Risk assessment of arrhythmias related to three antiseizure medications: a systematic review and single-arm meta-analysis.

Objective: Antiseizure medications (ASMs) are first line therapy for seizure disorders. Their effects on arrhythmias, especially the risk of arrhythmias associated with lacosamide (LCM), levetiracetam (LEV), and perampanel (PER), have been intensely investigated. Methods: We searched four databases (PubMed, EMBASE, Cochrane Library, and Web of Science) until August 6, 2023. We used a common effects model and reported data as pooled incidence with 95% CIs. Meta-analyses were conducted to elucidate the risk of arrhythmias with different drugs, and Egger's regression was performed to detect publication bias analysis. Results: We included 11 clinical trials with 1,031 participants. The pooled incidence of arrhythmias in the LEV group was 0.005 (95% CI: 0.001-0.013), while it was 0.014 in the LCM group (95% CI: 0.003-0.030). Publication bias analyses indicated no significant bias in the LEV group (t = 0.02, df = 4, p-value = 0.9852) but a significant bias in the LCM group (t = 5.94, df = 3, p-value = 0.0095). We corrected for this bias in the LCM group using the trim-and-fill method, which yielded a similar pooled incidence of 0.0137 (95% CI: 0.0036-0.0280), indicating good reliability. Due to insufficient studies, we could not conduct a meta-analysis for PER, and we analyzed them in our systematic review. Conclusion: The use of LCM significantly elevated the risk of arrhythmias, while LEV had non-significant arrhythmogenic effects. As for the arrhythmogenic effects of PER, more clinical trials are needed in the future.

On the optimization of 3D inflow-based vascular-space-occupancy (iVASO) MRI for the quantification of arterial cerebral blood volume (CBVa).

PURPOSE: The inflow-based vascular-space-occupancy (iVASO) MRI was originally developed in a single-slice mode to measure arterial cerebral blood volume (CBVa). When vascular crushers are applied in iVASO, the signals can be sensitized predominantly to small pial arteries and arterioles. The purpose of this study is to perform a systematic optimization and evaluation of a 3D iVASO sequence on both 3 T and 7 T for the quantification of CBVa values in the human brain. METHODS: Three sets of experiments were performed in three separate cohorts. (1) 3D iVASO MRI protocols were compared to single-slice iVASO, and the reproducibility of whole-brain 3D iVASO MRI was evaluated. (2) The effects from different vascular crushers in iVASO were assessed. (3) 3D iVASO MRI results were evaluated in arterial and venous blood vessels identified using ultrasmall-superparamagnetic-iron-oxides-enhanced MRI to validate its arterial origin. RESULTS: 3D iVASO scans showed signal-to-noise ratio (SNR) and CBVa measures consistent with single-slice iVASO with reasonable intrasubject reproducibility. Among the iVASO scans performed with different vascular crushers, the whole-brain 3D iVASO scan with a motion-sensitized-driven-equilibrium preparation with two binomial refocusing pulses and an effective TE of 50 ms showed the best suppression of macrovascular signals, with a relatively low specific absorption rate. When no vascular crusher was applied, the CBVa maps from 3D iVASO scans showed large CBVa values in arterial vessels but well-suppressed signals in venous vessels. CONCLUSION: A whole-brain 3D iVASO MRI scan was optimized for CBVa measurement in the human brain. When only microvascular signals are desired, a motion-sensitized-driven-equilibrium-based vascular crusher with binomial refocusing pulses can be applied in 3D iVASO.

Differential Laminar Activation Dissociates Encoding and Retrieval in the Human Medial and Lateral Entorhinal Cortex.

