OBJECTIVE:Dysfunction of GABABergic intracortical inhibition has previously been demonstrated in the primary motor cortex of patients suffering from post-COVID19 condition (pCVD). Here, we searched for alterations in GABAB-mediated inhibition in the prefrontal cortex (PFC), a crucial area for cognition. METHODS:Sixteen pCVD patients complaining cognitive complaints underwent a combined paired-pulse transcranial magnetic stimulation and electroencephalography (TMS-EEG) protocol of long-interval intracortical inhibition (LICI) over the left PFC. Global cognition was evaluated using the Montreal Cognitive Assessment. Twelve healthy volunteers (HV) matched for gender, age and education served as the control group. RESULTS:Patients with pCVD showed lower oscillatory activity and cognitive performance compared to HV (p < 0.05). No significant LICI effects were observable in the oscillatory activity of pCVD patients, whereas these were observable in HV. A linear relationship between individual levels of gamma (r = -0.479; p = 0.030) and beta (r = -0.478; p = 0.031) frequencies inhibition and cognitive performance was observed in pCVD patients. CONCLUSIONS:GABAB- receptor mediated intracortical inhibition in the PFC is disrupted in pCVD patients with cognitive complaints and inversely correlated to cognitive performance. SIGNIFICANCE:TMS-EEG could be used to identify early alterations of cortical oscillatory activity in prefrontal regions related to the pCVD and inducing subtle cognitive decline.

Goal-directed actions, such as picking up, manipulating, or using objects, are so ubiquitous that impairments in these skills can severely impact quality of life. Reaching-grasping behaviors are driven by a frontoparietal network, with the ventral premotor cortex (PMv) and the primary motor cortex (M1) serving as critical frontal nodes. PMv-M1 connectivity can be modulated using cortico-cortical paired associative stimulation (cc-PAS), which involves repeated paired transcranial magnetic stimulation (TMS) of both nodes. Stimulating M1 with an anterior-posterior (AP) current direction selectively enhances corticospinal excitability during isometric precision grip, but not during isometric power grip. However, it is unclear how the plasticity induction in the more superficial PMv-M1 connectivity may influence the preparation and execution of goal-directed, naturalistic reaching-grasping actions. In this study, participants performed reaching-grasping actions toward small or large objects, requiring precision or power grip, before and after applying the PMv-M1 cc-PASAP protocol. The plasticity-induction protocol selectively modulated the joint angles temporal synergies during precision grip actions, suggesting a reorganization of whole-arm reaching-grasping coordination. The analyses of the joint angles spatial synergies did not reveal comparable effects. Taken together, these findings suggest that the PMv-M1 plasticity-induction protocol primarily modulated the temporal, rather than the spatial, control of joint angles recruitment during precision grip actions. Given that such basic skills are often permanently lost in stroke patients, our findings may offer valuable insight for the development of innovative therapeutic approaches for this clinical population.

Fasudil hydrochloride (FAS) is a selective Ras homologous (Rho) associated kinase (ROCK) inhibitor and vasodilator used to treat cerebral vasospasm. Owing to its neuroprotective effects in preclinical models of neurodegeneration, FAS is currently under clinical investigation for several neurological diseases. Although the precise mechanism of action of FAS remains unclear, some preclinical studies suggest that it may exert anxiolytic and anticonvulsant effects—pharmacological activities typically associated with positive allosteric modulators of the γ‑aminobutyric acid (GABA)-A ​ receptor, such as benzodiazepines. This study investigates whether FAS acts as a modulator of the GABA-A ​ receptor and examines the effects of its chronic administration. Protein comparative analyses and in silico docking assays were performed to assess the binding affinity of FAS for the GABA-A​ receptor. CD1 mice received daily oral administration of FAS for 12 weeks. One week after treatment cessation, behavioural tests and magnetic resonance (MR) analyses were conducted to evaluate brain function and metabolism. In addition, Rho guanosine triphosphatase activity, GABA-A receptor expression, and levels of postsynaptic density protein 95 (PSD‑95) were assessed. The computational analysis predicted a strong binding affinity of FAS for the GABA-A​ receptor. In vivo assays revealed that FAS impaired contextual fear memory without affecting anxiety-like behaviour, motor coordination, or recognition memory. These behavioural alterations were accompanied by a reduction in the γ2 subunit of the GABA-A​ receptor in both the hippocampus and the prefrontal cortex (PFC). Within the PFC, PSD‑95 expression was decreased, whereas the activity of Ras-related C3 botulinum toxin substrate 1 was increased. MR analyses showed elevated glutamate levels in the PFC, together with a general increase in total choline and a mild impairment of white matter integrity. Our findings suggest that FAS influences GABA-A receptor expression and may act as an allosteric modulator. Chronic treatment in healthy mice appears to adversely affect the PFC, producing behavioural and molecular alterations resembling those observed following prolonged benzodiazepine exposure.

