CO2 as an engine for neurofluid flow: Exploring the coupling between vascular reactivity, brain clearance, and changes in tissue properties.

The brain relies on an effective clearance mechanism to remove metabolic waste products for the maintenance of homeostasis. Recent studies have focused on elucidating the forces that drive the motion of cerebrospinal fluid (CSF), responsible for removal of these waste products. We demonstrate that vascular responses evoked using controlled manipulations of partial pressure of carbon dioxide (PaCO2 ) levels, serve as an endogenous driver of CSF clearance from the brain. To demonstrate this, we retrospectively surveyed our database, which consists of brain metastases patients from whom blood oxygen level-dependent (BOLD) images were acquired during targeted hypercapnic and hyperoxic respiratory challenges. We observed a correlation between CSF inflow signal around the fourth ventricle and CO2 -induced changes in cerebral blood volume. By contrast, no inflow signal was observed in response to the nonvasoactive hyperoxic stimulus, validating our measurements. Moreover, our results establish a link between the rate of the hemodynamic response (to elevated PaCO2 ) and peritumoral edema load, which we suspect may affect CSF flow, consequently having implications for brain clearance. Our expanded perspective on the factors involved in neurofluid flow underscores the importance of considering both cerebrovascular responses, as well as the brain mechanical properties, when evaluating CSF dynamics in the context of disease processes.

A silent echo-planar spectroscopic imaging readout with high spectral bandwidth MRSI using an ultrasonic gradient axis.

PURPOSE: We present a novel silent echo-planar spectroscopic imaging (EPSI) readout, which uses an ultrasonic gradient insert to accelerate MRSI while producing a high spectral bandwidth (20 kHz) and a low sound level. METHODS: The ultrasonic gradient insert consisted of a single-axis (z-direction) plug-and-play gradient coil, powered by an audio amplifier, and produced 40 mT/m at 20 kHz. The silent EPSI readout was implemented in a phase-encoded MRSI acquisition. Here, the additional spatial encoding provided by this silent EPSI readout was used to reduce the number of phase-encoding steps. Spectroscopic acquisitions using phase-encoded MRSI, a conventional EPSI-readout, and the silent EPSI readout were performed on a phantom containing metabolites with resonance frequencies in the ppm range of brain metabolites (0-4 ppm). These acquisitions were used to determine sound levels, showcase the high spectral bandwidth of the silent EPSI readout, and determine the SNR efficiency and the scan efficiency. RESULTS: The silent EPSI readout featured a 19-dB lower sound level than a conventional EPSI readout while featuring a high spectral bandwidth of 20 kHz without spectral ghosting artifacts. Compared with phase-encoded MRSI, the silent EPSI readout provided a 4.5-fold reduction in scan time. In addition, the scan efficiency of the silent EPSI readout was higher (82.5% vs. 51.5%) than the conventional EPSI readout. CONCLUSIONS: We have for the first time demonstrated a silent spectroscopic imaging readout with a high spectral bandwidth and low sound level. This sound reduction provided by the silent readout is expected to have applications in sound-sensitive patient groups, whereas the high spectral bandwidth could benefit ultrahigh-field MR systems.

Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report.

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = -0.286, p < 0.001), CMRO2 (rrm = -0.254, p < 0.001), and CVR (rrm = -0.346, p < 0.001), but not in OEF (rrm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.

Hemodynamic imaging parameters in brain metastases patients - Agreement between multi-delay ASL and hypercapnic BOLD.

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = -0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.

Anesthesia Depresses Cerebrovascular Reactivity to Acetazolamide in Pediatric Moyamoya Vasculopathy.

