Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation tool for investigating the neurophysiology of different neurological and neuropsychiatric disorders, including Parkinson’s disease (PD) and other parkinsonian syndromes and movement disorders. Briefly, TMS enables targeted stimulation of specific cortical regions through externally applied magnetic pulses, avoiding surgical intervention (as it occurs in deep brain stimulation) and making it a safe, repeatable, and well-tolerated approach. Over the past two decades, extensive research has explored the clinical utility of TMS in PD, with particular emphasis on motor cortex excitability, synaptic plasticity, and functional connectivity, which are central contributors to both motor and non-motor symptoms in PD patients. In addition, repetitive TMS and related stimulation paradigms have been shown to positively modulate cortical plasticity, i.e., the brain’s capacity to reorganize neural circuits, suggesting potential benefits for longer-term non-pharmacological management and rehabilitation protocols. More recently, studies have also investigated the role of TMS in atypical and secondary parkinsonisms, indicating that it may help characterize distinct neurophysiological abnormalities and provide symptomatic improvement in selected patients. This narrative expert review provides a comprehensive summary of TMS applications across the wide spectrum of parkinsonian syndromes, highlighting not only clinical potential, but also methodological limitations and future research directions.

Abstract Introduction REM sleep behavior disorder (RBD) is classically considered a prodromal marker of α-synucleinopathies, yet it also occurs in association with other neurological disorders and with antidepressant use. Whether these forms represent clinically and biologically distinct entities remains insufficiently explored. This study aimed to compare multidimensional clinical profiles of idiopathic, antidepressant-associated, and tauopathy-associated RBD. Methods We retrospectively reviewed clinical and video-polysomnographic data of patients hospitalized between 2018 and 2023 with polysomnography-confirmed RBD, excluding individuals with Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. Patients were classified as idiopathic RBD (iRBD), antidepressant-associated RBD, or tauopathy-associated RBD. Demographic variables, disease duration, sleep-related comorbidities, cognitive status (including Mini-Mental State Examination), depressive symptoms, and neuroimaging findings (vascular damage and cerebral atrophy) were compared across groups using non-parametric statistics. Results Eighty-four patients were included (iRBD n = 45; antidepressant-associated RBD n = 27; tauopathy-associated RBD n = 12). Age at diagnosis did not differ between groups. Male predominance and longer disease duration characterized iRBD. Sleep-related comorbidities, including obstructive sleep apnea and periodic leg movements, were similarly prevalent across groups. Tauopathy-associated RBD showed a markedly higher prevalence of cognitive impairment or dementia, significantly lower MMSE scores, and more frequent and severe cerebral atrophy. Depressive symptoms were most prevalent in antidepressant-associated RBD, whereas vascular neuroimaging findings did not differ among groups. Conclusion RBD encompasses etiologically distinct clinical profiles. Stratification by underlying context reveals meaningful differences in cognitive, psychiatric, and neuroimaging features, with important implications for diagnosis, risk assessment, and clinical management. Support (if any) No specific external funding was received.

