Affine image registration of arterial spin labeling MRI using deep learning networks.

Convolutional neural networks (CNN) have demonstrated good accuracy and speed in spatially registering high signal-to-noise ratio (SNR) structural magnetic resonance imaging (sMRI) images. However, some functional magnetic resonance imaging (fMRI) images, e.g., those acquired from arterial spin labeling (ASL) perfusion fMRI, are of intrinsically low SNR and therefore the quality of registering ASL images using CNN is not clear. In this work, we aimed to explore the feasibility of a CNN-based affine registration network (ARN) for registration of low-SNR three-dimensional ASL perfusion image time series and compare its performance with that from the state-of-the-art statistical parametric mapping (SPM) algorithm. The six affine parameters were learned from the ARN using both simulated motion and real acquisitions from ASL perfusion fMRI data and the registered images were generated by applying the transformation derived from the affine parameters. The speed and registration accuracy were compared between ARN and SPM. Several independent datasets, including meditation study (10 subjects × 2), bipolar disorder study (26 controls, 19 bipolar disorder subjects), and aging study (27 young subjects, 33 older subjects), were used to validate the generality of the trained ARN model. The ARN method achieves superior image affine registration accuracy (total translation/total rotation errors of ARN vs. SPM: 1.17 mm/1.23° vs. 6.09 mm/12.90° for simulated images and reduced MSE/L1/DSSIM/Total errors of 18.07% / 19.02% / 0.04% / 29.59% for real ASL test images) and 4.4 times (ARN vs. SPM: 0.50 s vs. 2.21 s) faster speed compared to SPM. The trained ARN can be generalized to align ASL perfusion image time series acquired with different scanners, and from different image resolutions, and from healthy or diseased populations. The results demonstrated that our ARN markedly outperforms the iteration-based SPM both for simulated motion and real acquisitions in terms of registration accuracy, speed, and generalization.

Quantitative magnetization transfer MRI unbiased by on-resonance saturation and dipolar order contributions.

PURPOSE: To demonstrate the bias in quantitative MT (qMT) measures introduced by the presence of dipolar order and on-resonance saturation (ONRS) effects using magnetization transfer (MT) spoiled gradient-recalled (SPGR) acquisitions, and propose changes to the acquisition and analysis strategies to remove these biases. METHODS: The proposed framework consists of SPGR sequences prepared with simultaneous dual-offset frequency-saturation pulses to cancel out dipolar order and associated relaxation (T1D ) effects in Z-spectrum acquisitions, and a matched quantitative MT (qMT) mathematical model that includes ONRS effects of readout pulses. Variable flip angle and MT data were fitted jointly to simultaneously estimate qMT parameters (macromolecular proton fraction [MPF], T2,f , T2,b , R, and free pool T1 ). This framework is compared with standard qMT and investigated in terms of reproducibility, and then further developed to follow a joint single-point qMT methodology for combined estimation of MPF and T1 . RESULTS: Bland-Altman analyses demonstrated a systematic underestimation of MPF (-2.5% and -1.3%, on average, in white and gray matter, respectively) and overestimation of T1 (47.1 ms and 38.6 ms, on average, in white and gray matter, respectively) if both ONRS and dipolar order effects are ignored. Reproducibility of the proposed framework is excellent (ΔMPF = -0.03% and ΔT1 = -19.0 ms). The single-point methodology yielded consistent MPF and T1 values with respective maximum relative average bias of -0.15% and -3.5 ms found in white matter. CONCLUSION: The influence of acquisition strategy and matched mathematical model with regard to ONRS and dipolar order effects in qMT-SPGR frameworks has been investigated. The proposed framework holds promise for improved accuracy with reproducibility.

Levetiracetam Increases Hippocampal Blood Flow in Alzheimer's Disease as Measured by Arterial Spin Labelling MRI.

BACKGROUND: Patients with Alzheimer's disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. OBJECTIVE: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. METHODS: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random order in three sessions. Afterwards, the participants underwent ASL-MRI. RESULTS: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. CONCLUSION: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings.