Measurements of cerebrovascular reactivity (CVR) are essential for treatment decisions in moyamoya vasculopathy (MMV). Since MMV patients are often young or cognitively impaired, anesthesia is commonly used to limit motion artifacts. Our aim was to investigate the effect of anesthesia on the CVR in pediatric MMV. We compared the CVR with multidelay-ASL and BOLD MRI, using acetazolamide as a vascular stimulus, in all awake and anesthesia pediatric MMV scans at our institution. Since a heterogeneity in disease and treatment influences the CVR, we focused on the (unaffected) cerebellum. Ten awake and nine anesthetized patients were included. The post-acetazolamide CBF and ASL-CVR were significantly lower in anesthesia patients (47.1 ± 15.4 vs. 61.4 ± 12.1, p = 0.04; 12.3 ± 8.4 vs. 23.7 ± 12.2 mL/100 g/min, p = 0.03, respectively). The final BOLD-CVR increase (0.39 ± 0.58 vs. 3.6 ± 1.2% BOLD-change (mean/SD), p < 0.0001), maximum slope of increase (0.0050 ± 0.0040%/s vs. 0.017 ± 0.0059%, p < 0.0001), and time to maximum BOLD-increase (~463 ± 136 and ~697 ± 144 s, p = 0.0028) were all significantly lower in the anesthesia group. We conclude that the response to acetazolamide is distinctively different between awake and anesthetized MMV patients, and we hypothesize that these findings can also apply to other diseases and methods of measuring CVR under anesthesia. Considering that treatment decisions heavily depend on CVR status, caution is warranted when assessing CVR under anesthesia.

Deuterium echo-planar spectroscopic imaging (EPSI) in the human liver in vivo at 7 T.

PURPOSE: To demonstrate the feasibility of deuterium echo-planar spectroscopic imaging (EPSI) to accelerate 3D deuterium metabolic imaging in the human liver at 7 T. METHODS: A deuterium EPSI sequence, featuring a Hamming-weighted k-space acquisition pattern for the phase-encoding directions, was implemented. Three-dimensional deuterium EPSI and conventional MRSI were performed on a water/acetone phantom and in vivo in the human liver at natural abundance. Moreover, in vivo deuterium EPSI measurements were acquired after oral administration of deuterated glucose. The effect of acquisition time on SNR was evaluated by retrospectively reducing the number of averages. RESULTS: The SNR of natural abundance deuterated water signal in deuterium EPSI was 6.5% and 5.9% lower than that of MRSI in the phantom and in vivo experiments, respectively. In return, the acquisition time of in vivo EPSI data could be reduced retrospectively to 2 min, beyond the minimal acquisition time of conventional MRSI (of 20 min in this case), while still leaving sufficient SNR. Three-dimensional deuterium EPSI, after administration of deuterated glucose, enabled monitoring of hepatic glucose dynamics with full liver coverage, a spatial resolution of 20 mm isotropic, and a temporal resolution of 9 min 50 s, which could retrospectively be shortened to 2 min. CONCLUSION: In this work, we demonstrate the feasibility of accelerated 3D deuterium metabolic imaging of the human liver using deuterium EPSI. The acceleration obtained with EPSI can be used to increase temporal and/or spatial resolution, which will be valuable to study tissue metabolism of deuterated compounds over time.

The many layers of BOLD. The effect of hypercapnic and hyperoxic stimuli on macro- and micro-vascular compartments quantified by CVR, M, and CBV across cortical depth.

Ultra-high field functional magnetic resonance imaging (fMRI) offers the spatial resolution to measure neuronal activity at the scale of cortical layers. However, cortical depth dependent vascularization differences, such as a higher prevalence of macro-vascular compartments near the pial surface, have a confounding effect on depth-resolved blood-oxygen-level dependent (BOLD) fMRI signals. In the current study, we use hypercapnic and hyperoxic breathing conditions to quantify the influence of all venous vascular and micro-vascular compartments on laminar BOLD fMRI, as measured with gradient-echo (GE) and spin-echo (SE) scan sequences, respectively. We find that all venous vascular and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-value parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately two and a half times larger for all venous vascular compartments combined compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in estimates of CBV changes between all venous vascular and micro-vascular compartments, although this relative difference was approximately uniform across cortical depth. Thus, our results suggest that fMRI BOLD signal differences across cortical depth are likely caused by differences in dilation properties between macro- and micro-vascular compartments.

Quantifying cerebral blood arrival times using hypoxia-mediated arterial BOLD contrast.