The hierarchically organized structures of the medial temporal lobe are critically important for episodic memory function. Accumulating evidence suggests dissociable information processing pathways are maintained throughout these structures including in the medial and lateral entorhinal cortex. Cortical layers provide an additional dimension of dissociation as the primary input to the hippocampus derives from layer 2 neurons in the entorhinal cortex, whereas the deeper layers primarily receive output from the hippocampus. Here, novel high-resolution T2-prepared functional MRI methods were successfully used to mitigate susceptibility artifacts typically affecting MRI signals in this region providing uniform sensitivity across the medial and lateral entorhinal cortex. During the performance of a memory task, healthy human subjects (age 25-33 years, mean age 28.2 ± 3.3 years, 4 female) showed differential functional activation in the superficial and deep layers of the entorhinal cortex associated with task-related encoding and retrieval conditions, respectively. The methods provided here offer an approach to probe layer-specific activation in normal cognition and conditions contributing to memory impairment.SIGNIFICANCE STATEMENT This study provides new evidence for differential neuronal activation in the superficial versus deep layers of the entorhinal cortex associated with encoding and retrieval memory processes, respectively, in cognitively normal adults. The study further shows that this dissociation can be observed in both the medial and the lateral entorhinal cortex. The study was achieved by using a novel functional MRI method allowing us to measure robust functional MRI signals in both the medial and lateral entorhinal cortex that was not possible in previous studies. The methodology established here in healthy human subjects lays a solid foundation for subsequent studies investigating layer-specific and region-specific changes in the entorhinal cortex associated with memory impairment in various conditions such as Alzheimer's disease.

Evaluation of T2-prepared blood oxygenation level dependent functional magnetic resonance imaging with an event-related task: Hemodynamic response function and reproducibility.

T2-prepared (T2prep) blood oxygenation level dependent (BOLD) functional MRI (fMRI) is an alternative fMRI approach developed to mitigate the susceptibility artifacts that are typically observed in brain regions near air-filled cavities, bleeding and calcification, and metallic objects in echo-planar-imaging (EPI) based fMRI images. Here, T2prep BOLD fMRI was evaluated in an event-related paradigm for the first time. Functional experiments were performed using gradient-echo (GRE) EPI, spin-echo (SE) EPI, and T2prep BOLD fMRI during an event-related visual task in 10 healthy human subjects. Each fMRI method was performed with a low (3.4 × 3.4 × 4 mm3) and a high (1.5 mm isotropic) spatial resolution on 3T and a high resolution (1.5 mm isotropic) on 7T. Robust activation were detected in the visual cortex with all three fMRI methods. In each group of fMRI scans (3T low resolution, 3T high resolution, and 7T high resolution), GRE EPI showed the highest signal change (ΔS/S), largest full-width-at-half-maximum (FWHM) and longest time-to-peak (TTP) extracted from the hemodynamic response functions (HRF), indicating substantial signal contribution from large draining veins which have longer response times than microvessels. In contrast, T2prep BOLD showed the lowest ΔS/S, smallest FWHM, and shortest TTP, suggesting that T2prep BOLD may have a purer T2-weighted BOLD contrast that is more sensitive to microvessels compared to GRE/SE EPI BOLD. This trend was more obvious in fMRI scans performed with a lower spatial resolution on a lower field (3T with a 3.4 × 3.4 × 4 mm3 voxel). Scan-rescan reproducibility in the same subjects was comparable among the three fMRI methods. The results from the current study are expected to be useful to establish T2prep BOLD as a useful alternative fMRI approach for event-related fMRI in brain regions with large susceptibility artifacts.

Establishment of an antigen-capture enzyme-linked immunosorbent assay for detecting avian reticuloendotheliosis virus.

In this study, an antigen-capturing enzyme-linked immunosorbent assay (AC-ELISA) was established for the detection of avian reticuloendotheliosis virus (REV) using monoclonal and polyclonal antibodies against gp90. New Zealand white rabbits were immunized with recombinant REV-gp90 protein, and polyclonal antibodies were obtained after purification and used as the capture antibody. Mice monoclonal antibody 1A12D against REV-gp90 protein previously prepared in our laboratory was used as the detection antibody. The specificity of the AC-ELISA was confirmed with REV, avian leukosis virus subgroup J, Marek's disease virus serotype Ⅰ, avian hepatitis E virus and Fowl adenovirus serotype 4. The results showed that the AC-ELISA had specific binding reaction with REV, and did not react with other viruses. The detection limit of this assay was 195 TCID50 units of REV. Furthermore, commercial vaccine artificially contaminated with REV was detected by three methods: AC-ELISA, the TaqMan probe fluorescence real-time quantitative RT-PCR (RT-qPCR) and indirect immunofluorescence assay (IFA). The results showed that the positive coincidence rate of RT-qPCR and AC-ELISA was 90.63 %, and the positive coincidence rate of RT-qPCR and IFA was 96.88%, indicating that the AC-ELISA established in this study was effective and feasible. This method simplified the detection process for REV contamination in poultry attenuated vaccines, and provide necessary technical tools for high-throughput detection of REV.

