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Concussion imaging research has primarily focused on neuronal disruption with lesser emphasis directed toward vascular dysfunction. However, blood flow metrics may be more sensitive than measures of neuronal integrity. Vascular dysfunction can be assessed by measuring cerebrovascular reactivity (CVR)-the change in cerebral blood flow per unit change in vasodilatory stimulus. CVR metrics, including speed and magnitude of flow responses to a standardized well-controlled vasoactive stimulus, are potentially useful for assessing individual subjects following concussion given that blood flow dysregulation is known to occur with traumatic brain injury. We assessed changes in CVR metrics to a standardized vasodilatory stimulus during the acute phase of concussion. Using a case control design, 20 concussed participants and 20 healthy controls (HCs) underwent CVR assessment measuring blood oxygen-level dependent (BOLD) magnetic resonance imaging using precise changes in end-tidal partial pressure of CO2 (PETCO2). Metrics were calculated for the whole brain, gray matter (GM), and white matter (WM) using sex-stratification. A leave-one-out receiver operating characteristic (ROC) analysis classified concussed from HCs based on CVR metrics. CVR magnitude was greater and speed of response faster in concussed participants relative to HCs, with WM showing higher classification accuracy compared with GM. ROC analysis for WM-CVR metrics revealed an area under the curve of 0.94 in males and 0.90 in females for speed and magnitude of response respectively. These greater than normal responses to a vasodilatory stimulus warrant further investigation to compare the predictive ability of CVR metrics against structural injury metrics for diagnosis and prognosis in acute concussion.

Tourette Syndrome (TS) is a neuropsychiatric condition characterized by tics that are typically preceded by uncomfortable urges that build until the tic is performed. Both tics and their associated urges are commonly exacerbated during states of heightened emotion. However, the neural substrates that are responsible for the development of urges have not been fully elucidated, particularly with regards to the influence of emotion. In this study, we investigate the brain areas associated with the development of urges and their modulation by emotion in patients with TS. Moreover, we explore the influence of obsessive-compulsive symptoms (OCS) which are commonly comorbid in TS. Forty patients with TS and 20 healthy controls completed an emotional blink suppression paradigm while undergoing functional magnetic resonance imaging. For the paradigm, participants completed alternating blocks of blink inhibition and free blinking while viewing pictures of angry and neutral facial expressions. Compared to controls, patients exhibited greater activity in the superior temporal gyrus and midcingulate during the inhibition of urges. Within the patient group, tic severity was associated with activity in the superior frontal gyrus during the angry inhibition contrast as compared to neutral; greater premonitory urge severity was associated with greater activity in the hippocampus, middle temporal gyrus and in the subcortex; blink inhibition ability was negatively associated with activity in the thalamus and insula. There were no significant associations with OCS severity for the emotion-related contrasts. The observed activated regions may represent a network that produces urges in patients, or alternatively, could represent compensatory cortical activity needed to keep urges and tics under control during emotional situations. Additionally, our findings suggest that OCS in the context of TS is similar to traditional obsessive-compulsive disorder and is neurobiologically dissociable from tics.

Tourette Syndrome (TS) is characterized by the presence of tics and sensory phenomena, such as premonitory urges, and is often accompanied by significant obsessive-compulsive symptoms (OCS). The goal of this exploratory study was to determine the association between functional connectivity and the different symptom domains of TS, as little is currently known about how they differ. Resting-state functional magnetic resonance imaging was performed in 39 patients with TS and 20 matched healthy controls. Seed-based functional connectivity of the supplementary motor area (SMA), orbitofrontal cortex (OFC), insula, caudate and putamen were compared between the groups, and correlated with clinical measures within the patient group. When compared to controls, patients with TS exhibited greater connectivity between the temporal gyri, insula and putamen, and between the OFC and cingulate cortex. Tic severity was associated with greater connectivity between the putamen and the sensorimotor cortex; OCS severity was associated with less connectivity between the SMA and thalamus and between the caudate and precuneus; and premonitory urge severity was associated with less connectivity between the OFC and sensorimotor cortex and between the inferior frontal gyrus and the putamen and insula seeds. Functional connectivity within sensorimotor processing regions were associated with all of the investigated symptom domains, including OCS, suggesting dysfunctions in the sensorimotor system may explain most of the observed symptoms in TS, and not just tics.