Cerebral blood arrival and tissue transit times are sensitive measures of the efficiency of tissue perfusion and can provide clinically meaningful information on collateral blood flow status. We exploit the arterial blood oxygen level dependent (BOLD) signal contrast established by precisely decreasing, and then increasing, arterial hemoglobin saturation using respiratory re-oxygenation challenges to quantify arterial blood arrival times throughout the brain. We term this approach the Step Hemoglobin re-Oxygenation Contrast Stimulus (SHOCS). Carpet plot analysis yielded measures of signal onset (blood arrival), global transit time (gTT) and calculations of relative total blood volume. Onset times averaged across 12 healthy subjects were 1.1 ± 0.4 and 1.9 ± 0.6 for cortical gray and deep white matter, respectively. The average whole brain gTT was 4.5 ± 0.9 s. The SHOCS response was 1.7 fold higher in grey versus white matter; in line with known differences in tissue-specific blood volume fraction. SHOCS was also applied in a patient with unilateral carotid artery occlusion revealing ipsilateral prolonged signal onset with normal perfusion in the unaffected hemisphere. We anticipate that SHOCS will further inform on the extent of collateral blood flow in patients with upstream steno-occlusive vascular disease, including those already known to manifest reductions in vasodilatory reserve capacity or vascular steal.

Proton metabolic mapping of the brain at 7 T using a two-dimensional free induction decay-echo-planar spectroscopic imaging readout with lipid suppression.

The increased signal-to-noise ratio (SNR) and chemical shift dispersion at high magnetic fields (≥7 T) have enabled neuro-metabolic imaging at high spatial resolutions. To avoid very long acquisition times with conventional magnetic resonance spectroscopic imaging (MRSI) phase-encoding schemes, solutions such as pulse-acquire or free induction decay (FID) sequences with short repetition time and inner volume selection methods with acceleration (echo-planar spectroscopic imaging [EPSI]), have been proposed. With the inner volume selection methods, limited spatial coverage of the brain and long echo times may still impede clinical implementation. FID-MRSI sequences benefit from a short echo time and have a high SNR per time unit; however, contamination from strong extra-cranial lipid signals remains a problem that can hinder correct metabolite quantification. L2-regularization can be applied to remove lipid signals in cases with high spatial resolution and accurate prior knowledge. In this work, we developed an accelerated two-dimensional (2D) FID-MRSI sequence using an echo-planar readout and investigated the performance of lipid suppression by L2-regularization, an external crusher coil, and the combination of these two methods to compare the resulting spectral quality in three subjects. The reduction factor of lipid suppression using the crusher coil alone varies from 2 to 7 in the lipid region of the brain boundary. For the combination of the two methods, the average lipid area inside the brain was reduced by 2% to 38% compared with that of unsuppressed lipids, depending on the subject's region of interest. 2D FID-EPSI with external lipid crushing and L2-regularization provides high in-plane coverage and is suitable for investigating brain metabolite distributions at high fields.

Glutamate levels across deep brain structures in patients with a psychotic disorder and its relation to cognitive functioning.

BACKGROUND: Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but its role in deep gray matter (DGM) regions is unclear. AIMS: To evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction, and post-processing techniques. METHODS: A 7-Tesla magnetic resonance imaging scanner combined with a lipid suppression coil and subject-specific water suppression pulses was used to acquire high-resolution magnetic resonance spectroscopic imaging data. Tissue fraction correction and registration to a standard brain were performed for group comparison in specifically delineated DGM regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. RESULTS: Average glutamate levels across DGM structures (i.e. caudate, pallidum, putamen, and thalamus) in mostly medicated patients with a psychotic disorder (n = 16, age = 33, 4 females) were lower compared to healthy controls (n = 23, age = 24, 7 females; p = 0.005, d = 1.06). Stratified analyses showed lower glutamate levels in the caudate (p = 0.046, d = 0.76) and putamen p = 0.013, d = 0.94). These findings were largely explained by age differences between groups. DGM glutamate levels were positively correlated with psychomotor speed (r(30) = 0.49, p = 0.028), but not with other cognitive domains. CONCLUSIONS: We find reduced glutamate levels across DGM structures including the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Despite limitations concerning age differences, these results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in psychotic disorders.

Hemodynamic and metabolic changes during hypercapnia with normoxia and hyperoxia using pCASL and TRUST MRI in healthy adults.