Abstract Background and aims Cerebral small vessel disease underlies both vascular cognitive impairment (VCI) and the common occurrence of white matter lesions (WMLs) to MRI in subjects without overt cognitive deficits. However, distinguishing pathological progression from age-related changes remains a diagnostic challenge. We compared longitudinal cognitive and transcranial Doppler (TCD) hemodynamics in VCI patients and in cognitively intact elderly subjects with WMLs (non-VCI). Methods 127 VCI and 83 non-VCI with MRI-documented WMLs underwent baseline and follow-up evaluations after 23.1 ± 6.5 months, including clinical assessment, neuropsychological testing focusing on executive functions and depressive symptoms, and TCD. Mean blood flow velocity (MBFV), peak systolic velocity (PSV), end-diastolic velocity (EDV), pulsatility index (PI), and resistivity index (RI) were measured. Repeated-measures ANOVA tested longitudinal changes and group interactions. Results Both groups exhibited cognitive decline over time, although with significantly worse performance in VCI. MBFV and EDV decreased in both groups, with a steeper decline in non-VCI, resulting in convergence with VCI values at follow-up. PSV showed opposite trajectories, decreasing in non-VCI and increasing in VCI. PI increased similarly in both groups, whereas RI showed a significantly greater and persistent increase in VCI. Significant group-by-time interactions were observed across major hemodynamic parameters. Conclusions Overall, TCD changes were more pronounced in VCI than those simply expected by age in cognitively intact subjects with WMLs. Persistent elevation of RI reflects sustained microvascular resistance and might represent an early marker of cognitive progression in VCI. TCD is a valuable diagnostic tool for identifying VCI-related hemodynamic dysfunction beyond the presence of WMLs without cognitive impairment. Conflict of interest Mariagiovanna Cantone: nothing to disclose; Francesco Fisicaro: nothing to disclose; Manuela Pennisi: nothing to disclose; Klizia Cortese: nothing to disclose; Giuseppe Lanza: nothing to disclose; Rita Bella: nothing to disclose.

Transcranial magnetic stimulation (TMS) is a widely used non-invasive brain stimulation techniques that gained growing interest as a diagnostic and therapeutic tool for Parkinson’s disease (PD), as well as for some atypical parkinsonisms and secondary parkinsonian syndromes. Briefly, TMS enables targeted stimulation of specific cortical regions through externally applied magnetic pulses, avoiding surgical intervention (as occurs in deep brain stimulation) and making it a safe, repeatable, and well-tolerated approach. Over the past two decades, extensive research has explored the clinical utility of TMS in PD, with particular emphasis on motor cortex excitability, synaptic plasticity, and functional connectivity, which are central contributors to both motor and non-motor symptoms in PD patients. In addition, TMS has been shown to modulate cortical plasticity, i.e., the brain’s capacity to reorganize neural circuits, suggesting potential benefits for longer-term non-pharmacological management and rehabilitation protocols. More recently, studies have also investigated the role of TMS in atypical and secondary parkinsonisms, indicating that it may help characterize distinct neurophysiological abnormalities and provide symptomatic improvement in selected patients. This updated literature review critically synthesizes current evidence on the application of different TMS protocols across the spectrum of parkinsonian disorders, highlighting clinical potential, methodological limitations, and future research directions.

INTRODUCTION:Right-to-left shunt (RLS) associated with a patent foramen ovale has been related with ischemic stroke. However, its relationship with MRI white matter hyperintensities (WMHs) remains debated. This cross-sectional, single-centre study investigated the prevalence of RLS detected by transcranial Doppler sonography (TCD) and its association with vascular lesions on MRI. PATIENTS AND METHODS:502 outpatients (mean age 47.8 ± 13 years; 45% male) with non-specific neurological symptoms underwent brain MRI and TCD with contrast saline. WMH severity was visually graded using the Fazekas scale. RESULTS:RLS was detected in 39% of the sample. No difference was found in demographics and clinical variables between those with and without RLS. No association was also found between RLS and MRI lesion load. As expected, a significant (P < .001) positive correlation was identified between age and Fazekas scores (ie, higher scores with increasing age). No effect on lesion load was found for sex, hypercholesterolemia, diabetes, obesity and smoking, while a statistically significant association (P = .016) was present for arterial hypertension (odds ratio 1.68, 95% CI, 1.10-2.56; among those with higher Fazekas scores). Finally, no significant association was found between RLS magnitude, both at rest and during the Valsalva manoeuver and the Fazekas scores. DISCUSSION:Although RLS was frequently detected in this cohort, it was not associated with the presence or severity of WMHs, which were instead driven by age and arterial hypertension. These findings support WMHs as MRI marker of cerebral small vessel disease rather than subclinical paradoxical embolism. This also suggests limited utility of routine TCD screening for RLS in patients with incidental WMHs and no history or sign of embolic features. CONCLUSIONS:In patients with non-specific neurological symptoms, we detected a high occurrence of RLS, although this was not associated with an increased risk or severity of WMHs. As such, paradoxical embolism may not be a major determinant of subclinical WMHs in this population.