Functional Activities Detected in the Olfactory Bulb and Associated Olfactory Regions in the Human Brain Using T2-Prepared BOLD Functional MRI at 7T.

Olfaction is a fundamental sense that plays a vital role in daily life in humans, and can be altered in neuropsychiatric and neurodegenerative diseases. Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) using conventional echo-planar-imaging (EPI) based sequences can be challenging in brain regions important for olfactory processing, such as the olfactory bulb (OB) and orbitofrontal cortex, mainly due to the signal dropout and distortion artifacts caused by large susceptibility effects from the sinonasal cavity and temporal bone. To date, few studies have demonstrated successful fMRI in the OB in humans. T2-prepared (T2prep) BOLD fMRI is an alternative approach developed especially for performing fMRI in regions affected by large susceptibility artifacts. The purpose of this technical study is to evaluate T2prep BOLD fMRI for olfactory functional experiments in humans. Olfactory fMRI scans were performed on 7T in 14 healthy participants. T2prep BOLD showed greater sensitivity than GRE EPI BOLD in the OB, orbitofrontal cortex and the temporal pole. Functional activation was detected using T2prep BOLD in the OB and associated olfactory regions. Habituation effects and a bi-phasic pattern of fMRI signal changes during olfactory stimulation were observed in all regions. Both positively and negatively activated regions were observed during olfactory stimulation. These signal characteristics are generally consistent with literature and showed a good intra-subject reproducibility comparable to previous human BOLD fMRI studies. In conclusion, the methodology demonstrated in this study holds promise for future olfactory fMRI studies in the OB and other brain regions that suffer from large susceptibility artifacts.

Huntingtin silencing delays onset and slows progression of Huntington's disease: a biomarker study.

Huntington's disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we aim to develop non-invasive sensitive biomarkers that provide insight into therapeutic efficacy in the premanifest stage of Huntington's disease. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI in the heterozygous zQ175 mice, a full-length mHTT expressing and slowly progressing model with a premanifest period as in human Huntington's disease. Significantly elevated CBVa was evident in premanifest zQ175 mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest Huntington's disease. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study-for the first time-shows that a non-invasive functional MRI measure detects therapeutic efficacy in the premanifest stage and demonstrates long-term benefits of a non-allele-selective HTT silencing treatment introduced in the premanifest Huntington's disease.

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO2 during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO2 responses were observed in premanifest and early manifest HD patients compared to controls (P < 0.001), correlating with the CAG-Age Product scores in these patients (R2 = 0.4, P = 0.001). The results suggest the potential value of this reduced CMRO2 response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.

Differential Changes in Arteriolar Cerebral Blood Volume between Parkinson's Disease Patients with Normal and Impaired Cognition and Mild Cognitive Impairment (MCI) Patients without Movement Disorder - An Exploratory Study.

Cognitive impairment amongst Parkinson's disease (PD) patients is highly prevalent and associated with an increased risk of dementia. There is growing evidence that altered cerebrovascular functions contribute to cognitive impairment. Few studies have compared cerebrovascular changes in PD patients with normal and impaired cognition and those with mild-cognitive-impairment (MCI) without movement disorder. Here, we investigated arteriolar-cerebral-blood-volume (CBVa), an index reflecting the homeostasis of the most actively regulated segment in the microvasculature, using advanced MRI in various brain regions in PD and MCI patients and matched controls. Our goal is to find brain regions with altered CBVa that are specific to PD with normal and impaired cognition, and MCI-without-movement-disorder, respectively. In PD patients with normal cognition (n=10), CBVa was significantly decreased in the substantia nigra, caudate and putamen when compared to controls. In PD patients with impaired cognition (n=6), CBVa showed a decreasing trend in the substantia nigra, caudate and putamen, but was significantly increased in the presupplementary motor area and intracalcarine gyrus compared to controls. In MCI-patients-without-movement-disorder (n=18), CBVa was significantly increased in the caudate, putamen, hippocampus and lingual gyrus compared to controls. These findings provide important information for efforts towards developing biomarkers for the evaluation of potential risk of PD dementia (PDD) in PD patients. The current study is limited in sample size and therefore is exploratory in nature. The data from this pilot study will serve as the basis for power analysis for subsequent studies to further investigate and validate the current findings.

Fast whole brain MR imaging of dynamic susceptibility contrast changes in the cerebrospinal fluid (cDSC MRI).