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, 'CO2 in air' and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, 'CO2 in air' and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for 'CO2 in air' and carbogen, respectively). CMRO2 decreased for 'CO2 in air' (-13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO2 during carbogen did not significantly change. Our findings indicate that 'CO2 in air' is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Medullary vein architecture modulates the white matter BOLD cerebrovascular reactivity signal response to CO2: Observations from high-resolution T2* weighted imaging at 7T.

Brain stress testing using blood oxygenation level-dependent (BOLD) MRI to evaluate changes in cerebrovascular reactivity (CVR) is of growing interest for evaluating white matter integrity. However, even under healthy conditions, the white matter BOLD-CVR response differs notably from that observed in the gray matter. In addition to actual arterial vascular control, the venous draining topology may influence the WM-CVR response leading to signal delays and dispersions. These types of alterations in hemodynamic parameters are sometimes linked with pathology, but may also arise from differences in normal venous architecture. In this work, high-resolution T2*weighted anatomical images combined with BOLD imaging during a hypercapnic breathing protocol were acquired using a 7 tesla MRI system. Hemodynamic parameters including base CVR, hemodynamic lag, lag-corrected CVR, response onset and signal dispersion, and finally ΔCVR (corrected CVR minus base CVR) were calculated in 8 subjects. Parameter maps were spatially normalized and correlated against an MNI-registered white matter medullary vein atlas. Moderate correlations (Pearson's rho) were observed between medullary vessel frequency (MVF) and ΔCVR (0.52; 0.58 for total WM), MVF and hemodynamic lag (0.42; 0.54 for total WM), MVF and signal dispersion (0.44; 0.53 for total WM), and finally MVF and signal onset (0.43; 0.52 for total WM). Results indicate that, when assessed in the context of the WM venous architecture, changes in the response shape may only be partially reflective of the actual vascular reactivity response occurring further upstream by control vessels. This finding may have implications when attributing diseases mechanisms and/or progression to presumed impaired WM BOLD-CVR.

Contralateral improvement of cerebrovascular reactivity and TIA frequency after unilateral revascularization surgery in moyamoya vasculopathy.

OBJECTIVE: Moyamoya vasculopathy is a rare, often bilateral disease characterized by progressive stenosis and occlusion of the distal internal carotid artery, leading to a progressive deterioration of cerebrovascular reactivity (CVR) and increased risk of transient ischemic attacks (TIAs), infarction and hemorrhage. Surgical revascularization is a widely accepted symptomatic treatment, often performed bilaterally in one or two stages. To possibly further optimize treatment strategy, we investigated the effect of unilateral revascularization surgery on the CVR of, and TIA frequency originating from, the contralateral hemisphere. METHODS: From our database of 143 moyamoya vasculopathy patients we selected those with bilateral disease, who underwent hemodynamic imaging ([15O]H2O positron emission tomography (PET)-CT with acetazolamide challenge) before and 14 months (median) after unilateral revascularization. We evaluated CVR in three regions per hemisphere, and averaged these per hemisphere for statistical comparison. Conservatively treated patients were showed as a comparison group. To examine TIA frequency, we selected patients who presented with TIAs that (also) originated from the contralateral - not to be operated - hemisphere. We scored changes in CVR and TIA frequency of the ipsilateral and contralateral hemisphere over time. RESULTS: Seven surgical and seven conservative patients were included for CVR comparison. Of the 20 scored contralateral regions in the surgical group, 15 showed improved CVR after unilateral revascularization, while 5 remained stable. The averaged scores improved significantly for both hemispheres. In conservatively treated patients, however, only 3 of the 20 scored regions improved in the least-affected (contralateral) hemispheres, and 9 deteriorated. From the 6 patients with contralateral TIAs at presentation, 4 had a decreased TIA frequency originating from the contralateral hemisphere after unilateral surgery, while 2 patients remained stable. CONCLUSION: Both CVR and TIA frequency in the contralateral hemisphere can improve after unilateral revascularization surgery in bilateral MMV.

Insights Into Cerebral Tissue-Specific Response to Respiratory Challenges at 7T: Evidence for Combined Blood Flow and CO2-Mediated Effects.

