Shih-Pin Chen

BACKGROUND: The meningeal lymphatic system contributes to hematoma resolution and neurological recovery after intracerebral hemorrhage (ICH). We previously demonstrated that intraperitoneal cilostazol administration promotes dural lymphatic growth and enhances clearance of intracerebrally injected red blood cells; however, the antiplatelet effects of cilostazol raise safety concerns in ICH, potentially limiting clinical translation. Here, we evaluated whether oral cilostazol at clinical-equivalent doses in mice enhances dural lymphatic function and improves outcomes after ICH. METHODS: ICH was induced by collagenase injection to model microvascular rupture. Cilostazol was orally administered to ICH mice at clinically equivalent doses, given at different time points and for varying durations. Prolymphangiogenic effects of cilostazol were examined in healthy in vivo and ex vivo meninges. Flow cytometry and immunofluorescence were performed to assess lymphatic endothelial cell proliferation and dural lymphatic remodeling. Lymphatic function was evaluated by in vivo live imaging and histological analysis of fluorescent tracer drainage. Short- and long-term histopathologic and behavioral outcomes were also evaluated. RESULTS: Oral cilostazol treatment initiated either 3 hours or 3 days after ICH enhanced dural lymphatic coverage and function, accompanied by reduced hematoma volume, neuronal injury, synapse loss, and long-term neurological deficits. Cilostazol increased CD31 ⁺ PDPN ⁺ lymphatic endothelial cells in ex vivo meninges, induced dural lymphatic hyperplasia, and enhanced lymphatic drainage in healthy mice. Both pretreatment and delayed treatment of cilostazol did not increase hematoma volume but rather improved ICH outcomes. CONCLUSIONS: By promoting dural lymphatic remodeling and drainage, cilostazol facilitates hematoma resolution and neurological recovery after ICH. Cilostazol treatment does not exacerbate initial bleeding or provoke hematoma expansion in the experimental ICH. These findings support clinical translation and provide mechanistic and dosing rationale for an ongoing phase II randomized trial (URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06504576).

Elucidating functional brain dynamics under different blood-brain barrier (BBB) permeabilities may resolve the enigmatic pathophysiology of reversible cerebral vasoconstriction (RCVS); however, relevant investigations are lacking. We aimed determine the relationship between brain functional dynamics and BBB permeability in patients with RCVS. We prospectively recruited RCVS patients and healthy controls (HCs) from November 2016 to January 2023 in Headache Center in a tertiary medical center (> 3000 beds) and adjacent communities. RCVS patients who were diagnosed according to the International Headache Society criteria, and age- and sex-matched HCs were enrolled. Normalized entropy, derived from resting-state fMRI (rs-fMRI), was compared at the network and parcel levels between RCVS patients with and without BBB disruption. Dynamic contrast-enhanced MRI (DCE-MRI)-derived K^trans BBB permeability and ultrasonographic findings were analyzed. In total, 188 subjects (100 RCVS + 88 HCs) were enrolled. Compared with the HCs, the RCVS patients had greater entropy (p = 0.014), which was greater in the RCVS patients without than in those with (adjusted p = 0.040) BBB disruption. Compared with HCs, patients without BBB disruption had greater entropy between 60 and 90 days after headache onset (adjusted p = 0.006). No significant differences in entropy were noted between disease stages in BBB-disrupted patients. Parcels within subnetworks of the Default mode network (Default A and C) exhibited higher entropy in patients without BBB disruption. In specific anatomical locations, entropy values were negatively correlated with ultrasonographic Lindegaard index vasoconstriction severity (p = 4.3 × 10^- 6; within the Default A network) and DCE-MRI K^trans BBB permeability (p = 0.005; within the Default C network). The differential changes in normalized entropy suggest that increased rs-fMRI signal complexity may reflect a compensatory functional response to abrupt vasoconstriction. In contrast, the loss of entropy fluctuations in the context of severe BBB disruption indicates a state of impaired cerebral autoregulation in patients with RCVS. The compensatory capacity decreased as vasoconstriction or BBB disruption exacerbated.