Fast-spin-echo versus rapid gradient-echo for 3D magnetization-prepared acquisitions: Application to inhomogeneous magnetization transfer.

PURPOSE: To evaluate the benefits of fast spin echo (FSE) imaging over rapid gradient-echo (RAGE) for magnetization-prepared inhomogeneous magnetization transfer (ihMT) imaging. METHODS: A 3D FSE sequence was modified to include an ihMT preparation (ihMT-FSE) with an optional CSF suppression based on an inversion-recovery (ihMT-FLAIR). After numeric simulations assessing SNR benefits of FSE and the potential impact of an additional inversion-recovery, ihMT-RAGE, ihMT-FSE, and ihMT-FLAIR sequences were compared in a group of six healthy volunteers, evaluating image quality, thermal, and physiological noise as well as quantification using an ihMT saturation (ihMTsat) approach. A preliminary exploration in the cervical spinal cord was also conducted in a group of three healthy volunteers. RESULTS: Several fold improvements in thermal SNR were observed with ihMT-FSE in agreement with numerical simulations. However, we observed significantly higher physiological noise in ihMT-FSE compared to ihMT-RAGE that was mitigated in ihMT-FLAIR, which provided the best total SNR (+74% and +49% compared to ihMT-RAGE in the white and gray matter, P ≤ 0.004). IhMTsat quantification was successful in all cases with strong correlation between all sequences (r2 > 0.75). Early experiments showed potential for spinal cord imaging. CONCLUSIONS: FSE generally offers higher SNR compared to gradient-echo based acquisitions for magnetization-prepared contrasts as illustrated here in the case of ihMT. However, physiological noise has a significant effect, but an inversion-recovery-based CSF suppression was shown to be efficient in mitigating effects of CSF motion.

Inhomogeneous Magnetization Transfer (ihMT) imaging in the acute cuprizone mouse model of demyelination/remyelination.

BACKGROUND: To investigate the association of ihMT (inhom signals with the demyelination and remyelination phases of the acute cuprizone mouse model in comparison with histology, and to assess the extent of tissue damage and repair from MRI data. METHODS: Acute demyelination by feeding 0.2% cuprizone for five weeks, followed by a four-week remyelination period was applied on genetically modified plp-GFP mice. Animals were scanned at different time points of the demyelination and remyelination phases of the cuprizone model using a multimodal MRI protocol, including ihMT T1D-filters, MPF (Macromolecular Proton Fraction) and R1 (longitudinal relaxation rate). For histology, plp-GFP (proteolipid protein - Green Fluorescent Protein) microscopy and LFB (Luxol Fast Blue) staining were employed as references for the myelin content. Comparison of MRI with histology was performed in the medial corpus callosum (mCC) and cerebral cortex (CTX) at two brain levels whereas ROI-wise and voxel-based analyses of the MRI metrics allowed investigating in vivo the spatial extent of myelin alterations. RESULTS: IhMT high-pass T1D-filters, targeted toward long T1D components, showed significant temporal variations in the mCC consistent with the effects induced by the cuprizone toxin. In addition, the corresponding signals correlated strongly and significantly with the myelin content assessed by GFP fluorescence and LFB staining over the demyelination and the remyelination phases. The signal of the band-pass T1D-filter, which isolates short T1D components, showed changes over time that were poorly correlated with histology, hence suggesting a sensitivity to pathological processes possibly not related to myelin. Although MPF was also highly correlated to histology, ihMT high-pass T1D-filters showed better capability to characterize the spatial-temporal patterns during the demyelination and remyelination phases of the acute cuprizone model (e.g., rostro-caudal gradient of demyelination in the mCC previously described in the literature). CONCLUSIONS: IhMT sequences selective for long T1D components are specific and sensitive in vivo markers of demyelination and remyelination and have successfully captured the spatially heterogeneous pattern of the demyelination and remyelination mechanisms in the cuprizone model. Interestingly, differences in signal variations between the ihMT high-pass and band-pass T1D-filter, suggest a sensitivity of the ihMT sequences targeted to short T1Ds to alterations other than those of myelin. Future studies will need to further address these differences by examining more closely the origin of the short T1D components and the variation of each T1D component in pathology.