Cerebrovascular reactivity (CVR) mapping is finding increasing clinical applications as a non-invasive probe for vascular health. Further analysis extracting temporal delay information from the CVR response provide additional insight that reflect arterial transit time, blood redistribution, and vascular response speed. Untangling these factors can help better understand the (patho)physiology and improve diagnosis/prognosis associated with vascular impairments. Here, we use hypercapnic (HC) and hyperoxic (HO) challenges to gather insight about factors driving temporal delays between gray-matter (GM) and white-matter (WM). Blood Oxygen Level Dependent (BOLD) datasets were acquired at 7T in nine healthy subjects throughout BLOCK- and RAMP-HC paradigms. In a subset of seven participants, a combined HC+HO block, referred as the "BOOST" protocol, was also acquired. Tissue-based differences in Rapid Interpolation at Progressive Time Delays (RIPTiDe) were compared across stimulus to explore dynamic (BLOCK-HC) versus progressive (RAMP-HC) changes in CO2, as well as the effect of bolus arrival time on CVR delays (BLOCK-HC versus BOOST). While GM delays were similar between the BLOCK- (21.80 ± 10.17 s) and RAMP-HC (24.29 ± 14.64 s), longer WM lag times were observed during the RAMP-HC (42.66 ± 17.79 s), compared to the BLOCK-HC (34.15 ± 10.72 s), suggesting that the progressive stimulus may predispose WM vasculature to longer delays due to the smaller arterial content of CO2 delivered to WM tissues, which in turn, decreases intravascular CO2 gradients modulating CO2 diffusion into WM tissues. This was supported by a maintained ∼10 s offset in GM (11.66 ± 9.54 s) versus WM (21.40 ± 11.17 s) BOOST-delays with respect to the BLOCK-HC, suggesting that the vasoactive effect of CO2 remains constant and that shortening of BOOST delays was be driven by blood arrival reflected through the non-vasodilatory HO contrast. These findings support that differences in temporal and magnitude aspects of CVR between vascular networks reflect a component of CO2 sensitivity, in addition to redistribution and steal blood flow effects. Moreover, these results emphasize that the addition of a BOOST paradigm may provide clinical insights into whether vascular diseases causing changes in CVR do so by way of severe blood flow redistribution effects, alterations in vascular properties associated with CO2 diffusion, or changes in blood arrival time.

Lipid-suppressed and tissue-fraction corrected metabolic distributions in human central brain structures using 2D 1 H magnetic resonance spectroscopic imaging at 7 T.

INTRODUCTION: Magnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low signal-to-noise ratios data, signal variations due to partial-volume effects, acquisition and extracranial lipid artifacts, along with clinically relevant aspects such as scan time constraints, are among the challenges associated with in vivo MRSI. METHODS: The aim of this work was to address some of these factors and to develop an acquisition, reconstruction, and postprocessing pipeline to derive lipid-suppressed metabolite values of central brain structures based on free-induction decay measurements made using a 7 T MR scanner. Anatomical images were used to perform high-resolution (1 mm3 ) partial-volume correction to account for gray matter, white matter (WM), and cerebral-spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the Montreal Neurological Institute (MNI) standard atlas facilitated the creation of high-resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions. Partial-volume correction improved the delineation of deep brain nuclei. We report average metabolite values including glutamate + glutamine (Glx), glycerophosphocholine, choline and phosphocholine (tCho), (phospo)creatine, myo-inositol and glycine (mI-Gly), glutathione, N-acetyl-aspartyl glutamate(and glutamine), and N-acetyl-aspartate in the basal ganglia, central WM (thalamic radiation, corpus callosum) as well as insular cortex and intracalcarine sulcus. CONCLUSION: MNI-registered average metabolite maps facilitate group-based analysis, thus offering the possibility to mitigate uncertainty in variable MRSI data.

Changes in volumetric and metabolic parameters relate to differences in exposure to sub-concussive head impacts.