OBJECTIVEPhysicians are more frequently encountering patients who are treated with deep brain stimulation (DBS), yet many MRI centers do not routinely perform MRI in this population. This warrants a safety assessment to improve DBS patients’ accessibility to MRI, thereby improving their care while simultaneously providing a new tool for neuromodulation research.METHODSA phantom simulating a patient with a DBS neuromodulation device (DBS lead model 3387 and IPG Activa PC model 37601) was constructed and used. Temperature changes at the most ventral DBS electrode contacts, implantable pulse generator (IPG) voltages, specific absorption rate (SAR), and B1+rms were recorded during 3-T MRI scanning. Safety data were acquired with a transmit body multi-array receive and quadrature transmit-receive head coil during various pulse sequences, using numerous DBS configurations from “the worst” to “the most common.”In addition, 3-T MRI scanning (T1 and fMRI) was performed on 41 patients with fully internalized and active DBS using a quadrature transmit-receive head coil. MR images, neurological examination findings, and stability of the IPG impedances were assessed.RESULTSIn the phantom study, temperature rises at the DBS electrodes were less than 2°C for both coils during 3D SPGR, EPI, DTI, and SWI. Sequences with intense radiofrequency pulses such as T2-weighted sequences may cause higher heating (due to their higher SAR). The IPG did not power off and kept a constant firing rate, and its average voltage output was unchanged. The 41 DBS patients underwent 3-T MRI with no adverse event.CONCLUSIONSUnder the experimental conditions used in this study, 3-T MRI scanning of DBS patients with selected pulse sequences appears to be safe. Generally, T2-weighted sequences (using routine protocols) should be avoided in DBS patients. Complementary 3-T MRI phantom safety data suggest that imaging conditions that are less restrictive than those used in the patients in this study, such as using transmit body multi-array receive coils, may also be safe. Given the interplay between the implanted DBS neuromodulation device and the MRI system, these findings are specific to the experimental conditions in this study.

BACKGROUND: The aim of this study was to determine the relationship between blood oxygen level dependent (BOLD) cerebrovascular reactivity (CVR) and cerebral blood flow (CBF) obtained from arterial spin labeling (ASL) using different post labeling delays (PLD). METHODS: Forty-two patients with steno-occlusive diseases and impaired CVR were divided into two groups, one scanned with a 1.5-second (1.5-s) and the other with a 2.5-second (2.5-s) PLD ASL protocol. For all patients, a region of interest (ROI) was drawn around the CVR impairment. This affected ROI was then left-right flipped across the brain midline to obtain the control ROI. For both groups, the difference in grey matter CVR between affected and control ROI was first tested to confirm significance. The average grey matter CBF of affected and control ROIs were then compared. The same analysis method was used to compare affected and control hemispheres. RESULTS: In both groups of 1.5-s and 2.5-s PLD, CVR values in the affected ROI (−0.049±0.055 and −0.042±0.074%/mmHg, respectively) were significantly lower compared to that in the control ROI (0.152±0.054 and 0.152±0.053%/mmHg, respectively, P

Concussions are associated with a range of cognitive, neuropsychological and behavioral sequelae that, at times, persist beyond typical recovery times and are referred to as postconcussion syndrome (PCS). There is growing support that concussion can disrupt network-based connectivity post-injury. To date, a significant knowledge gap remains regarding the sex-specific impact of concussion on resting state functional connectivity (rs-FC). The aims of this study were to (1) investigate the injury-based rs-FC differences across three large-scale neural networks and (2) explore the sex-specific impact of injury on network-based connectivity. MRI data was collected from a sample of 80 concussed participants who fulfilled the criteria for postconcussion syndrome and 31 control participants who did not have any history of concussion. Connectivity maps between network nodes and brain regions were used to assess connectivity using the Functional Connectivity (CONN) toolbox. Network based statistics showed that concussed participants were significantly different from healthy controls across both salience and fronto-parietal network nodes. More specifically, distinct subnetwork components were identified in the concussed sample, with hyperconnected frontal nodes and hypoconnected posterior nodes across both the salience and fronto-parietal networks, when compared to the healthy controls. Node-to-region analyses showed sex-specific differences across association cortices, however, driven by distinct networks. Sex-specific network-based alterations in rs-FC post concussion need to be examined to better understand the underlying mechanisms and associations to clinical outcomes.