To compare clinical and polysomnographic features of patients with isolated REM sleep behavior disorder (iRBD) and patients with clinically reported dream-enactment behaviors (DEB) occurring in the absence of REM sleep without atonia (RSWA), and to clarify the clinical significance of DEB without RSWA. We retrospectively reviewed clinical records and polysomnography of consecutive patients referred to a tertiary sleep and neurology center. Twenty-six patients with polysomnography-confirmed iRBD, 21 patients with DEB without RSWA, and 24 control subjects were included. Clinical features related to prodromal neurodegeneration, neuroimaging findings, sleep architecture, REM atonia indices, limb movements, and respiratory parameters were analyzed using age-adjusted comparisons with effect size estimation. Compared with DEB patients, iRBD patients were older and showed a higher prevalence of subtle extrapyramidal signs, lower cognitive performance, and a greater burden of vascular neuroimaging abnormalities. Clinically reported hyposmia and depression were infrequent and did not differ between groups. Both clinical groups exhibited increased sleep fragmentation and instability, most pronounced in iRBD, with DEB patients showing intermediate values. REM atonia robustly differentiated groups, whereas periodic limb movements during sleep and respiratory disturbance did not differ significantly after age adjustment. DEB occurring without RSWA are associated with a clinical and polysomnographic profile distinct from iRBD, characterized by preserved REM atonia and a lower burden of markers linked to prodromal neurodegeneration. These findings highlight the heterogeneity of DEB and support characterization beyond conventional RBD diagnostic criteria. Current knowledge/study rationale: Isolated REM sleep behavior disorder (iRBD) is defined by dream-enactment behaviors (DEB) with REM sleep without atonia (RSWA), whereas clinically reported DEB without RSWA presents a diagnostic challenge and unclear significance in relation to prodromal neurodegeneration. Study impact: In this retrospective tertiary-center cohort, iRBD patients had more extrapyramidal signs, lower cognitive performance, and greater vascular imaging abnormalities compared with DEB without RSWA, whereas both groups showed increased sleep instability. These findings highlight that DEB without RSWA has a distinct clinical and polysomnographic profile, supporting the need for characterization beyond conventional RBD diagnostic criteria.

BACKGROUND:REM sleep behavior disorder (RBD) is increasingly recognized as a heterogeneous condition that may arise in different etiological contexts, including an isolated form that is often a prodromal synucleinopathy, antidepressant exposure, and RBD occurring in the context of clinically diagnosed tau-spectrum neurodegenerative syndromes. The aim of this study was to compare clinical, cognitive, neuroimaging, and polysomnographic features of isolated RBD (iRBD), antidepressant-associated RBD (iatroRBD), and tauopathy-associated RBD (tauRBD) associated with Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, or frontotemporal dementia, within a single cohort. METHODS:We conducted a retrospective analysis of patients with polysomnographically confirmed RBD evaluated at a tertiary sleep center, excluding individuals with established synucleinopathies. Patients were classified as iRBD (n = 26), iatroRBD (n = 16), or tauRBD (n = 6) based on the current criteria. Demographics, non-motor symptoms, Mini-Mental State Examination (MMSE) scores, neuroimaging reports, and detailed polysomnographic parameters were compared using non-parametric statistics and effect sizes. RESULTS:Age, age at onset, and disease duration did not differ across groups. Sex distribution showed a significant male predominance in iRBD, with a more balanced distribution in iatroRBD and tauRBD. Cognitive performance differed markedly, with tauRBD patients showing significantly lower MMSE scores than both iRBD and iatroRBD, whereas cognition was largely preserved in the latter groups. Non-motor symptoms, including hyposmia and depressive symptoms, showed limited discriminatory value. Polysomnography revealed selective differences in REM sleep architecture, including reduced REM sleep percentage in tauRBD and prolonged REM sleep latency in iatroRBD, while REM atonia, limb movements, and respiratory parameters were broadly similar. CONCLUSIONS:RBD appears to be a shared motor phenotype that can arise in different etiological contexts. In this cohort, cognitive status, sex distribution, and selected REM sleep features were the most informative contextual markers, whereas history-derived non-motor features available in this retrospective dataset (hyposmia and depressive symptoms) and routine PSG metrics showed limited discrimination.