Cerebellar rhythms provide frequency-specific support for motor, cognitive and affective functions. These oscillations are not epiphenomenal but rather dynamically regulated, spatially organized control signals that contribute to the coordination of prediction, error correction, learning and internal model updating. By synchronizing neuronal activity across cerebellar and distributed brain networks at multiple timescales, cerebellar rhythms enable precise and adaptable behaviour and coordination across neural systems. Accordingly, they offer biologically grounded targets for network-level diagnostics and therapeutic neuromodulation. At the circuit level, cerebellar rhythms within distinct frequency bands, ranging from theta and beta to gamma and very high-frequency oscillations, arise from specific microcircuit mechanisms within the inferior olive, the granular and molecular layers of the cerebellar cortex, and the deep cerebellar nuclei. These rhythms structure spike timing and help shape synaptic plasticity windows, forming a frequency-organized substrate for learning and control. Here we describe a frequency-function-modulation framework that links cerebellar oscillations to their behavioural roles and to neuromodulatory interventions. By integrating evidence from animal studies, computational models and non-invasive stimulation studies, we position cerebellar oscillations as a bridge between cerebellar circuit dynamics and systems-level coordination, thereby providing a mechanistic rationale for precision neuromodulation across motor and cognitive domains in neurological and psychiatric conditions.

Matching brain stimulation to the brain's natural rhythms can drive plasticity, yet this principle has rarely been tested in humans. We targeted the cerebellum, a key hub for motor coordination and learning, using a rhythm-tuned protocol that pairs theta-frequency transcranial alternating current stimulation with intermittent theta-burst stimulation to engage plasticity of cerebello-cortical circuits. In young healthy adults, this pairing enhanced fine motor control and hand dexterity, with gains closely tracking physiological markers of cerebellar-driven plasticity. Applying the same approach in chronic stroke survivors yielded parallel behavioral and neural gains, demonstrating preserved rhythm-plasticity coupling despite injury. Control experiments confirmed both frequency specificity and site specificity, underscoring the mechanistic precision of the intervention. By linking theta-frequency cerebellar stimulation to circuit-level and functional outcomes, these findings establish a biologically grounded framework for targeted neurorehabilitation. Rhythm-specific cerebellar stimulation provides a scalable strategy for enhancing plasticity and improving motor function across movement disorders and motor impairments.

Transcranial magnetic stimulation (TMS) is a non-invasive technique to stimulate the brain, while electroencephalography (EEG) is a non-invasive technique to record its electrical activity. Their combined use (TMS-EEG) has been established only relatively recently, after successful development of TMS-compatible EEG amplifiers. TMS-EEG offers the unparalleled opportunity to directly perturb the brain with TMS and simultaneously record its response with EEG. This allows inferences on causal input-output relationships, therefore going critically beyond purely observational techniques, such as resting-state EEG or functional MRI, in the study of brain dynamics. This consensus review updates the work of Tremblay and coworkers [Clin Neurophysiol 2019; 130: 802-844]. Since then, substantial advances have been made in understanding contamination of TMS-EEG signals by physiological and non-physiological artifacts, as well as in developing strategies to avoid or control them. In parallel, new insights have emerged regarding the physiological mechanisms underlying TMS-EEG responses and their diagnostic and prognostic utility in a broad range of psychiatric and neurological disorders. As such, TMS-EEG is rapidly shaping a dynamic new field in clinical neurophysiology and neuroscience. This review provides a critical and comprehensive synthesis of current knowledge, including practical guidance for implementing TMS-EEG in the clinical setting.