BACKGROUND: Evidence suggests that cerebrovascular reactivity (CVR) increases within the first week after the incidence of concussion, indicating a disruption of normal autoregulation. We sought to extend these findings by investigating the effects of acute concussion on the speed of CVR response and by visualizing global and regional impairments in individual patients with acute concussion. METHODS: Twelve patients aged 18–40 years who experienced concussion less than a week before this prospective study were included. Twelve age and sex-matched healthy subjects constituted the control group. In all subjects, CVR was assessed using blood oxygenation level-dependent (BOLD) echo-planar imaging with a 3.0T MRI scanner, in combination with changes in end-tidal partial pressure of CO(2) (P(ET)CO(2)). In each subject, we calculated the CVR amplitude and CVR response time in the gray and white matter using a step and ramp P(ET)CO(2) challenge. In addition, a separate group of 39 healthy controls who underwent the same evaluation was used to create atlases with voxel-wise mean and standard deviation of CVR amplitude and CVR response time. This allowed us to convert each metric of the 12 patients with concussion and the 12 healthy controls into z-score maps. These maps were then used to generate and compare z-scores for each of the two groups. Group differences were calculated using an unpaired t-test. RESULTS: All studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study subjects. No differences in CO(2) stimulus and O(2) targeting were observed between the two participant groups during BOLD MRI. With regard to the gray matter, the CVR magnitude step (P=0.117) and ramp + 10 (P=0.085) were not significantly different between patients with concussion and healthy controls. However, the tau value was significantly lower in patients with concussion than in the healthy controls (P=0.04). With regard to the white matter, the CVR magnitude step (P=0.003) and ramp + 10 (P=0.031) were significantly higher and the tau value (P=0.024) was significantly shorter in patients with concussion than in healthy controls. After z-score transformation, the z tau value was significantly lower in patients with concussion than in healthy controls (Grey matter P=0.021, White matter P=0.003). Comparison of the three parameters, z ramp + 10, z step, and z tau, between the two groups showed that z step (Grey matter P=0.035, White matter P=0.005) was the most sensitive parameter and that z ramp + 10 (Grey matter P=0.073, White matter P=0.126) was the least sensitive parameter. CONCLUSIONS: Concussion is associated with patient-specific abnormalities in BOLD cerebrovascular responsiveness that occur in the setting of normal global CVR. This study demonstrates that the measurement of CVR using BOLD MRI and precise CO(2) control is a safe, reliable, reproducible, and clinically useful method for evaluating the state of patients with concussion. It has the potential to be an important tool for assessing the severity and duration of symptoms after concussion.

BACKGROUND AND PURPOSE: One feature that patients with steno-occlusive cerebrovascular disease have in common is the presence of white matter (WM) lesions on MRI. The purpose of this study was to evaluate the effect of direct surgical revascularization on impaired WM cerebrovascular reactivity in patients with steno-occlusive disease. MATERIALS AND METHODS: We recruited 35 patients with steno-occlusive disease, Moyamoya disease (n = 24), Moyamoya syndrome (n = 3), atherosclerosis (n = 6), vasculitis (n = 1), and idiopathic stenosis (n = 1), who underwent unilateral brain revascularization using a direct superficial temporal artery–to-MCA bypass (19 women; mean age, 45.8 ± 16.5 years). WM cerebrovascular reactivity was measured preoperatively and postoperatively using blood oxygen level–dependent (BOLD) MR imaging during iso-oxic hypercapnic changes in end-tidal carbon dioxide and was expressed as %Δ BOLD MR signal intensity per millimeter end-tidal partial pressure of CO(2). RESULTS: WM cerebrovascular reactivity significantly improved after direct unilateral superficial temporal artery–to-middle cerebral artery (STA-MCA) bypass in the revascularized hemisphere in the MCA territory (mean ± SD, −0.0005 ± 0.053 to 0.053 ± 0.046 %BOLD/mm Hg; P < .0001) and in the anterior cerebral artery territory (mean, 0.0015 ± 0.059 to 0.021 ± 0.052 %BOLD/mm Hg; P = .005). There was no difference in WM cerebrovascular reactivity in the ipsilateral posterior cerebral artery territory nor in the vascular territories of the nonrevascularized hemisphere (P < .05). CONCLUSIONS: Cerebral revascularization surgery is an effective treatment for reversing preoperative cerebrovascular reactivity deficits in WM. In addition, direct–STA-MCA bypass may prevent recurrence of preoperative symptoms.