Inhomogeneous magnetization transfer imaging: Concepts and directions for further development.

Off-resonance radio frequency irradiation can induce the ordering of proton spins in the dipolar fields of their neighbors, in molecules with restricted mobility. This dipolar order decays with a characteristic relaxation time, T1D , that is very different from the T1 and T2 relaxation of the nuclear alignment with the main magnetic field. Inhomogeneous magnetization transfer (ihMT) imaging is a refinement of magnetization transfer (MT) imaging that isolates the MT signal dependence on dipolar order relaxation times within motion-constrained molecules. Because T1D relaxation is a unique contrast mechanism, ihMT may enable improved characterization of tissue. Initial work has stressed the high correlation between ihMT signal and myelin density. Dipolar order relaxation appears to be much longer in membrane lipids than other molecules. Recent work has shown, however, that ihMT acquisitions may also be adjusted to emphasize different ranges of T1D . These newer approaches may be sensitive to other microstructural components of tissue. Here, we review the concepts and history of ihMT and outline the requirements for further development to realize its full potential.

The Boston ASL Template and Simulator: Initial development and implementation.

BACKGROUND AND PURPOSE: Templates are a hallmark of image analysis in neuroimaging. However, while numerous structural templates exist and have facilitated single-subject and large group studies, templates based on functional contrasts, such as arterial spin labeling (ASL) perfusion, are scarce, have an inherently low spatial resolution, and are not as widely distributed. Having such tools at one's disposal is desirable, for example, in the case of studies not acquiring structural scans. We here propose an initial development of an ASL adult template based on high-resolution fast spin echo acquisitions. METHODS: High-resolution single-delay ASL, low-resolution multi-delay ASL, T1 -weighted magnetization prepared rapid acquisition 2 gradient echoes, and T2 fluid attenuated inversion recovery data were acquired in a cohort of 10 healthy volunteers (6 males and 4 females, 30± 7 years old). After offline reconstruction of high-resolution perfusion arterial transit time (ATT) and T1 maps, we built a multi-contrast template relying on the Advanced Normalization Toolbox multivariate template nonlinear construction framework. We offer examples for the registration of ASL data acquired with different sequences. Finally, we propose an ASL simulator based on our templates and a standard kinetic model that allows generating synthetic ASL contrasts based on user-specified parameters. RESULTS: Boston ASL Template and Simulator (BATS) offers high-quality, high-resolution perfusion-weighted and quantitative perfusion templates accompanied by ATT and different anatomical contrasts readily available in the Montreal Neurological Institute space. In addition, examples of use for data registration and as a synthetic contrast generator show various applications in which BATS could be used. CONCLUSIONS: We propose a new ASL template collection, named BATS, that also includes a simulator allowing the generation of synthetic ASL contrasts. BATS is available at http://github.com/manueltaso/batsasltemplate.

ASL-BIDS, the brain imaging data structure extension for arterial spin labeling.

Arterial spin labeling (ASL) is a non-invasive MRI technique that allows for quantitative measurement of cerebral perfusion. Incomplete or inaccurate reporting of acquisition parameters complicates quantification, analysis, and sharing of ASL data, particularly for studies across multiple sites, platforms, and ASL methods. There is a strong need for standardization of ASL data storage, including acquisition metadata. Recently, ASL-BIDS, the BIDS extension for ASL, was developed and released in BIDS 1.5.0. This manuscript provides an overview of the development and design choices of this first ASL-BIDS extension, which is mainly aimed at clinical ASL applications. Discussed are the structure of the ASL data, focussing on storage order of the ASL time series and implementation of calibration approaches, unit scaling, ASL-related BIDS fields, and storage of the labeling plane information. Additionally, an overview of ASL-BIDS compatible conversion and ASL analysis software and ASL example datasets in BIDS format is provided. We anticipate that large-scale adoption of ASL-BIDS will improve the reproducibility of ASL research.