Structural and calibrated magnetic resonance imaging data were acquired on 44 collegiate football players prior to the season (PRE), following the first four weeks in-season (PTC) and one month after the last game (POST). Exposure data collected from g-Force accelerometers mounted to the helmet of each player were used to split participants into HIGH (N = 22) and LOW (N = 22) exposure groups, based on the frequency of impacts sustained by each athlete. Significant decreases in grey-matter volume specific to the HIGH group were documented at POST (P = 0.009), compared to baseline. Changes in resting cerebral blood flow (CBF0), corrected for partial volume effects, were observed within the HIGH group, throughout the season (P < 0.0001), suggesting that alterations in perfusion may follow exposure to sub-concussive collisions. Co-localized significant increases in cerebral metabolic rate of oxygen consumption (CMRO2|0) mid-season were also documented in the HIGH group, with respect to both PRE- and POST values. No physiological changes were observed in the LOW group. Therefore, cerebral metabolic demand may be elevated in players with greater exposure to head impacts. These results provide novel insight into the effects of sub-concussive collisions on brain structure and cerebrovascular physiology and emphasize the importance of multi-modal imaging for a complete characterization of cerebral health.

A novel perspective to calibrate temporal delays in cerebrovascular reactivity using hypercapnic and hyperoxic respiratory challenges.

Redistribution of blood flow across different brain regions, arising from the vasoactive nature of hypercapnia, can introduce errors when examining cerebrovascular reactivity (CVR) response delays. In this study, we propose a novel analysis method to characterize hemodynamic delays in the blood oxygen level dependent (BOLD) response to hypercapnia, and hyperoxia, as a way to provide insight into transient differences in vascular reactivity between cortical regions, and across tissue depths. A pseudo-continuous arterial spin labeling sequence was used to acquire BOLD and cerebral blood flow simultaneously in 19 healthy adults (12 F; 20 ± 2 years) during boxcar CO2 and O2 gas inhalation paradigms. Despite showing distinct differences in hypercapnia-induced response delay times (P < 0.05; Bonferroni corrected), grey matter regions showed homogenous hemodynamic latencies (P > 0.05) once calibrated for bolus arrival time derived using non-vasoactive hyperoxic gas challenges. Longer hypercapnic temporal delays were observed as the depth of the white matter tissue increased, although no significant differences in response lag were found during hyperoxia across tissue depth, or between grey and white matter. Furthermore, calibration of hypercapnic delays using hyperoxia revealed that deeper white matter layers may be more prone to dynamic redistribution of blood flow, which introduces response lag times ranging between 1 and 3 s in healthy subjects. These findings suggest that the combination of hypercapnic and hyperoxic gas-inhalation MRI can be used to distinguish between differences in CVR that arise as a result of delayed stimulus arrival time (due to the local architecture of the cerebrovasculature), or preferential blood flow distribution. Calibrated response delays to hypercapnia provide important insights into cerebrovascular physiology, and may be used to correct response delays associated with vascular impairment.

GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay.

Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/-12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal-but submaximal-GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.

Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients.

BACKGROUND AND PURPOSE: The BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV. MATERIALS AND METHODS: Fifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated. RESULTS: The effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2  mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD. CONCLUSION: ALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV.

Vascular reactivity in small cerebral perforating arteries with 7 T phase contrast MRI - A proof of concept study.

Existing cerebrovascular reactivity (CVR) techniques assess flow reactivity in either the largest cerebral vessels or at the level of the parenchyma. We examined the ability of 2D phase contrast MRI at 7 T to measure CVR in small cerebral perforating arteries. Blood flow velocity in perforators was measured in 10 healthy volunteers (mean age 26 years) using a 7 T MR scanner, using phase contrast acquisitions in the semioval center (CSO), the basal ganglia (BG) and the middle cerebral artery (MCA). Changes in flow velocity in response to a hypercapnic breathing challenge were assessed, and expressed as the percentual increase of flow velocity as a function of the increase in end tidal partial pressure of CO2. The hypercapnic challenge increased (fit ±â€¯standard error) flow velocity by 0.7 ±â€¯0.3%/mmHg in the CSO (P < 0.01). Moreover, the number of detected perforators (mean [range]) increased from 63 [27-88] to 108 [61-178] (P < 0.001). In the BG, the hypercapnic challenge increased flow velocity by 1.6 ±â€¯0.5%/mmHg (P < 0.001), and the number of detected perforators increased from 48 [24-66] to 63 [32-91] (P < 0.01). The flow in the MCA increased by 5.2 ±â€¯1.4%/mmHg (P < 0.01). Small vessel specific reactivity can now be measured in perforators of the CSO and BG, using 2D phase contrast at 7 T.