Patients with Alzheimer’s disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN. This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale–Sum of Boxes (CDR-SoB), the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively. This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment. ClinicalTrials.gov, NCT07075770, registered 10 July 2025.

Cerebellar ataxia (CA) is a neurodegenerative disorder characterized by progressive impairments in coordination, balance, and gait disturbances. Conventional rehabilitation therapies offer only limited benefits, driving interest toward exploring alternative non-invasive interventions. Among these, non-invasive brain stimulation techniques, such as cerebellar transcranial alternating current stimulation (tACS) and intermittent theta burst stimulation (iTBS) have emerged as promising approaches. This study aims to investigate the effectiveness of a combined cerebellar tACS-iTBS protocol in alleviating symptoms of CA, specifically targeting improvements in motor coordination, balance control, and quality of life. In this randomized, sham-controlled crossover study, 31 patients diagnosed with CA will participate in two experimental conditions (real and sham stimulation), each lasting 2 weeks (phase A and B) and separated by a 3-week washout period. In the real condition, patients will receive cerebellar tACS at 5 Hz (2 mA, 190 s) delivered simultaneously with iTBS (600 pulses at 50 Hz; 80

IntroductionCognitive reserve (CR) has been proposed as a key factor explaining inter-individual variability in cognitive performance despite comparable neuropathology. However, its role across the Alzheimer’s disease (AD) continuum remains unclear. This study investigates stage-dependent effects of CR on the relationship between memory performance and brain structural network integrity across healthy subjects (HS), individuals with subjective cognitive decline (SCD), and patients with amnestic mild cognitive impairment (a-MCI), and AD dementia.Materials and methodsA total of 209 participants underwent a comprehensive neuropsychological assessment and 3T MRI. Source-based morphometry identified three grey matter structural covariance networks, involving orbitofrontal-temporal-insular regions (OTIN), precuneus-posterior cingulate cortex (PreCiN), and cingulate-hippocampal regions (CHiN). A composite memory score was derived using factor analysis. Regression and moderation models examined the predictive and moderating effects of CR (operationalized as years of education) and network integrity on cognitive performance within each group.ResultsOTIN and PreCiN showed progressive structural vulnerability along the AD continuum, whereas CHiN showed no significant between-group differences. Across the sample, OTIN and PreCiN integrity significantly predicted cognitive performance. In HS, CR was positively associated with memory performance independently of structural network integrity, suggesting an additive protective role of cognitive reserve in healthy aging. In the SCD group, CR was not directly associated with memory, and only limited effects emerged, indicating early alterations in reserve-related processes. In a-MCI patients, the significant interaction between CR and OTIN integrity suggested patterns consistent with compensatory mechanisms, with higher reserve supporting memory despite structural decline. In AD patients, CR and its interaction with structural networks no longer predicted cognitive outcomes, suggesting a possible exhaustion of reserve capacity.ConclusionThese findings support a stage-dependent model of CR, characterized by an additive protective role in healthy aging, patterns consistent with compensatory recruitment in early cognitive decline, and a possible loss of reserve effectiveness beyond a critical neuropathological threshold. Distinct network vulnerabilities and stage-specific CR effects highlight potential windows for reserve-enhancing interventions across the AD continuum.