Background:Transcranial color-coded sonography (TCCS) is widely used to detect middle cerebral artery (MCA) stenosis in clinical settings; however, the image quality can be affected by temporal bone window acoustic transmission conditions. In this study, we evaluated the value of contrast-enhanced (CE)-TCCS for diagnosing MCA stenosis in patients with poor temporal bone windows. Methods:In total, 77 patients with 154 MCA images were assessed. The clinical symptoms were classified as symptomatic (n=28, 36.4%) and asymptomatic (n=49, 63.6%). The flow velocity parameters of the MCA images were measured, including the peak systolic velocity (PSV), end diastolic velocity (EDV), and mean flow velocity (MFV), with computed tomography angiography (CTA) used as a reference. The best cutoff value for the various velocity parameters measured by CE-TCCS for diagnosing MCA stenosis and its severity was determined based on the maximum Youden's index through receiver operating characteristic (ROC) curve analysis. Results:Symptomatic patients had a high prevalence of MCA stenosis [odds ratio (OR) =4.386; 95% confidence interval (CI): 1.110-17.324]. Out of the 154 MCA images with a poor temporal bone window under the TCCS modality, 133 (86.4%) had a good temporal bone window under the CE-TCCS modality. In the stenosis group, the PSV, EDV, and MFV values measured via CE-TCCS were significantly greater than those in the normal group (P<0.001). The flow velocity increases gradually with worsening stenosis severity (P<0.001). The optimal cutoff values for the mild stenosis and normal groups were as follows: PSV ≥173.5 cm/s (sensitivity: 96.7%, specificity: 95.2%), EDV ≥66.6 cm/s (sensitivity: 76.7%, specificity: 87.3%), MFV ≥102.5 cm/s (sensitivity: 83.3%, specificity: 95.2%); the optimal cutoff values for the moderate and mild stenosis were as follows: PSV ≥213 cm/s (sensitivity: 91.7%, specificity: 100%), EDV ≥84.5 cm/s (sensitivity: 83.3%, specificity: 80.0%), MFV ≥130.5 cm/s (sensitivity: 87.5%, specificity: 100%); the optimal cutoff values for the severe and moderate stenosis were as follows: PSV ≥261.5 cm/s (sensitivity: 93.8%, specificity: 100%), EDV ≥105 cm/s (sensitivity: 93.8%, specificity: 83.3%), MFV ≥159.5 cm/s (sensitivity: 93.8%, specificity: 95.8%). Conclusions:CE-TCCS can enhance the temporal bone window visualization in patients with poor temporal window under TCCS, providing diagnostic value for varying degrees of MCA stenosis.