Primary Multiparametric Quantitative Brain MRI: State-of-the-Art Relaxometric and Proton Density Mapping Techniques.

This review on brain multiparametric quantitative MRI (MP-qMRI) focuses on the primary subset of quantitative MRI (qMRI) parameters that represent the mobile ("free") and bound ("motion-restricted") proton pools. Such primary parameters are the proton densities, relaxation times, and magnetization transfer parameters. Diffusion qMRI is also included because of its wide implementation in complete clinical MP-qMRI application. MP-qMRI advances were reviewed over the past 2 decades, with substantial progress observed toward accelerating image acquisition and increasing mapping accuracy. Areas that need further investigation and refinement are identified as follows: (a) the biologic underpinnings of qMRI parameter values and their changes with age and/or disease and (b) the theoretical limitations implicitly built into most qMRI mapping algorithms that do not distinguish between the different spatial scales of voxels versus spin packets, the central physical object of the Bloch theory. With rapidly improving image processing techniques and continuous advances in computer hardware, MP-qMRI has the potential for implementation in a wide range of clinical applications. Currently, three emerging MP-qMRI applications are synthetic MRI, macrostructural qMRI, and microstructural tissue modeling.

Structural integrity of the anterior mid-cingulate cortex contributes to resilience to delirium in SuperAging.

Despite its devastating clinical and societal impact, approaches to treat delirium in older adults remain elusive, making it important to identify factors that may confer resilience to this syndrome. Here, we investigated a cohort of 93 cognitively normal older patients undergoing elective surgery recruited as part of the Successful Aging after Elective Surgery study. Each participant was classified either as a SuperAger (n = 19) or typically aging older adult (n = 74) based on neuropsychological criteria, where the former was defined as those older adults whose memory function rivals that of young adults. We compared these subgroups to examine the role of preoperative memory function in the incidence and severity of postoperative delirium. We additionally investigated the association between indices of postoperative delirium symptoms and cortical thickness in functional networks implicated in SuperAging based on structural magnetic resonance imaging data that were collected preoperatively. We found that SuperAging confers the real-world benefit of resilience to delirium, as shown by lower (i.e. zero) incidence of postoperative delirium and decreased severity scores compared with typical older adults. Furthermore, greater baseline cortical thickness of the anterior mid-cingulate cortex-a key node of the brain's salience network that is also consistently implicated in SuperAging-predicted lower postoperative delirium severity scores in all patients. Taken together, these findings suggest that baseline memory function in older adults may be a useful predictor of postoperative delirium risk and severity and that superior memory function may contribute to resilience to delirium. In particular, the integrity of the anterior mid-cingulate cortex may be a potential biomarker of resilience to delirium, pointing to this region as a potential target for preventive or therapeutic interventions designed to mitigate the risk or consequences of developing this prevalent clinical syndrome.

Velocity-selective arterial spin labeling perfusion MRI: A review of the state of the art and recommendations for clinical implementation.

This review article provides an overview of the current status of velocity-selective arterial spin labeling (VSASL) perfusion MRI and is part of a wider effort arising from the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group. Since publication of the 2015 consensus paper on arterial spin labeling (ASL) for cerebral perfusion imaging, important advancements have been made in the field. The ASL community has, therefore, decided to provide an extended perspective on various aspects of technical development and application. Because VSASL has the potential to become a principal ASL method because of its unique advantages over traditional approaches, an in-depth discussion was warranted. VSASL labels blood based on its velocity and creates a magnetic bolus immediately proximal to the microvasculature within the imaging volume. VSASL is, therefore, insensitive to transit delay effects, in contrast to spatially selective pulsed and (pseudo-) continuous ASL approaches. Recent technical developments have improved the robustness and the labeling efficiency of VSASL, making it a potentially more favorable ASL approach in a wide range of applications where transit delay effects are of concern. In this review article, we (1) describe the concepts and theoretical basis of VSASL; (2) describe different variants of VSASL and their implementation; (3) provide recommended parameters and practices for clinical adoption; (4) describe challenges in developing and implementing VSASL; and (5) describe its current applications. As VSASL continues to undergo rapid development, the focus of this review is to summarize the fundamental concepts of VSASL, describe existing VSASL techniques and applications, and provide recommendations to help the clinical community adopt VSASL.

