Huston, John

Introduction: Understanding mid-term test-retest reliability and within-subject variability is important for interpreting changes observed in longitudinal and intervention studies. The reliability of resting-state functional magnetic resonance imaging (rs-fMRI) is known to vary across measures and brain regions. However, how reliability differs across functional networks and connectivity- and amplitude-based measures, and whether multi-echo acquisition and processing modify these patterns, remain incompletely characterized. Methods: Twenty-two healthy volunteers underwent two rs-fMRI sessions 15.7 ± 4.0 days apart on a Compact 3T scanner. Multi-echo, middle-echo, and independently acquired single-echo datasets were compared, with multi-echo independent component analysis additionally evaluated as a denoising approach. Functional connectivity (FC) and three amplitude-based measures were evaluated using the Schaefer 400 parcellation. Reliability was systematically assessed using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and systematic bias at edge or regional, and network levels. Results: Acquisition-dependent differences in reliability were generally modest. Multi-echo acquisition and processing increased functional connectivity strength and the magnitude of amplitude-based measures and improved inferior cortical coverage, but these enhancements did not consistently translate into substantially higher ICC or lower wSD. In contrast, reliability showed clear network-dependent differences. FC reliability varied markedly across network pairs and was not explained by connectivity strength alone; pairs involving the default mode and control networks generally showed more favorable profiles than several somatomotor and visual network pairs. Fractional amplitude of low-frequency fluctuations (fALFF) also showed network-dependent reliability, with the most favorable regional reproducibility observed in the default mode and control networks and lower reproducibility in the somatomotor and visual networks. Conclusion: These findings provide practical mid-term reliability benchmarks for rs-fMRI on a Compact 3T scanner and show that measurement stability varies more clearly across measures and functional networks than across acquisition approaches.

BACKGROUND: Cerebral hemodynamic impairment in patients with asymptomatic high-grade (>70%) internal carotid artery (ICA) stenosis is associated with risk of stroke and cognitive decline, but correlations between the degree of stenosis and hemodynamic impairment are derived from small case series. Using baseline data from 242 participants in the CREST-H study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics), we hypothesized that the degree of stenosis in the ICA would correlate with time-to-peak (TTP) delay in ipsilateral cerebral blood flow using MR/CT perfusion scans, adjusting for demographic and cardiovascular risk variables. METHODS: From all participants, ICAs were insonated using a 7 to 10 MHz probe for peak systolic velocity (PSV) and end diastolic velocity. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using standard sequential T2*-weighted perfusion imaging. CT perfusion used standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral hemispheres. In cross-sectional analysis, linear regression was used to model TTP delay as the outcome variable and PSV, end diastolic velocity, and PSV ICA/common carotid artery ratio on the index and nonindex side as primary predictor variables in 6 separate models, adjusting for covariates, followed by automated backward elimination model reduction. RESULTS: Among 392 CREST-H participants, the 242 with complete data for all variables were included in the regression analysis (age, 70±7.6; 62% M). End diastolic velocity on the index side correlated with TTP delay (β=0.003, P =0.005). PSV had a similar correlation but did not reach significance (β=0.001, P =0.099), nor did ICA/common carotid artery ratio (β=0.003, P =0.126). Nonindex side PSV, end diastolic velocity, and ICA/common carotid artery ratio showed no correlation with TTP delay ( P =0.268, P =0.495, P =0.380, respectively). Circle of Willis completeness did not correlate with TTP. CONCLUSIONS: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher end-diastolic flow velocities correlated with greater TTP delays, supporting a definition of hemodynamically significant stenosis. Our findings have implications for the management of asymptomatic carotid stenosis, which will be tested in the CREST-H study. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03121209.

Recent advancements in compact MRI scanners, portable low-field-strength MRI systems, and high-performance gradient inserts address the challenges of conventional MRI for brain imaging, providing more accessible and versatile technology.

BACKGROUND: Spinal cord involvement is infrequently reported in primary central nervous system vasculitis (PCNSV). This study describes the clinical findings, therapeutic responses, and outcomes of spinal cord involvement in a large cohort of patients with PCNSV. METHODS: We retrospectively studied 216 consecutive patients with PCNSV evaluated at the Mayo Clinic from 1983 to 2023. Spinal cord involvement was documented by histological examination or imaging. The clinical, laboratory, radiological, and pathological findings, along with management and outcomes, were compared between patients with and without spinal cord involvement. RESULTS: Of 216 patients, 10 (4.6%) had spinal cord involvement, with cerebral involvement in 9 cases. One patient (0.5%) had isolated spinal cord vasculitis. Histological evidence of vasculitis was found in all 10, with necrotizing vasculitis in 5 (50%). Magnetic resonance imaging showed thoracic abnormalities in 8 patients, cervical spine involvement in 2, conus medullaris involvement in 3, and cauda equina enhancement in 4. Compared with the 206 patients without spinal cord involvement, those with spinal cord vasculitis were more likely to present with paraparesis/tetraparesis ( P <0.001) and necrotizing vasculitis ( P =0.01) and less likely with hemiparesis ( P =0.006) and granulomatous vasculitis ( P =0.03). Patients with spinal cord involvement were more likely to have at least 1 relapse ( P <0.001) or more ( P <0.001). No differences between the 2 groups were observed regarding long-term remission, therapy response, and high disability scores (modified Rankin Scale score, 4–6) or death at last follow-up. Spinal cord involvement was associated with meningeal enhancement on brain imaging (odds ratio, 10.50) and the presence of lymphoma (odds ratio, 6.49), specifically Hodgkin lymphoma diagnosed simultaneously with PCNSV. Spinal involvement was negatively associated with increasing age (odds ratio, 0.64) and cerebral infarction on imaging (odds ratio, 0.08). CONCLUSIONS: Spinal cord involvement defines a distinct subset of patients with PCNSV.

Abstract Functional MRI (fMRI) is widely used to spatially localize neural activity in the brain associated with functional stimuli. Functional MR Elastography (fMRE) has recently been introduced as a complementary approach that measures the mechanical response to functional stimulus. The hypothesis of the current study is that the stiffness change in fMRE is proportional to the underlying neural activity. This hypothesis is tested by measuring the median stiffness change in the visual cortex as a function of luminance-matched contrast intensity of a checkerboard visual stimulus in 16 healthy subjects. The fMRE signal in the visual cortex was observed to be proportional to the contrast intensity of the visual stimulus. In regions of activation, fMRE signal increased in the range of 2 ± 1% to 5.8 ± 1% and fMRI signal increased by the expected 0.4 ± 0.2% to 0.9 ± 0.2%, for contrast levels of 5% to 100%, respectively. In conclusion, this study shows that the fMRE signal in the visual cortex can be directly modulated by the contrast intensity of a visual stimulus. The presence of some overlap between fMRI and fMRE regions of activation may suggest two distinct mechanisms governing the fMRI and fMRE signals, which will be investigated in future studies.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03652181.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project ( https://www.clinicaltrials.gov ; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% ( P =0.03) and 100% ( P =0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years ( P =0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.