Background Transitional multiple sclerosis represents a critical phase in the evolution from relapsing-remitting multiple sclerosis to secondary-progressive multiple sclerosis for which there is no specific disease-modifying treatment available. Objectives (i) To evaluate the efficacy of siponimod in relapsing-remitting multiple sclerosis on first-line therapy who are likely to be in a transitional stage; (ii) to investigate the potential modulatory effect of Siponimod on functional brain connectivity using resting-state functional MRI. Methods Fifty-five relapsing-remitting multiple sclerosis patients likely to be in a transitional stage were screened. After applying selective exclusion criteria, 16 patients were randomized into two groups: the siponimod group and the first-line group (patients remaining on their own therapy). Patients were assessed longitudinally, at baseline (T0) and six months later (T1), trough neurological evaluations, 3T-MRI scanning, and gait analysis. Voxel-wise methods of image analysis were used to assess longitudinal changes. Results At T0, there were no between-group differences in any considered parameter. Longitudinal resting state MRI analysis of the salience network revealed a significant group-by-time interaction in the cerebellum and temporal lobe. Specifically, patients in the first-line group showed a marked decline in functional connectivity over time, whereas siponimod group patients exhibited relative preservation of connectivity. Conclusion This preliminary and exploratory study suggests that siponimod may exert a protective effect on brain functional networks in transitional multiple sclerosis patients, reflecting a potential neuro-protective mechanism that reduces central inflammation. These findings support further investigation in larger, controlled studies to clarify the role of siponimod in early progressive multiple sclerosis stages.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging non-invasive therapeutic approach to slow down cognitive and functional decline in Alzheimer’s disease (AD), potentially through plasticity-related mechanisms. MicroRNAs (miRNAs) play a crucial role in synaptic plasticity, and their deregulation contributes to AD-related cognitive impairment. In the present study, we first used a dosimetric model to translate rTMS field applied in AD patients to an in vitro system, identifying miRNAs as potential biomarkers responsive to rTMS. We found that rTMS induced in vitro deregulation of miR-26b, miR-125b, miR-181c, and miR-146a. Then, we investigated the effects of rTMS over precuneus during a 3-week, randomized, sham-controlled trial in AD patients. In patient serum, miR-26b, miR-30b, and miR-125b were significantly modulated in AD patients compared to healthy controls, though no significant modulation emerged between sham and rTMS groups before or after stimulation. Subsequently, the correlation analyses, which incorporated patients’ cognitive scores, revealed that reduced miR-25 levels were significantly associated with cognitive improvement. However, no significant differences emerged between Real- and sham-rTMS correlation coefficients, likely due to the limited sample size, indicating that miR-25 may represent a general prognostic marker rather than a treatment-specific indicator. Furthermore, the ability of this miRNA to discriminate responders from non-responders, shown by ROC analysis, highlights its potential as a promising predictor of rTMS treatment efficacy to be validated in a larger patient cohort. Altogether, our findings suggest, for the first time, that rTMS may modulate specific miRNAs in AD patients, with miR-25 representing a pivotal key target for future validation studies.

Neural plasticity and memory mechanisms progressively change during pathological aging. This study aimed to identify patterns of structural covariance across Alzheimer's disease (AD) stages and their relationship with episodic memory performance. Fifty-nine AD patients, 59 patients with amnestic Mild Cognitive Impairment (a-MCI), 46 individuals with Subjective Cognitive Decline (SCD), and 49 Healthy Controls (HC) underwent neuropsychological assessment, including verbal episodic memory tests (15-Word List and Short Story) and 3 T Magnetic Resonance Imaging (MRI). T1-weighted images were processed using the Source-Based Morphometry (SBM) pipeline to extract structural covariance networks. Group differences were assessed using ANCOVA, and correlations with memory performance were examined using Pearson's coefficients. Three hippocampal-cortical networks were identified: the hippocampal-diencephalic network (HDN), hippocampal-anterior cingulate-occipital network (HACON), and mesiotemporal-orbitofrontal network (MTON). AD patients showed marked reductions in grey matter connectivity across all networks, while a-MCI patients exhibited intermediate values, particularly in HDN and MTON. Network-memory correlations showed distinct patterns across groups: in HC, HDN and HACON correlated with recall and recognition, whereas MTON connectivity correlated with memory performance in SCD, a-MCI, and AD. These findings indicate a stage-dependent disruption of hippocampal-cortical networks and suggest that MTON integrity supports long-term memory, with progressive disconnection contributing to severe impairment in AD.