Moyamoya angiopathy (MMA) is a rare, chronic progressive cerebrovascular condition characterized by bilateral stenosis or occlusion of the terminal internal carotid arteries and their major branches. This progressive occlusion triggers the development of telangiectatic and fragile vessels at the base of the brain, creating the characteristic angiographic appearance of a “puff of smoke.” Depending on the etiology, MMA is classified as Moyamoya Disease (MMD) when idiopathic and primary or Moyamoya Syndrome (MMS) when associated with underlying systemic conditions. While the RNF213 gene, particularly the p.R4810K variant, is recognized as the major susceptibility locus for MMD in East Asian populations, it does not fully account for the global genetic landscape or the phenotypic diversity of the disease. This review provides a comprehensive overview of the genetic architecture of the entire MMA spectrum, exploring loci beyond RNF213. We analyze the role of genes involved in vascular smooth muscle cell contractility (ACTA2, MYH11), TGF-β signaling, and DNA repair mechanisms that drive MMS, alongside the genetic basis of syndromic forms associated with neurofibromatosis type 1, trisomy 21, and RASopathies. Understanding these diverse genetic drivers is crucial for early diagnosis, risk stratification, and the development of targeted molecular therapies.

Background: Functional dizziness and persistent postural-perceptual dizziness (PPPD) involve mutually reinforcing vestibular symptoms and anxiety. Non-pharmacological interventions, such as vestibular rehabilitation therapy (VRT) and cognitive behavioral therapy (CBT), aim to address both mechanisms, yet their overall effectiveness remains unclear. Methods: We systematically examined randomized controlled trials (RCTs) published between 2000 and 2025 that evaluated VRT, CBT, or multimodal approaches for adults with functional or chronic dizziness (including PPPD and related functional dizziness constructs) accompanied by significant anxiety. Twelve RCTs (513 participants) met the criteria, involving individuals with PPPD, chronic subjective dizziness, chronic vestibular disorders with prominent anxiety, and residual dizziness after benign paroxysmal positional vertigo. Results: Conventional VRT delivered in clinic or as structured home-based programs produced small-to-moderate improvements in dizziness-related disability versus usual care. Combining VRT with CBT or psychologically informed components yielded larger and more consistent reductions in disability and maladaptive dizziness-related beliefs. CBT-based interventions reduced anxiety and dizziness-related distress compared with supportive controls. Emerging modalities, including virtual-reality-based VRT, non-invasive neuromodulation, and heart-rate-variability biofeedback, showed potential, although they were limited by small samples and methodological issues. Most trials had some risk-of-bias concerns and evidence certainty ranged from very low to moderate. Conclusions: Integrated multimodal rehabilitation shows promise, although larger, high-quality RCTs using standardized procedures and outcome measures are required.

STUDY OBJECTIVES:Isolated REM sleep Behavior Disorder (iRBD) is viewed as a prodromal stage of alpha-synuclein-related neurodegeneration. Transcranial Magnetic Stimulation (TMS) revealed early cortical excitability abnormalities in this condition. However, interhemispheric inhibitory mechanisms, measured through transcallosal inhibition, have not been previously investigated. METHODS:In this pilot study, we explored both intracortical and interhemispheric inhibition in 20 de novo right-handed iRBD patients compared with 20 right-handed healthy controls. Participants underwent cognitive testing, mood and sleepiness assessments, and extrapyramidal motor and non-motor evaluations. TMS was used to measure contralateral and ipsilateral silent periods (cSP, iSP) during stimulation of the left primary motor cortex. Although groups were age-matched, patients had lower educational levels and were predominantly male. RESULTS:iRBD patients displayed reduced cognitive performance but similar mood and sleepiness profiles. Motor symptoms were minimal, while non-motor symptoms showed a mild-to-moderate burden. Most TMS indices, ie, resting motor threshold, cSP latency, cSP duration, and iSP latency, were comparable between groups. Conversely, iSP duration was significantly shorter in iRBD patients, indicating pronounced interhemispheric disinhibition. After correction for multiple comparisons, only the positive correlation between non-motor symptoms scale scores and cSP latency remained significant. This suggests that delayed onset of intracortical inhibition may accompany a greater non-motor symptom load. CONCLUSION:Prolonged iSP duration and the finding on cSP latency in iRBD strengthen the notion of GABAergic dysfunction extending to transcallosal pathways. Such alterations might contribute to dream-enactment behaviors and subtle cognitive deficits observed. These exploratory findings open new avenues for understanding RBD pathophysiology and may support the development of targeted "pharmaco-TMS" strategies in prodromal synucleinopathies.