PURPOSE: The circulation of cerebrospinal fluid (CSF) is closely associated with many aspects of brain physiology. When gadolinium(Gd)-based contrast is administered intravenously, pre- and post-contrast MR signal changes can often be observed in the CSF at certain locations within the intra-cranial space, mainly due to the lack of a blood-brain barrier in the dural blood vessels. This study aims to develop and systemically optimize MRI sequences that can detect dynamic signal changes in the CSF after Gd administration with a sub-millimeter spatial resolution, a temporal resolution of <10 s, and whole brain coverage. METHODS: Bloch simulations were performed to determine optimal imaging parameters for maximum CSF contrast before and after Gd injection. Simulations were validated with phantom scans. An optimized turbo-spin-echo (TSE) sequence was performed on healthy volunteers on 3T and 7T. RESULTS: Simulation results agreed well with phantom scans. In human scans, dynamic signal changes after Gd injection in the CSF were detected at several locations where cerebral lymphatic vessels were identified in previous studies. The concentration of Gd in CSF in these regions was estimated to be approximately 0.2 mmol/L. CONCLUSION: Dynamic signal changes induced by the distribution of Gd in the CSF can be detected in healthy human subjects with an optimized TSE sequence. The proposed methodology does not rely on any particular theory on CSF circulation. We expect it to be useful for studies on CSF circulation and cerebral lymphatic vessels in the brain.

Whole-Brain Functional and Diffusion Tensor MRI in Human Participants with Metallic Orthodontic Braces.

Background MRI performed with echo-planar imaging (EPI) sequences is sensitive to susceptibility artifacts in the presence of metallic objects, which presents a substantial barrier for performing functional MRI and diffusion tensor imaging (DTI) in patients with metallic orthodontic material and other head implants. Purpose To evaluate the ability to reduce susceptibility artifacts in healthy human participants wearing metallic orthodontic braces for two alternative approaches: T2-prepared functional MRI and diffusion-prepared DTI with three-dimensional fast gradient-echo readout. Materials and Methods In this prospective study conducted from February to September 2018, T2-prepared functional MRI and diffusion-prepared DTI were performed in healthy human participants. Removable dental braces with bonding trays were used so that MRI could be performed with braces and without braces in the same participants. Results were evaluated in regions with strong (EPI dropout regions for functional MRI and the inferior fronto-occipital fasciculus for DTI) and minimal (motor cortex for functional MRI and the posterior limb of internal capsule for DTI) susceptibility artifacts. Signal-to-noise ratio (SNR), contrast-to-noise ratio for functional MRI, apparent diffusion coefficient and fractional anisotropy for DTI, and degree of distortion (quantified with the Jaccard index, which measures the similarity of geometric shapes) were compared in regions with strong or minimal susceptibility effects between the current standard EPI sequences and the proposed alternatives by using paired t test. Results Six participants were evaluated (mean age ± standard deviation, 40 years ± 6; three women). In brain regions with strong susceptibility effects from the metallic braces, T2-prepared functional MRI showed significantly higher SNR (37.8 ± 2.4 vs 15.5 ± 5.3; P < .001) and contrast-to-noise ratio (0.83 ± 0.16 vs 0.29 ± 0.10; P < .001), whereas diffusion-prepared DTI showed higher SNR (5.8 ± 1.5 vs 3.8 ± 0.7; P = .03) than did conventional EPI methods. Apparent diffusion coefficient and fractional anisotropy were consistent with the literature. Geometric distortion was substantially reduced throughout the brain with the proposed methods (significantly higher Jaccard index, 0.95 ± 0.12 vs 0.81 ± 0.61; P < .001). Conclusion T2-prepared functional MRI and diffusion-prepared diffusion tensor imaging can acquire functional and diffusion MRI, respectively, in healthy human participants wearing metallic dental braces with less susceptibility artifacts and geometric distortion than with conventional echo-planar imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Dietrich in this issue.

Differential Changes in Functional Connectivity of Striatum-Prefrontal and Striatum-Motor Circuits in Premanifest Huntington's Disease.

BACKGROUND: Huntington's disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. OBJECTIVES: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. METHOD: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington's Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. RESULTS: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. CONCLUSIONS: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.

Obtaining High-Quality Blood Specimens for Downstream Applications: A Review of Current Knowledge and Best Practices.