BACKGROUND Early detection of cognitive decline is crucial, yet conventional cognitive assessments may fail to capture subtle motor impairments. This study examined whether upper-limb motor features extracted from immersive Virtual Reality (IVR) tasks can differentiate stages along the Alzheimer’s disease (AD) continuum. Among motor behaviors, reaching and catching movements are particularly informative, as cognitive decline has been associated with generalized slowing of movement, reflecting deficits in visuomotor planning. METHODS Sixty-one older adults with Alzheimer’s disease (AD), mild cognitive impairment (MCI), or healthy aging performed reaching and catching tasks in IVR environment. Upper-limb performance was quantified using success rate, reaction time, maximum speed, and kinematic features. RESULTS Upper-limb reaching and catching motor performance showed a graded declined across groups. Participants with AD exhibited reduced accuracy, slower reaction times, and reduced movement speed with respect to healthy controls, while those with MCI exhibited intermediate impairments. Group differences in the catching task were most pronounced when visual and gravitational cues were absent. Based on these kinematics features, LDA successfully discriminated between groups well above chance level. DISCUSSION Individuals with MCI and AD exhibit marked deficits in the performance and accuracy of upper-limb reaching and catching movements when assessed in a VR environment. IVR enables sensitive and ecologically valid detection of upper-limb motor alterations associated with cognitive decline, supporting its potential for early diagnosis and monitoring.

BackgroundLeisure activities (LAs) are recognized as major contributors to cognitive reserve (CR), potentially mitigating age-related cognitive decline and dementia progression. However, the specific associations between lifelong engagement in different types of LAs, education (as a proxy of CR), and cognitive functioning along the Alzheimer’s disease (AD) continuum remain poorly defined. This study aimed to investigate the association between education and LAs in relation to current cognitive performance in healthy subjects (HS), individuals with subjective cognitive decline (SCD), amnestic mild cognitive impairment (a-MCI), and AD patients.MethodsTwo hundred eighty-six participants (82 AD, 98 a-MCI, 39 SCD, 67 HS) underwent comprehensive neuropsychological testing and completed a validated questionnaire assessing the frequency of cognitive (C1–C8), social (S1–S5), and physical (P1–P5) activities during youth, middle, and late adulthood. Associations among education, LAs, and cognitive outcomes were analyzed using Spearman’s correlations and moderation analyses, while between-group differences were explored with Kruskal–Wallis ANOVAs.ResultsEducation showed significant correlations with most LA domains across all groups. Distinct activity-cognition patterns emerged along the disease continuum. In HS, participation in individual sports during youth and midlife correlated with global cognitive efficiency and memory. In SCD individuals, pet care during midlife was associated with memory, whereas in a-MCI patients, attending lectures and sewing/knitting were related to current cognitive efficiency. No significant associations were observed in AD patients. Moderation analyses revealed that education was significantly associated with the relationship between LA engagement and cognitive outcomes in HS, SCD, and a-MCI, but not in AD. Kruskal-Wallis analyses indicated reduced engagement in cognitive and social activities across disease stages compared with HS, particularly during youth and midlife.DiscussionDifferences in lifelong LA engagement were evident across diagnostic groups, and education was associated with variations in cognition-activity relationships. These findings suggest that the role of CR through leisure engagement may vary across disease stages.ConclusionEducation-related cognitive reserve was linked to the relationship between lifelong leisure activities and cognitive performance in healthy individuals and early-stage AD conditions, but not in advanced AD, highlighting the potential role of early-life cognitive, social, and physical enrichment in supporting preserved cognitive function.