Background: Spasticity is a common and disabling feature of several neuromotor disorders. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a non-invasive approach to modulate corticospinal excitability and reduce spasticity, although its clinical effectiveness remains debated. This systematic review evaluated the efficacy and safety of rTMS in reducing spasticity in stroke and other neuromotor conditions. Methods: A systematic search of PubMed, Scopus, and Cochrane Library was conducted up to June 2025 in accordance with PRISMA 2020 guidelines. Eligible studies were randomized controlled trials (RCTs) comparing rTMS with sham stimulation or conventional therapy and assessing spasticity using validated scales, primarily the Modified Ashworth Scale. Included populations comprised patients with stroke, spinal cord injury, multiple sclerosis, cerebral palsy, and hereditary spastic paraplegia. Risk of bias was assessed using the RoB 2.0 tool, and certainty of evidence was evaluated with GRADE. Results: Twenty-six RCTs were included, mainly involving stroke patients. Most studies reported a significant reduction in spasticity with rTMS compared with control interventions. Low-frequency stimulation was commonly used after stroke, while excitatory protocols predominated in other conditions. Benefits generally persisted for up to 12 weeks. Evidence quality was moderate, and no serious adverse events were reported. Conclusions: rTMS appears to be a safe and promising adjunctive treatment for spasticity across neuromotor disorders. However, protocol heterogeneity and small sample sizes limit definitive clinical recommendations, highlighting the need for standardized, larger-scale studies.

Background: We synthesized evidence from randomized clinical trials (RCTs) published between 2019 and 2025 on repetitive transcranial magnetic stimulation (rTMS) in post-stroke cognitive impairment (PSCI) and compared different stimulation parameters, cortical targets, and combinations with rehabilitation interventions. Methods: A systematic review according to PRISMA guidelines examined the RCTs applying rTMS in adults with PSCI compared with control or sham groups. The primary outcome was improvement in cognitive function and functional outcomes measured with standardized scales. Results: Fifteen studies, involving a total of 732 patients, were included. The most frequently investigated were high-frequency (≥10 Hz) stimulation protocols of the left dorsolateral prefrontal cortex, with treatment cycles ranging from 2 to 6 weeks. Overall, rTMS was generally safe and well tolerated, with rare and mild adverse events. Several studies reported improvements in cognitive performance following rTMS, although effects were variable across trials and need caution in light of heterogeneity in stimulation protocols, sample sizes, outcome measures, and methodological quality. In most cases, rTMS or intermittent theta burst stimulation combined with structured cognitive training yielded greater cognitive and functional gains than stimulation or rehabilitation alone. This suggests a positive interaction between rTMS and cognitive training, although current evidence does not yet allow definitive conclusions. Conclusions: rTMS appears to be a promising strategy for post-stroke cognitive rehabilitation, particularly for attention and executive functioning. However, heterogeneity in stimulation protocols and outcome measures, along with limited sample sizes and short follow-up, reduces the certainty and comparability of current evidence. The widespread reliance on global screening tools may further underestimate domain-specific effects. Future multicentre trials with standardized protocols and more sensitive cognitive assessments are needed to clarify efficacy and guide further clinical application of rTMS in PSCI.