T1D -weighted ihMT imaging - Part I. Isolation of long- and short-T1D components by T1D -filtering.

PURPOSE: To identify T1D -filtering methods, which can specifically isolate various ranges of T1D components as they may be sensitive to different microstructural properties. METHODS: Modified Bloch-Provotorov equations describing a bi-T1D component biophysical model were used to simulate the inhomogeneous magnetization transfer (ihMT) signal from ihMTRAGE sequences at high RF power and low duty-cycle with different switching time values for the dual saturation experiment: Δt = 0.0, 0.8, 1.6, and 3.2 ms. Simulations were compared with experimental signals on the brain gray and white matter tissues of healthy mice at 7T. RESULTS: The lengthening of Δt created ihMT high-pass T1D -filters, which efficiently eliminated the signal from T1D components shorter than 1 ms, while partially attenuating that of longer components (≥ 1 ms). Subtraction of ihMTR images obtained with Δt = 0.0 ms and Δt = 0.8 ms generated a new ihMT band-pass T1D -filter isolating short-T1D components in the 100-µs to 1-ms range. Simulated ihMTR values in central nervous system tissues were confirmed experimentally. CONCLUSION: Long- and short-T1D components were successfully isolated with high RF power and low duty-cycle ihMT filters in the healthy mouse brain. Future studies should investigate the various T1D -range microstructural correlations in in vivo tissues.

T1D -weighted ihMT imaging - Part II. Investigating the long- and short-T1D components correlation with myelin content. Comparison with R1 and the macromolecular proton fraction.

PURPOSE: To investigate the long- and short-T1D components correlation with myelin content using inhomogeneous magnetization transfer (ihMT) high-pass and band-pass T1D -filters and to compare ihMT, R1 , and the macromolecular proton fraction (MPF) for myelin specific imaging. METHODS: The 3D ihMT rapid gradient echo (ihMTRAGE) sequences with increasing switching times (Δt) were used to derive ihMT high-pass T1D -filters with increasing T1D cutoff values and an ihMT band-pass T1D -filter for components in the 100 µs to 1 ms range. 3D spoiled gradient echo quantitative MT (SPGR-qMT) protocols were used to derive R1 and MPF maps. The specificity of R1 , MPF, and ihMT T1D -filters was evaluated by comparison with two histological reference techniques for myelin imaging. RESULTS: The higher contribution of long-T1D s as compared to the short components as Δt got longer led to an increase in the specificity to myelination. In contrast, focusing on the signal originating from a narrow range of short-T1D s (< 1 ms) as isolated by the band-pass T1D -filter led to lower specificity. In addition, the significantly lower r2 correlation coefficient of the band-pass T1D -filter suggests that the origin of short-T1D components is mostly associated with non-myelin protons. Also, the important contribution of short-T1D s to the estimated MPF, explains its low specificity to myelination as compared to the ihMT high-pass T1D -filters. CONCLUSION: Long-T1D components imaging by means of ihMT high-pass T1D -filters is proposed as an MRI biomarker for myelin content. Future studies should enable the investigation of the sensitivity of ihMT T1D -filters for demyelinating processes.

Priming of Sorafenib Prior to Radiofrequency Ablation Does Not Increase Treatment Effect in Hepatocellular Carcinoma.