Blood is a biological fluid that contains multiple blood fraction and cellular components. High-quality blood specimens are essential prerequisites for various downstream applications such as molecular epidemiology studies, genomics, and proteomics studies. Currently, protocols and research publications concerning the collection, handling, preservation, and stability of blood or blood fractions are constantly emerging. Moreover, standardized guidelines are a requirement for biorepositories to tightly control preanalytical variables originating from these procedures and obtain high-quality blood specimen for downstream analyses. In this review article, we summarize the best practices and fit-for-purpose protocols regarding blood collection, processing, storage, and stability. In addition, we present some typical quality biomarkers, which could be used to evaluate the integrity of blood specimens.

Noncontrast-enhanced time-resolved 4D dynamic intracranial MR angiography at 7T: A feasibility study.

BACKGROUND: Arterial spin labeling (ASL) based-noncontrast-enhanced 4D MR angiography (NCE 4D MRA) shows potential in characterizing cerebrovascular hemodynamics in cerebrovascular disorders. Ultrahigh-field theoretically benefits ASL signal with increased inherent signal-to-noise ratio (SNR) and prolonged blood T1 , which may provide improved delineation of vasculature in 4D MRA. PURPOSE: To investigate the feasibility of NCE 4D MRA using 3D Cartesian trajectory and stack-of-stars (SOS) golden angle radial trajectory at 7T. STUDY TYPE: A prospective study. SUBJECTS: Six normal volunteers and eight patients with arteriovenous malformation (AVM). FIELD STRENGTH/SEQUENCE: NCE 4D MRA with Cartesian and radial trajectories were performed at 3T and 7T. ASSESSMENT: Subjective image quality of 4D MRA was evaluated using a 4-point scale by two experienced neuroradiologists. The characterization of AVM components with 4D MRA and DSA was also graded using the Spetzler-Martin grading scale. STATISTICAL TESTS: Cohen's kappa coefficient was calculated to evaluate the agreement between two readers within each 4D MRA technique (Cartesian and Radial). A Wilcoxon signed-rank test was performed to compare the subjective image quality scores of 4D MRA between Cartesian and radial trajectories, and between 7T and 3T, respectively. RESULTS: Good-to-excellent image quality was achieved in 4D MRA with both Cartesian (3.83 ± 0.41) and radial (3.42 ± 0.49) acquisitions in healthy volunteers at 7T. However, markedly reduced scan time was needed with radial acquisition. 4D MRA at 7T (3.31 ± 0.59) shows better delineation of AVM lesion features, especially the vein drainage, compared with that of 3T (2.83 ± 0.75), although no statistical significance was achieved (P = 0.180). DATA CONCLUSION: The feasibility of ASL based 4D MRA at 7T with Cartesian and SOS golden angle radial acquisition was demonstrated. The clinical evaluation of 4D MRA in AVMs between 3T and 7T suggested 7T 4D MRA images acquired with radial acquisition demonstrate excellent delineation of AVM features, especially the draining veins. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2017.

The Spatial Associations of Cerebral Blood Flow and Spontaneous Brain Activities with White Matter Hyperintensities-An Exploratory Study Using Multimodal Magnetic Resonance Imaging.

White matter hyperintensities (WMHs) have been reported to be correlated with functional brain changes, but the association of the specific WMHs distribution pattern with regional functional changes remains uncertain. The aim of this study is to explore the possible spatial correlation of WMH with changes in cerebral blood flow (CBF) and spontaneous brain activities in elderly using a novel approach. The WMHs, CBF, and spontaneous brain activities measured by intrinsic connectivity contrast (ICC), were quantified using multimodal magnetic resonance imaging for 69 elderly subjects. Such approach enables us to expand our search for newly identified correlated areas by drawing strengths of different modes and provides a means for triangulation as well as complementary insights. The results showed significant positive correlations between WMH volumes in the right superior corona radiata and CBF in the left supplementary motor area, as well as between WMH volumes in left anterior limb internal capsule and CBF in the right putamen. Significant correlations of regional WMH volumes and ICC were also detected between the right anterior corona radiata and the left cuneus, and the right superior occipital cortex, as well as between the right superior corona radiata and the left superior occipital cortex. These findings may suggest a regional compensatory functional enhancement accounting for the maintenance of cognitively normal status, which can be supported by the widely observed phenomenon that mild to moderate WMH load could have little effect on global cognitive performance.