Accumulating preclinical evidence has highlighted the importance of cerebrospinal fluid (CSF) compartmentalization and transport. However, detailed structural characterization in humans remains challenging. This study utilized contrast-enhanced T2-fluid-attenuated inversion recovery imaging on 3-Tesla magnetic resonance imaging (MRI) in a cohort of 477 patients, primarily with reversible cerebral vasoconstriction syndrome (RCVS), to provide a noninvasive in vivo diseased model to delineate distinct subarachnoid compartmentalization and potential leptomeningeal arteriovenous perivascular shunting. We characterized a homogeneous CSF milieu within the ensheathed periarterial glymphatic space. This environment, structurally defined by the perivascular membrane, exhibited uniform tracer intensities across both proximal and distal arterial segments (p = 0.118) on both static and dynamic models, opposed to the heterogeneous CSF appearance observed outside the perivascular membrane. We also observed nodal tracer enrichment in specific locations of the leptomeningeal perivenous space (PVeS) across initial and follow-up MRI. Furthermore, the periarterial tracer enrichment intensities matched those in these nodal portions of the PVeS but significantly exceeded those in the non-nodal portions (p < 0.0001). A dynamic MRI subgroup analysis further revealed that the periarterial tracer kinetics were nearly identical to those of these PVeS nodes. Notably, the nodal–non-nodal gradient of the tracer intensity was significantly amplified in participants exhibiting overt periarterial tracer leakage (p = 0.0006). Although we could not directly visualize the arteriovenous perivascular shunting demonstrated in animal models, our findings may be supportive of potential human periarterial and meningeal border pathways. By establishing a diseased model-based imaging framework to characterize these glymphatic microstructures noninvasively, our results offer a preliminary basis for understanding the perivascular CSF environment and a hypothesized periarterial and meningeal border pathways in living humans.

Migraine is increasingly recognized as more than just an episodic headache disorder—it often carries a profound burden marked by emotional and cognitive disturbances. Recent insights point towards a possible link between migraine and accelerated brain ageing, yet the specific brain regions affected and the clinical implications remain poorly understood. We investigated grey matter-based brain age using voxel-based morphometry in 110 preventive treatment–naïve patients with migraine and 70 healthy controls, based on T1-weighted MRI and a validated brain-age prediction framework trained on data from 1318 healthy individuals. Compared with controls, patients with migraine exhibited a significantly higher global brain-age gap [mean difference = 4.24 years; confidence interval (CI, 0.12, 8.36); P = 0.039; ηp² = 0.024]. Regionally, 66 out of 442 brain parcels—primarily within the prefrontal, frontal, cingulate, parietal and temporal cortices and the amygdala—showed elevated ageing patterns. Permutation-based canonical correlation analysis revealed a stable multivariate association between regional brain-age deviations and a combination of migraine-related clinical factors (headache frequency, painkiller usage and depressive symptoms), although individual factor contributions were variable. Functional annotation of the affected regions highlighted their roles in cognitive, emotional and perceptual processing. Together, these findings reveal that migraine is linked to widespread, regionally patterned brain ageing, mirroring the clinical and neurobiological complexity of the disease. This work not only deepens our understanding of migraine’s impact on the brain but also opens new avenues for exploring how timely intervention might protect brain health in this population.

Blood-brain barrier (BBB) disruption was found to be critical in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). We hypothesized that increased central arterial stiffness, resulting in the excessive transmission of central pulsatile flow to the dysregulated cerebral microcirculation, may contribute to the disruption of BBB. This is a cross-sectional study. Participants with RCVS in the acute phase were recruited from both outpatient and inpatient settings between January 2018 and September 2020. The diagnosis was established based on clinical presentations and neuroradiologic evidence. Age-matched and sex-matched healthy controls (HCs) were recruited from nearby communities. Patients with RCVS were recruited and underwent 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize BBB disruption. The central arterial stiffness was assessed with hemodynamic parameters such as carotid-femoral pulse wave velocity (cfPWV), carotid augmentation index (cAI), and central blood pressure (ceBP). Arterial stiffness was compared between patients with RCVS and HCs, and between patients with RCVS with and without BBB disruption. Sixty-five patients with RCVS (mean age 44.3 ± 9.6 years; 42 women) and 65 HCs (mean age 45.4 ± 8.9 years; 42 women) completed the study. Among the patients with RCVS, 33 exhibited imaging-proven BBB disruption. Those with BBB disruption were older (48.3 ± 9.2 vs 40.2 ± 8.3 years, p < 0.001) and had a higher proportion of women (81.8% vs 46.9%, p = 0.003). Arterial stiffness was increased in patients with RCVS, as indicated by a higher cfPWV compared with controls (10.8 ± 2.5 m/s vs 9.2 ± 2.3 m/s, p < 0.001). Among patients with RCVS, those with BBB disruption had greater central arterial stiffness, reflected by higher cfPWV and cAI (11.4 ± 2.7 m/s vs 10.1 ± 2.1 m/s, p = 0.036; 15 ± 18% vs 2 ± 19%, p = 0.007). There were no significant differences in ceBP between patients with RCVS (regardless of BBB disruption) and HCs. Our study confirmed increased central arterial stiffness in patients with RCVS, especially among those with BBB disruption. These findings suggest a potential contribution of central arterial stiffness and excessive pulsatile flow to cerebral microvascular dysfunction in the pathogenesis of RCVS.