BACKGROUND: Preclinical studies have shown that modulation of the tumor microvasculature with anti-angiogenic agents decreases tumor perfusion and may increase the efficacy of radiofrequency ablation (RFA) in hepatocellular carcinoma (HCC). Retrospective studies suggest that sorafenib given prior to RFA promotes an increase in the ablation zone, but prospective randomized data are lacking. AIMS: We conducted a randomized, double-blind, placebo-controlled phase II trial to evaluate the efficacy of a short-course of sorafenib prior to RFA for HCC tumors sized 3.5-7 cm (NCT00813293). METHODS: Treatment consisted of sorafenib 400 mg twice daily for 10 days or matching placebo, followed by RFA on day 10. The primary objectives were to assess if priming with sorafenib increased the volume and diameter of the RFA coagulation zone and to evaluate its impact on RFA thermal parameters. Secondary objectives included feasibility, safety and to explore the relationship between tumor blood flow on MRI and RFA effectiveness. RESULTS: Twenty patients were randomized 1:1. Priming with sorafenib did not increase the size of ablation zone achieved with RFA and did not promote significant changes in thermal parameters, although it significantly decreased blood perfusion to the tumor by 27.9% (p = 0.01) as analyzed by DCE-MRI. No subject discontinued treatment owing to adverse events and no grade 4 toxicity was observed. CONCLUSION: Priming of sorafenib did not enhance the effect of RFA in intermediate sized HCC. Future studies should investigate whether longer duration of treatment or a different antiangiogenic strategy in the post-procedure setting would be more effective in impairing tumor perfusion and increasing RFA efficacy.

A strategy to reduce the sensitivity of inhomogeneous magnetization transfer (ihMT) imaging to radiofrequency transmit field variations at 3 T.

PURPOSE: To minimize the sensitivity of inhomogeneous magnetization transfer gradient-echo (ihMT-GRE) imaging to radiofrequency (RF) transmit field ( B1+ ) inhomogeneities at 3 T. METHODS: The ihMT-GRE sequence was optimized by varying the concentration of the RF saturation energy over time, obtained by increasing the saturation pulse power while extending the sequence repetition time (TR). Different protocols were tested using numerical simulations and human in vivo experiments in the brain white matter (WM) of healthy subjects at 3 T. The sensitivity of the ihMT ratio (ihMTR) to B1+ variations was investigated by comparing measurements obtained at nominal transmitter adjustments and following a 20% global B1+ drop. The resulting relative variations (δihMTR ) were evaluated voxelwise as a function of the local B1+ distribution. The reproducibility of the protocol providing minimal B1+ bias was assessed in a test-retest experiment. RESULTS: In line with simulations, ihMT-GRE experiments conducted at high concentration of the RF energy over time demonstrated strong reduction of the B1+ inhomogeneity effects in the human WM. Under the optimal conditions of 350-ms TR and 3-µT root mean square (RMS) saturation power, 73% of all WM voxels presented δihMTR below 10%. Reproducibility analysis yielded a close-to-zero systematic bias (ΔihMTR = -0.081%) and a high correlation (ρ² = 0.977) between test and retest experiments. CONCLUSION: Concentrating RF saturation energy in ihMT-GRE sequences mitigates the sensitivity of the ihMTR to B1+ variations and allows for clinical-ready ihMT imaging at 3 T. This feature is of particular interest for high and ultra-high field applications.