Major depressive disorder (MDD) is a prevalent and disabling condition. Transcranial direct current stimulation (tDCS) may improve symptoms by modulating neuroplastic and inflammatory mechanisms. This randomized, double-blind, placebo-controlled trial will recruit adult outpatients with MDD showing residual symptoms despite at least four weeks of stable SSRI treatment. Participants will be randomized to active or sham add-on tDCS while continuing their antidepressant regimen. The intervention will consist of 15 sessions over 3 weeks, targeting the left dorsolateral prefrontal cortex (anode F3, cathode F4) at 2 mA for 30 min per session. The primary outcome is the reduction of depressive symptoms measured by the Hamilton Depression Rating Scale-17 (HDRS), with remission defined as HDRS-17 ≤ 7. Secondary outcomes include cognitive performance (attention, executive functioning, memory), serum biomarkers (BDNF, VEGF, NGF, NRG1, angiogenin, IGF1, IL-6, TNF-α), cortical excitability assessed by transcranial magnetic stimulation (motor threshold, silent period, intracortical inhibition/facilitation), and cerebral hemodynamics by transcranial Doppler sonography (blood flow velocity, pulsatility, resistivity). Assessments will occur at baseline, post-treatment, and 3- and 6-month follow-ups. This trial aims to evaluate the efficacy of adjunctive tDCS in MDD with residual symptoms and its biological correlates, bridging clinical improvement with electrophysiological and neurovascular mechanisms.

Background To date, few data to transcranial Doppler sonography (TCD) are available in patients with mild vascular cognitive impairment (VCI) at risk for vascular or mixed dementia. In a previous study in patients with mild VCI and cerebral small vessels disease, a hemodynamic pattern of cerebral hypoperfusion and enhanced vascular resistance were observed; however, longitudinal data are currently lacking. Here, we perform a clinical, psychopathological, and neurosonological follow-up of patients with VCI in order to monitor any progression and to identify TCD measures to detect it. Methods From the original cohort of 161 patients, 127 with VCI (mean age 73.6 ± 7.1; 67 males) were re-evaluated after 5.0 ± 1.8 years. Namely, the Montreal Cognitive Assessment (MoCA), the 17-items Hamilton Depression Rating Scale (HDRS), and the Stroop Color-Word Interference Test (StroopT) were administered to screen for global cognitive status, to quantify depressive symptoms, and to explore executive functions, respectively. Mean blood flow velocity (MBFV), peak systolic blood flow velocity (PSV), end-diastolic blood flow velocity (EDV), pulsatility index (PI), and resistivity index (RI) were recorded from the middle cerebral artery, bilaterally. Results At follow up, patients exhibited a significant worsening of both MoCA (21.7 ± 2.1 vs. 20.7 ± 2.0) and StroopT scores (57.4 ± 19.4 vs. 59.7 ± 18.6), whereas HDRS showed an improvement, although the mean raw score remained above the cut-off value for depression (10.3 ± 6.6 vs. 9.8 ± 6.3). MBFV, PSV, and EDV showed a significant increase in PSV and PI and a reduction in EDV. When focused to younger patients (<65 years), we confirmed the significant worsening of both MoCA and StroopT but not HDRS, as well as the significant changes in PI and RI. Finally, considering the differences (D) between baseline and follow-up, the following significant correlations emerged, although with a small-to-medium effect size for all of them: positive correlation between MBFV-D and MoCA-D and between RI-D and STROOP-D, and a negative significant correlation between RI-D and MoCA-D. Conclusions Notwithstanding some limitations, such as the lack of a control group and neuroimaging data at follow-up, TCD may contribute to the early detection, monitoring, and management of VCI patients at risk for dementia. Together with compatible clinical and cognitive features, the exploration of early TCD markers that possibly indicate a higher risk of progression might represent an intriguing research direction and a significant clinical perspective.