Vestibular symptoms (VS) in migraine are underinvestigated, and vestibular migraine (VM) remains underdiagnosed. This study aimed to determine the prevalence, clinical correlates, and functional impact of VS and VM among migraine patients. This cross-sectional study recruited newly diagnosed migraine patients from a tertiary medical center and a community hospital between August 2020 and October 2023. Questionnaire-based interviews were carried out to collect headache characteristics, Migraine Disability Assessment (MIDAS), Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), including anxiety (HADS-A) and depression (HADS-D) subscales, and VS, as defined by the International Classification of Vestibular Disorders. The diagnosis of VM was based on the International Classification of Headache Disorders, 3rd edition. In total, 2,801 patients with newly diagnosed migraine (2,147F/654M, mean age 37.8 ± 12.5 years) were recruited, including 1,916 (1,548F/368M, mean age 36.9 ± 12.3 years) with VS (68.4%), and external and internal vertigo was the most common. Overall, 426 (347F/79M, mean age 36.6 ± 12.6 years) fulfilled the criteria for VM (15.2%). When compared with patients without VS (group I), those with non-VM VS (group II) or VM (group III) had greater disability associated with headache (MIDAS: 23.6 ± 36.4 vs 33.8 ± 45.8 vs 40.9 ± 48.9), poorer sleep (PSQI: 8.6 ± 3.9 vs 10.1 ± 4.0 vs 10.6 ± 4.0), and more symptoms of anxiety (HADS-A: 6.9 ± 4.3 vs 9.0 ± 4.1 vs 9.1 ± 4.1) or depression (HADS-D: 5.8 ± 4.2 vs 6.9 ± 4.2 vs 7.1 ± 4.5) (all p < 0.001 vs group I), although the difference between groups II and III was significant only for MIDAS (p < 0.001), but not PSQI, HADS-A, or HADS-D (all p > 0.100). VS are very common in patients with migraine and are associated with significant disability, even when the criteria for VM are not met. VS should be screened for in the clinical evaluation of migraine. The current diagnostic criteria of VM may not be able to capture all of the patients suffering from substantial impact associated with VS. It remains to be determined whether VS in migraine could respond to migraine treatment.

Clinical and preclinical evidence suggests an association between higher levels of IL-6 and migraine. The present study aimed to determine whether pretreatment serum IL-6 levels were associated with headache outcomes at month 3 following migraine preventive treatment. In this prospective study, newly diagnosed migraine patients without current or recent use of preventive medications within 3 months were recruited, and were dichotomized as having higher or lower IL-6 serum levels according to the median at baseline among all of the patients who started preventive treatment with flunarizine. Primary and secondary outcomes were the mean change from baseline in the number of monthly headache days (MHDs) at month 3 based on headache diaries, and the percentage of non-responders, i.e., patients without ≥ 50% MHD reduction at month 3 compared to baseline, respectively. Logistic regression analysis was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between higher IL-6 levels and treatment non-response, which were further controlled for demographics, headache profiles, disability (measured by Migraine Disability Assessment), psychiatric comorbidities (measured by Hospital Anxiety and Depression Scale), and sleep quality (measured by Pittsburgh Sleep Quality Index). In total, 236 migraine patients (187 F/49 M, mean age ± standard deviation 37.1 ± 10.3 years) were analyzed. At baseline, the median IL-6 level was 0.79 pg/mL, and a higher IL-6 level was associated with an older age (mean age 39.5 ± 10.6 vs. 34.6 ± 9.5 years, p < 0.001) and female sex (85.6% vs. 72.9%, p = 0.016), and a trend toward more MHDs (17.1 ± 8.1 vs. 15.0 ± 8.1 days/month, p = 0.050). After preventive treatment, patients with higher baseline IL-6 levels had less improvement in headache frequency (-5.7 vs. -8.2 MHDs, p = 0.004), and were more likely to be non-responders (72.0% vs. 44.9%, p < 0.001) (adjusted OR = 2.90, 95% CI = 1.61–5.25, p < 0.001). The results were consistent in sensitivity analysis across different subgroups. There was an independent association between higher pretreatment IL-6 levels and poorer response to preventive treatment with flunarizine at month 3 in this large cohort of migraine patients. Whether this finding could be generalizable to other preventives and whether such patients could benefit from preventives of immunomodulatory properties need to be further explored. ClinicalTrials.gov. NCT02747940, NCT04702971.