Impact of multisession 40Hz tACS on hippocampal perfusion in patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with alterations in cortical perfusion that correlate with cognitive impairment. Recently, neural activity in the gamma band has been identified as a driver of arteriolar vasomotion while, on the other hand, gamma activity induction on preclinical models of AD has been shown to promote protein clearance and cognitive protection. METHODS: In two open-label studies, we assessed the possibility to modulate cerebral perfusion in 15 mild to moderate AD participants via 40Hz (gamma) transcranial alternating current stimulation (tACS) administered 1 h daily for 2 or 4 weeks, primarily targeting the temporal lobe. Perfusion-sensitive MRI scans were acquired at baseline and right after the intervention, along with electrophysiological recording and cognitive assessments. RESULTS: No serious adverse effects were reported by any of the participants. Arterial spin labeling MRI revealed a significant increase in blood perfusion in the bilateral temporal lobes after the tACS treatment. Moreover, perfusion changes displayed a positive correlation with changes in episodic memory and spectral power changes in the gamma band. CONCLUSIONS: Results suggest 40Hz tACS should be further investigated in larger placebo-controlled trials as a safe, non-invasive countermeasure to increase fast brain oscillatory activity and increase perfusion in critical brain areas in AD patients. TRIAL REGISTRATION: Studies were registered separately on ClinicalTrials.gov ( NCT03290326 , registered on September 21, 2017; NCT03412604 , registered on January 26, 2018).

Effects of tDCS dose and electrode montage on regional cerebral blood flow and motor behavior.

We used three dose levels (Sham, 2 mA, and 4 mA) and two different electrode montages (unihemispheric and bihemispheric) to examine DOSE and MONTAGE effects on regional cerebral blood flow (rCBF) as a surrogate marker of neural activity, and on a finger sequence task, as a surrogate behavioral measure drawing on brain regions targeted by transcranial direct current stimulation (tDCS). We placed the anodal electrode over the right motor region (C4) while the cathodal or return electrode was placed either over a left supraorbital region (unihemispheric montage) or over the left motor region (C3 in the bihemispheric montage). Performance changes in the finger sequence task for both hands (left hand: p = 0.0026, and right hand: p = 0.0002) showed a linear tDCS dose response but no montage effect. rCBF in the right hemispheric perirolandic area increased with dose under the anodal electrode (p = 0.027). In contrast, in the perirolandic ROI in the left hemisphere, rCBF showed a trend to increase with dose (p = 0.053) and a significant effect of montage (p = 0.00004). The bihemispheric montage showed additional rCBF increases in frontomesial regions in the 4mA condition but not in the 2 mA condition. Furthermore, we found strong correlations between simulated current density in the left and right perirolandic region and improvements in the finger sequence task performance (FSP) for the contralateral hand. Our data support not only a strong direct tDCS dose effect for rCBF and FSP as surrogate measures of targeted brain regions but also indirect effects on rCBF in functionally connected regions (e.g., frontomesial regions), particularly in the higher dose condition and on FSP of the ipsilateral hand (to the anodal electrode). At a higher dose and irrespective of polarity, a wider network of sensorimotor regions is positively affected by tDCS.

Regional and depth-dependence of cortical blood-flow assessed with high-resolution Arterial Spin Labeling (ASL).

Methods for imaging of cerebral blood flow do not typically resolve the cortex and thus underestimate flow. However, recent work with high-resolution MRI has emphasized the regional and depth-dependent structural, functional and relaxation times variations within the cortex. Using high-resolution Arterial Spin Labeling (ASL) and T1 mapping acquisitions, we sought to probe the effects of spatial resolution and tissue heterogeneity on cortical cerebral blood flow (CBF) measurements with ASL. We acquired high-resolution (1.6mm)3 whole brain ASL data in a cohort of 10 volunteers at 3T, along with T1 and transit-time (ATT) mapping, followed by group cortical surface-based analysis using FreeSurfer of the different measured parameters. Fully resolved regional analysis showed higher than average mid-thickness CBF in primary motor areas (+15%,p<0.002), frontal regions (+17%,p<0.01) and auditory cortex, while occipital regions had lower average CBF (-20%,p<10-5). ASL signal was higher towards the pial surface but correction for the shorter T1 near the white matter surface reverses this gradient, at least when using the low-resolution ATT map. Similar to structural measures, fully-resolved ASL CBF measures show significant differences across cortical regions. Depth-dependent variation of T1 in the cortex complicates interpretation of depth-dependent ASL signal and may have implications for the accurate CBF quantification at lower resolutions.