Background:Frontotemporal dementia (FTD) is a common form of dementia with no approved pharmacological treatment. Clinical and experimental evidence suggest that dopaminergic transmission is impaired in FTD. Here we aimed at investigating the clinical impact of treatment with dopaminergic agonists in FTD. Methods:This was a phase IIa 24-week randomized, double-blind, multicenter, placebo-controlled study, conducted in Italy from June 16th 2021 to April 30th 2023. Patients with a diagnosis of probable behavioral variant FTD (bvFTD) were randomly assigned in a 1:1:1 ratio to receive rotigotine transdermal patches at 4 mg/24 h, rotigotine transdermal patches at 6 mg/24 h, or placebo transdermal patches for 24 weeks. Randomization was centralized and performed using a double-blind covariate-adaptive scheme. The primary outcome was analyzed in the intention-to treat (ITT) population. The primary efficacy outcome measure was the change at 24-weeks from baseline in the Frontal Assessment Battery (FAB). The trial is completed and was registered on the clinicaltrial.gov website (NCT04937452). Findings:A total of 128 patients were screened, of which 75 were randomized. 25 patients were randomized to receive Rotigotine 4 mg, 26 patients to Rotigotine 6 mg, and 24 patients to placebo. The mean age of patients was 66.5 ± 8 of which 31 (41%) were female. A total of 69 patients (92%) completed the study. The estimated mean change from baseline at 24 weeks in the FAB score in the ITT population was 0.18 (95% confidence interval [CI] -0.79 to 1.15) in the rotigotine 4 mg group, 0.89 (95% CI -0.09 to 1.88) in the rotigotine 6 mg group and 1.08 (95% CI 0.19-1.98) in the placebo group (rotigotine 4 mg vs placebo, -0.90; 95% CI -2.22 to 0.42; p = 0.18; rotigotine 6 mg vs placebo, -0.19; 95% CI -1.52 to 1.14; p = 0.77). No significant effect was found on secondary outcome measures. Adverse events were mild in all groups and more common in the rotigotine (4 mg: 4/25; 6 mg: 3/26) than in the placebo (1/24) group. Interpretation:Rotigotine administration may not be a viable therapeutic option for enhancing frontal function, slowing disease progression, mitigating functional decline or ameliorating behavioral disturbances in bvFTD patients. The current findings provide data in a large sample of bvFTD that might be useful for the design of future clinical trials. Funding:This trial was funded by a joint grant from the Alzheimer Drug Discovery Foundation (ADDF) and the Association for Frontotemporal Degeneration (AFTD) grant to GK and BB (GFTD-201902-2017958).

The cerebellum plays a crucial role in motor learning, facilitating processes such as timing, error correction, and coordination. However, optimizing noninvasive brain stimulation (NIBS) to enhance these processes remains challenging. This study investigated the effects of cerebellar transcranial alternating current stimulation (tACS) at 5 Hz and 50 Hz on motor learning during a serial reaction time task (SRTT). Twenty-six healthy participants completed three sessions, receiving 5 Hz, 50 Hz, or Sham stimulation during SRTT performance. Changes in reaction time and sequence performance were measured during the online stimulation phase, with motor retention assessed 24 h later. We found that 5 Hz tACS significantly improved motor performance during the early stages of sequence learning, as demonstrated by faster reaction times compared to the 50 Hz and Sham conditions. These effects, specific to early acquisition phases, align with the cerebellum's involvement in motor timing and error correction. No significant improvements were observed during offline motor retention, possibly due to the weaker entrainment or lack of prolonged sessions required for long-term plasticity. Furthermore, 50 Hz tACS did not influence SRTT performance, highlighting the frequency-specific nature of tACS-induced modulation. These findings suggest that theta-frequency tACS can selectively enhance cerebellar contributions to motor learning by aligning stimulation with intrinsic oscillations. Although transient, theta-tACS shows promise for modulating motor circuits in both research and clinical contexts. Future studies should investigate theta-tACS in more complex tasks and explore its therapeutic potential for sustained motor rehabilitation outcomes.NEW & NOTEWORTHY This study highlights the potential of 5-Hz theta-frequency cerebellar transcranial alternating current stimulation (tACS) to enhance early motor learning. During a serial reaction time task, 5-Hz tACS significantly improved reaction times compared with 50 Hz and Sham conditions, aligning with the cerebellum's role in motor timing and error correction. Though effects were transient, these findings underscore the frequency-specific benefits of tACS and its promise for advancing motor learning research and therapeutic applications.