Elucidating the spatiotemporal dynamics of cerebral blood flow (CBF) may resolve the enigmatic pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS), a condition with variable clinical and vascular manifestations, where the current understanding of perfusion is limited to inconsistent case report findings. We aimed to determine the spatiotemporal perfusion dynamics and their clinical and vascular correlations in RCVS. We prospectively recruited RCVS patients and age- and sex-matched healthy controls (HCs) over a 5-year period (June 2018 to April 2023) in the Headache center in a tertiary medical center (>3000 beds) and adjacent communities. RCVS patients were diagnosed according to the International Headache Society criteria. Voxelwise and whole-brain gray matter CBF on magnetic resonance imaging were compared between RCVS patients and HCs. The time-trend CBF dynamics in RCVS patients and correlations with ultrasonographic and clinical findings were analyzed. Totally, 316 participants (281 RCVS patients + 35 HCs) were enrolled. Acute RCVS (aRCVS; ≤30 days onset) patients presented lower global and regional CBF values (49.0 ± 10.2 vs. 53.9 ± 6.7 mL/100 g/min; p = 0.033) than HCs, but these values normalized by two weeks after headache onset and in the remission stage (rRCVS; ≥90 days onset; 52.8 ± 9.3 mL/100 g/min; p = 0.005), particularly in posterior regions. The distinct abrupt CBF fluctuations that occurred between days 2-16 and 7-21 in aRCVS were consistent across the different analytic models (significance as p < 0.05, 0.01, 0.005 or 0.001; sliding analytic time intervals of 5, 7 or 10 days). The ultrasonographic flow velocities of the middle cerebral (2nd week: r = 0.628; p < 0.001; 4th week: r = 0.471; p = 0.010) and internal carotid arteries (2nd week: r = 0.626; p < 0.001; 4th week: r = 0.381; p = 0.041) were positively correlated with CBF during similar periods in aRCVS patients. The unique CBF dynamics in patients with RCVS, particularly aRCVS, revealed potential roles of perfusion changes in RCVS pathophysiology.

Background: Extensive white matter hyperintensities are a hallmark of cerebral autosomal‐dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a monogenic small‐vessel disease caused by pathogenic NOTCH3 variants. This study aimed to assess microstructural white matter integrity in symptomatic and premanifest CADASIL individuals utilizing peak width of skeletonized mean diffusivity (PSMD), a diffusion tensor imaging‐based metric. Methods: A total of 161 participants were recruited, including 60 patients with symptomatic CADASIL, 67 preclinical NOTCH3 variant carriers, and 34 healthy controls. All participants underwent brain magnetic resonance imaging and PSMD analysis. Cognitive function and disability were assessed using the Mini‐Mental State Examination, Trail Making Test Part A, and modified Rankin Scale. Longitudinal magnetic resonance imaging scans were available for 35 participants, and their radiological progression was assessed. PSMD was analyzed in projection, association, and commissural fibers. Results: Among fiber tracts, commissural fiber PSMD exhibited the strongest correlations with cognitive function and disability, explaining the most variance (40%–60%). Symptomatic patients with CADASIL had significantly higher commissural fiber PSMD values (5.78±1.94×10 ⁻⁴ mm ² /s) compared with preclinical carriers (2.79±0.68×10 ⁻⁴ mm ² /s) and healthy controls (2.82±0.68×10 ⁻⁴ mm ² /s). Higher commissural fiber PSMD distinguished patients with symptomatic CADASIL from preclinical carriers (odds ratio, 13.59 [95% CI, 5.25–35.20]; P <0.001) and predicted faster disease progression, including increased lacune numbers, cerebral microbleed counts, and advancing brain atrophy. Conclusions: Commissural fiber PSMD may serve as a robust biomarker for assessing disease severity and progression in CADASIL. These findings highlight its potential clinical utility in patient stratification and prognostication.