Language Mapping Using T2-Prepared BOLD Functional MRI in the Presence of Large Susceptibility Artifacts-Initial Results in Patients With Brain Tumor and Epilepsy.

At present, presurgical functional mapping is the most prevalent clinical application of functional magnetic resonance imaging (fMRI). Signal dropouts and distortions caused by susceptibility effects in the current standard echo planar imaging (EPI)-based fMRI images are well-known problems and pose a major hurdle for the application of fMRI in several brain regions, many of which are related to language mapping in presurgical planning. Such artifacts are particularly problematic in patients with previous surgical resection cavities, craniotomy hardware, hemorrhage, and vascular malformation. A recently developed T2-prepared (T2prep) fMRI approach showed negligible distortion and dropouts in the entire brain even in the presence of large susceptibility effects. Here, we present initial results comparing T2prep- and multiband EPI-fMRI scans for presurgical language mapping using a sentence completion task in patients with brain tumor and epilepsy. In all patients scanned, T2prep-fMRI showed minimal image artifacts (distortion and dropout) and greater functional sensitivity than EPI-fMRI around the lesions containing blood products and in air-filled cavities. This enhanced sensitivity in T2prep-fMRI was also evidenced by the fact that functional activation during the sentence completion task was detected with T2prep-fMRI but not with EPI-fMRI in the affected areas with the same statistical threshold, whereas cerebrovascular reactivity during a breath-hold task was preserved in these same regions, implying intact neurovascular coupling in these patients. Although further investigations are required to validate these findings with invasive methods such as direct cortical stimulation mapping as the gold standard, this approach provides an alternative method for performing fMRI in brain regions with large susceptibility effects.

Reliability comparison of spontaneous brain activities between BOLD and CBF contrasts in eyes-open and eyes-closed resting states.

Blood oxygenation level dependent (BOLD) and arterial spin labeling (ASL) are two predominant resting-state fMRI techniques in mapping spontaneous brain activities. At single voxel level, cerebral blood flow (CBF) measured by ASL and amplitude of low frequency fluctuations (ALFF) of BOLD have been recognized as useful indices to characterize brain function in health and disease. However, no study has directly compared the test-retest reliability between BOLD and CBF contrasts on the same group of subjects at single voxel level. Moreover, both eyes-open and eyes-closed conditions have been employed as resting states, but it is still not clear which state is more reliable. Here we collected BOLD and ASL data during eyes-open and eyes-closed states across three scanning visits on twenty-two healthy young subjects. CBF-mean, BOLD- and CBF-ALFF were computed to characterize corresponding brain activities at single voxel level. Seed-based functional connectivity (FC) with the posterior cingulate cortex (PCC) was further calculated for both BOLD and CBF data. Intra-class correlation was used as the index of long-term reliability between visits 1 and 2 (two months apart) and short-term reliability between visits 2 and 3 (on the same day). Both short- and long-term reliabilities for CBF-mean and BOLD-ALFF were high, but were lower for CBF-ALFF, BOLD- and CBF-FC in both eyes-open and eyes-closed states. Direct comparisons showed that brain regions with the highest reliability of CBF-mean were mainly in the gray matter. The reliability of CBF-ALFF and BOLD-FC was lower than that of BOLD-ALFF, and the reliability of CBF-FC was lower than those of both CBF-ALFF and BOLD-FC. Furthermore, we observed that reliabilities of the eyes-open state were higher than those of the eyes-closed state for both imaging contrasts, though the effect size was small. Voxel-wise comparisons demonstrated that the long-term reliability of BOLD-ALFF was significantly higher with eyes open in the visual system, and both the short- and long-term reliability of BOLD-FC was slightly higher with eyes open in the default mode network. Moreover, we showed that denoising decreased the reliability of both ALFF and FC of both BOLD and ASL contrasts. In conclusion, our results indicated that CBF-mean and BOLD-ALFF could both be used as reliable indices for characterizing resting-state brain activities at single voxel level and recommended the eyes-open state for resting-state studies, especially for those targeting the visual system and default mode network.

Functional Connectivity-Based Parcellation of the Thalamus: An Unsupervised Clustering Method and Its Validity Investigation.