BACKGROUND:Though cortical changes in frontotemporal dementia (FTD) are well-documented, the cerebellum's role, closely linked to these areas, remains unclear. OBJECTIVES:To provide evidence on cerebellar involvement in FTD across clinical, genetic, imaging, neuropathological, and neurophysiological perspectives. Additionally, we sought evidence supporting the application of cerebellar non-invasive brain stimulation (NIBS) in FTD for both diagnostic and therapeutic purposes. METHODS:We performed a literature review using MEDLINE (via PubMed), Scopus, and Web of Science databases. RESULTS:We emphasized the involvement of specific cerebellar regions which differentiate each FTD subtypes and may account for some of the characteristic symptoms. Furthermore, we highlighted peculiarities in FTD genetic alterations. Finally, we outlined neurophysiological evidence supporting a role for the cerebellum in FTD pathogenesis. CONCLUSION:The cerebellum is critically involved in the FTD spectrum. Moreover, it can be speculated that cerebellar modulation, as already shown in other neurodegenerative disorders, could restore the interneuronal intracortical circuits typically impaired in FTD patients, providing clinical improvements and fundamental outcome measures in clinical trials.

Motor control relies on the dynamic interplay between excitatory and inhibitory influences shaping sensorimotor integration during hand movements. In this study, we investigated short-latency afferent inhibition (SAI)-a neurophysiological marker of sensorimotor integration-during different isometric grasping behaviors (precision vs. power grip). We applied transcranial magnetic stimulation (TMS) with different coil orientations [antero-posterior (AP) vs. postero-anterior (PA)] to engage distinct neuronal populations within the primary motor cortex (M1). We found increased SAI in the AP direction during grasp execution and enhanced corticospinal excitability for precision grip when tested with AP stimulation. These findings provide evidence that distinct cortical circuits within M1 are differentially engaged during different hand configurations. Notably, we observe no grip-specific modulation of SAI, which may reflect a less topographically precise distribution of thalamocortical afferents-along with their lower temporal resolution, potentially shaped by cholinergic modulation. Future studies should investigate SAI dynamics across different phases (i.e., preparation vs. execution) of naturalistic prehension.NEW & NOTEWORTHY In the present study, we assessed SAI in M1 using different coil orientations (AP vs. PA) to determine whether distinct M1-S1 circuits are selectively engaged during rest and grasping behaviors (precision vs. power grip). We found increased SAI in the AP direction during grasp execution and greater corticospinal excitability for precision grip with AP stimulation, supporting the idea that distinct M1 circuits are differentially recruited depending on hand configuration and sensorimotor demands.

Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid-β and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co-pathology, TDP-43 also aggregates in astrocytes and endothelial cells, impairing blood-brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP-43 loss disrupts β-catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin-4 (AQP4) and CD146, further compromising clearance pathways. These vascular-glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP-43-positive patients. We argue for the reclassification of TDP-43 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction. HIGHLIGHTS: Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD). We propose reclassifying TDP-43 from co-pathology to upstream contributor. TDP-43 affects endothelial cells and astrocytes, disrupting blood-brain barrier (BBB) and clearance. Neurovascular unit (NVU) dysfunction links TDP-43 to inflammation, hypoperfusion, and cognitive decline. A vascular-glial model of AD opens new therapeutic and biomarker opportunities.