhenoAge as exposure and incident PD as outcome, and linear models testing prevalent PD as exposure and ΔPhenoAge as outcome. All models were incrementally adjusted for age, sex, education level completed and other risk/protective factors previously associated with PD risk in the same cohort (prevalent dysthyroidism, hypertension, diabetes, use of oral contraceptives, exposure to paints, daily coffee intake and cigarette smoking).ResultsNo significant association between incident PD risk (209 cases, median (IQR) follow-up time 11.19 (2.03) years) and PhenoAging was observed (Hazard Ratio [95% Confidence Interval] = 0.98 [0.71; 1.37]). However, a small but significant increase of ΔPhenoAge was observed in prevalent PD cases vs healthy subjects (β (Standard Error) = 1.39 (0.70)). An analysis of each component biomarker of PhenoAge revealed a significant positive association of prevalent PD status with red cell distribution width (RDW; β (SE) = 0.46 (0.18)). All the remaining markers did not show any significant evidence of association.ConclusionThe reported evidence highlights systemic effects of prevalent PD status on biological aging and red cell distribution width. Further cohort and functional studies may help shedding a light on the related pathways altered at the organism level in prevalent PD, like red cells variability, inflammatory and oxidative stress mechanisms.

Summary: Background: Suicide is a serious but preventable public health concern at the global level, showing relevant geographical differences. This study aims to monitor global temporal and geographical patterns in suicide mortality in pre-adolescents, adolescents, and young adults (i.e., aged 10–24 years), from 1990 to 2020 or the most recent available year. Methods: Using the World Health Organisation mortality database, we conducted an analysis on a subset of 52 countries with valid and high-quality data. We computed age-standardised suicide rates (ASR) by sex, country, and calendar year, and performed a joinpoint regression analysis to identify significant changes in the temporal suicide trends over the studied period. Findings: High variability in suicide rates and trends was observed, with a male-to-female ratio of two to five. Between 1990 and 2020, most European countries reported declining suicide trends, with some exceptions. In particular, alarming trends emerged in the United Kingdom, with annual rises of 2.5% (95% CI: 1.6–3.5) since 2005 among males and 8.5% (95% CI: 4.7–12.6) since 2012 among females. The most favorable trends and lowest suicide rates were in Southern Europe, with 3.1/100,000 persons in Italy (2020) and 3.5/100,000 persons in Spain (2021) among males, and 0.9/100,000 persons in Italy (2020) and 1.1/100,000 persons in Romania (2019) among females. Conversely, the highest rates were in Central-Eastern Europe, with 10.2/100,000 males in the Russian Federation (2019) and 10.0/100,000 males in Poland (2002). Higher suicide rates and significant increases were reported in not European areas. The highest ASR was 15.5/100,000 males in the United States of America, with an annual increase of 3.8% (95% CI: 3.1–4.5) among males in 2009–2020 and 6.7% (95% CI: 5.6–7.8) among females in 2007–2017, followed by a levelling off. Interpretation: Temporal and geographical comparisons of suicide mortality should be interpreted with caution due to potential misclassification or under-reporting of suicide deaths in some countries. Funding: None.

Oligomeric alpha-synuclein (α-syn) in saliva and phosphorylated α-syn deposits in the skin have emerged as promising diagnostic biomarkers for Parkinson’s disease (PD). This study aimed to assess and compare the diagnostic value of these biomarkers in discriminating between 38 PD patients and 24 healthy subjects (HSs) using easily accessible biological samples. Additionally, the study sought to determine the diagnostic potential of combining these biomarkers and to explore their correlations with clinical features. Salivary oligomeric α-syn levels were quantified using competitive ELISA, while skin biopsies were analyzed through immunofluorescence to detect phosphorylated α-syn at Ser129 (p-S129). Both biomarkers individually were accurate in discriminating PD patients from HSs, with a modest agreement between them. The combined positivity of salivary α-syn oligomers and skin p-S129 aggregates differentiated PD patients from HSs with an excellent discriminative ability with an AUC of 0.9095. The modest agreement observed between salivary and skin biomarkers individually suggests that they may reflect different aspects of PD pathology, thus providing complementary information when combined. This study’s results highlight the potential of utilizing a multimodal biomarker approach to enhance diagnostic accuracy in PD.

Background: Ischemic stroke may trigger neuroplastic changes via proliferation, migration towards the lesion, and differentiation of neuroprogenitor cells into mature neurons. Repetitive Transcranial Magnetic Stimulation (rTMS) may promote brain plasticity. This study aimed to assess rTMS’s effect on post-stroke endogenous neuroplasticity by dosing plasma miRs 17~92, Netrin-1, Sema3A, and BDNF. Methods: In this case-controlled study, we randomized 19 ischemic stroke patients within five days from symptoms onset (T0) to neuronavigated-rTMS or sham stimulation. Stimulation was applied on the stroke hemisphere daily between the 7th and 14th day from stroke onset. Blood samples were collected at T0, before the first rTMS section (T7), and at the end of the last rTMS session (T14). Five healthy controls were also enrolled in this study. Results: Of 19 patients, 10 received rTMS and 9 sham stimulation. Compared with the sham group, in the rTMS group, plasma levels of miRs17~92 and Ntn-1 significantly increased whereas Sema3A levels tended to decrease. In multivariate linear regression analyses, rTMS was independently related to Ntn-1 and miR-25 levels at T14. Conclusions: We found an association between rTMS and neurogenesis/axonogenesis biomarker enhancement. Our preliminary data suggest that rTMS may positively interfere with natural endogenous plasticity phenomena of the post-ischemic human brain.

Abstract Background The reduction of multiple psychiatric hospitalizations is an important clinical challenge in mental health care. In fact, psychiatric re-hospitalization negatively affects the quality of life and the life expectancy of patients with psychiatric disorders. For these reasons, identifying predictors of re-hospitalization is important for better managing psychiatric patients. The first purpose of the present study was to examine the readmission rate in a large sample of inpatients with a psychiatric disorder. Second, we investigated the role of several demographical and clinical features impacting re-hospitalization. Method This retrospective study enrolled 1001 adult inpatients (510 men and 491 women) consecutively admitted to the University Psychiatric Clinic, Sant'Andrea Hospital, Sapienza University of Rome between January 2018 and January 2022. To identify risk factors for psychiatric re-hospitalization, we divided the sample into 3 subgroups: the Zero-Re group which had no readmission after the index hospitalization, the One-Re group with patients re-admitted only once, and the Two-Re with at least two re-admissions. Results The groups differed according to previous hospitalizations, a history of suicide attempts, age at onset, and length of stay. Furthermore, the results of the regression model demonstrated that the Two-Re group was more likely to have a history of suicide attempts and previous hospitalizations. Discussion These results indicate the importance of assessing risk factors in psychiatric hospitalized patients and implementing ad hoc prevention strategies for reducing subsequent re-hospitalizations.