Node definition or delineating how the brain is parcellated into individual functionally related regions is the first step to accurately map the human connectome. As a result, parcellation of the human brain has drawn considerable attention in the field of neuroscience. The thalamus is known as a relay in the human brain, with its nuclei sending fibers to the cortical and subcortical regions. Functional magnetic resonance imaging techniques offer a way to parcellate the thalamus in vivo based on its connectivity properties. However, the parcellations from previous studies show that both the number and the distribution of thalamic subdivisions vary with different cortical segmentation methods. In this study, we used an unsupervised clustering method that does not rely on a priori information of the cortical segmentation to parcellate the thalamus. Instead, this approach is based on the intrinsic resting-state functional connectivity profiles of the thalamus with the whole brain. A series of cluster solutions were obtained, and an optimal solution was determined. Furthermore, the validity of our parcellation was investigated through the following: (1) identifying specific resting-state connectivity patterns of thalamic parcels with different brain networks and (2) investigating the task activation and psychophysiological interactions of specific thalamic clusters during 8-Hz flashing checkerboard stimulation with simultaneous finger tapping. Together, the current study provides a reliable parcellation of the thalamus and enhances our understating of thalamic. Furthermore, the current study provides a framework for parcellation that could be potentially extended to other subcortical and cortical regions.

Detecting resting-state brain activity by spontaneous cerebral blood volume fluctuations using whole brain vascular space occupancy imaging.

Resting-state brain activity has been investigated extensively using BOLD contrast. However, BOLD signal represents the combined effects of multiple physiological processes and its spatial localization is less accurate than that of cerebral blood flow and volume (CBF and CBF, respectively). In this study, we demonstrate that resting-state brain activity can be reliably detected by spontaneous fluctuations of CBV-weighted signal using whole-brain gradient and spin echo (GRASE) based vascular space occupancy (VASO) imaging. Specifically, using independent component analysis, intrinsic brain networks, including default mode, salience, executive control, visual, auditory, and sensorimotor networks were revealed robustly by the VASO technique. We further demonstrate that task-evoked VASO signal aligned well with expected gray matter areas, while blood-oxygenation level dependent (BOLD) signal extended outside of these areas probably due to their different spatial specificity. The improved spatial localization of VASO is consistent with previous studies using animal models. Moreover, we showed that the 3D-GRASE VASO images had reduced susceptibility-induced signal voiding, compared to the BOLD technique. This is attributed to the fact that VASO does not require T2* weighting, thus the acquisition can use a shorter TE and can employ spin-echo scheme. Consequently VASO-based functional connectivity signals were well preserved in brain regions that tend to suffer from signal loss and geometric distortion in BOLD, such as orbital prefrontal cortex. Our study suggests that 3D-GRASE VASO imaging, with its improved spatial specificity and less sensitivity to susceptibility artifacts, may have advantages in resting-state fMRI studies.

Noncontrast dynamic MRA in intracranial arteriovenous malformation (AVM), comparison with time of flight (TOF) and digital subtraction angiography (DSA).

Digital subtraction angiography (DSA) remains the gold standard to diagnose intracranial arteriovenous malformations (AVMs) but is invasive. Existing magnetic resonance angiography (MRA) is suboptimal for assessing the hemodynamics of AVMs. The objective of this study was to evaluate the clinical utility of a novel noncontrast four-dimensional (4D) dynamic MRA (dMRA) in the evaluation of intracranial AVMs through comparison with DSA and time-of-flight (TOF) MRA. Nineteen patients (12 women, mean age 26.2±10.7 years) with intracranial AVMs were examined with 4D dMRA, TOF and DSA. Spetzler-Martin grading scale was evaluated using each of the above three methods independently by two raters. Diagnostic confidence scores for three components of AVMs (feeding artery, nidus and draining vein) were also rated. Kendall's coefficient of concordance was calculated to evaluate the reliability between two raters within each modality (dMRA, TOF, TOF plus dMRA). The Wilcoxon signed-rank test was applied to compare the diagnostic confidence scores between each pair of the three modalities. dMRA was able to detect 16 out of 19 AVMs, and the ratings of AVM size and location matched those of DSA. The diagnostic confidence scores by dMRA were adequate for nidus (3.5/5), moderate for feeding arteries (2.5/5) and poor for draining veins (1.5/5). The hemodynamic information provided by dMRA improved diagnostic confidence scores by TOF MRA. As a completely noninvasive method, 4D dMRA offers hemodynamic information with a temporal resolution of 50-100 ms for the evaluation of AVMs and can complement existing methods such as DSA and TOF MRA.