Patent foramen ovale (PFO) represents a frequent congenital cardiac anomaly and the most common cause of right-to-left shunt (RLS), with relevant clinical implications in cryptogenic ischemic stroke among young adults. Accurate and standardized diagnostic strategies are essential to identify clinically significant shunts and guide therapeutic decisions, particularly regarding PFO closure. Under the auspices of the Italian Society of Neurosonology and Cerebral Haemodynamics (SINSEC), this position statement provides evidence-based recommendations on the diagnostic use of contrast-enhanced transcranial Doppler (c-TCD) for RLS detection. A structured literature review was conducted according to PRISMA 2020 methodology to ensure methodological transparency and rigor. The search covered PubMed, Scopus, and Web of Science databases for studies published between January 1990 and February 2025, using predefined keywords related to RLS, PFO, c-TCD, diagnostic accuracy, and procedural protocols. Eligible studies were screened and critically appraised to synthesize current evidence on diagnostic applications, methodological variability, and clinical utility of c-TCD. Subsequently, a Delphi consensus process was undertaken among representatives from 11 neurosonology centers with recognized expertise in cerebrovascular diagnostics. Three iterative rounds were conducted to reach agreement on key aspects of the c-TCD protocol, including patient preparation, contrast agent administration, monitoring settings, and shunt grading criteria. Draft recommendations were developed, revised collectively, and approved through a final plenary consensus meeting. The resulting position statement defines a standardized protocol for the execution, interpretation, and reporting of c-TCD in RLS diagnosis. Adoption of these consensus-based recommendations aims to enhance diagnostic accuracy, improve inter-center consistency, and support the broader clinical and research integration of c-TCD in cerebrovascular diagnostics.

The continuously increasing life expectancy contributes to the aging of populations, making them more susceptible to chronic diseases, including neurodegenerative disorders. The lack of effective disease-modifying treatments for these conditions highlights the importance of prevention strategies and the shift towards balanced diets and healthy lifestyles. It is thus highly relevant to study dietary exposures such as coffee, which is a rich source of many bioactive molecules, including caffeine and (poly)phenols, and is one of the most widely consumed beverages globally. Given this context, this chapter explores the current evidence on the relationship between habitual coffee consumption and neurodegenerative diseases. Emerging evidence from observational studies indicates that consuming coffee in moderate amounts could be linked to a lower risk of developing Alzheimer’s and Parkinson’s disease. These potential beneficial effects of coffee could be partially attributed to its richness in bioactive compounds such as caffeine and (poly)phenols, which may exert neuroprotective effects through direct and indirect mechanisms, including regulation of neuroinflammatory pathways, neuronal apoptosis, mitochondrial function, and aberrant protein aggregation. However, due to inconsistencies in the scientific literature regarding the association between coffee and cognitive disorders, further research is warranted. This research should consider different types of coffee and distinguish between the types and progression stages of neurocognitive disorders.

Introduction:One of the commonly used indices of short-term memory (STM) is the digit span task. Prior studies have proposed pupil dilation as a measure of task engagement and as a promising biomarker of vagal activation. Transcutaneous auricular vagus nerve stimulation (taVNS) is a novel non-invasive brain stimulation technique which might be used to improve cognition and modulate pupil size through its effects on the noradrenergic release in the locus coeruleus. No previous study has investigated the effects of off-line taVNS on a digit span task. With this single-blind, sham-controlled, crossover design trial, we aimed to assess whether taVNS was able to improve the digit span score, as well as to modulate the pupillary response to cognitive load in a sample of 18 elderly Japanese volunteers with no self-reported cognitive impairments. Results:Subjects were randomized to receive either real or sham taVNS during a digit span task while recording the pupil size, and then switched over to the other treatment group. We found that real stimulation significantly reduced the mean number of errors performed at span length 7, 8, and 9 (-0.83, -0.90, and -0.39, respectively compared to pre-stimulation values, and -0.71, -1.08, and -0.79, respectively, compared to sham stimulation). Additionally, real taVNS stimulation slightly but significantly increased the pupil size at all span lengths during the encoding period of the task, with larger effects for span 7-10 compared to pre-stimulation, and for span 5-10 compared to sham. No effect over the pupil size was found during the recall period. Discussion:Our results suggest that taVNS might selectively improve the cognitive performance during the encoding phase of the task. Although further studies are needed to better clarify the optimal stimulation parameters, findings from this study could support the use of taVNS as a safe neuromodulation technique to improve cognitive function.