Chronic pain is a common occurrence in multiple sclerosis (MS) that severely affects quality of life, but the underlying brain mechanisms related to these symptoms are unknown. Previous electroencephalography studies have demonstrated a role of alpha-band and beta-band power in pain processing. However, how and where these brain signals change in MS-related chronic pain is unknown. Here, we used resting state magnetoencephalography to examine regional spectral power in the dynamic pain connectome-including areas of the ascending nociceptive pathway, default mode network (DMN), and the salience network (SN)-in patients with chronic MS pain and in healthy controls. Each patient was assessed for pain, neuropathic pain (NP), and pain interference with activities of daily living. We found that patients with MS exhibited an increase of alpha-band power and a decrease of beta-band power, most prominently in the thalamus and the posterior insula of the ascending nociceptive pathway and in the right temporoparietal junction of the SN. In addition, patients with mixed-NP exhibited slowing of alpha peak power within the thalamus and the posterior insula, and in the posterior cingulate cortex of the DMN. Finally, pain interference scores in patients with mixed-NP were strongly correlated with alpha and beta peak power in the thalamus and posterior insula. These novel findings reveal brain mechanisms of MS-related pain in the ascending nociceptive pathway, SN, and DMN, and that these spectral abnormalities reflect the impact of pain on quality of life measures.

OBJECTIVEThe aim of this study was to evaluate the safety of 3-T MRI in patients with implanted deep brain stimulation (DBS) systems.METHODSThis study was performed in 2 phases. In an initial phantom study, a Lucite phantom filled with tissue-mimicking gel was assembled. The system was equipped with a single DBS electrode connected to an internal pulse generator. The tip of the electrode was coupled to a fiber optic thermometer with a temperature resolution of 0.1°C. Both anatomical (T1- and T2-weighted) and functional MRI sequences were tested. A temperature change within 2°C from baseline was considered safe. After findings from the phantom study suggested safety, 10 patients with implanted DBS systems targeting various brain areas provided informed consent and underwent 3-T MRI using the same imaging sequences. Detailed neurological evaluations and internal pulse generator interrogations were performed before and after imaging.RESULTSDuring phantom testing, the maximum temperature increase was registered using the T2-weighted sequence. The maximal temperature changes at the tip of the DBS electrode were < 1°C for all sequences tested. In all patients, adequate images were obtained with structural imaging, although a significant artifact from lead connectors interfered with functional imaging quality. No heating, warmth, or adverse neurological effects were observed.CONCLUSIONSTo the authors' knowledge, this was the first study to assess the clinical safety of 3-T MRI in patients with a fully implanted DBS system (electrodes, extensions, and pulse generator). It provided preliminary data that will allow further examination and assessment of the safety of 3-T imaging studies in patients with implanted DBS systems. The authors cannot advocate widespread use of this type of imaging in patients with DBS implants until more safety data are obtained.

Background:Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer’s disease (AD) and may underpin part of the disease’s neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD.Methods:Thirty-three subjects (age range: 52–83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite.Results:Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction.Conclusion:The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.

Highlights • Patients with Tourette Syndrome completed an obsessive–compulsive provocation task. • Patients reported higher anxiety for the provocation conditions than did controls. • Group differences found in the insula, sensorimotor cortex and supramarginal gyri. • Obsessive–compulsive severity associated with frontal and parietal lobe activity. • Tic severity associated with anterior cingulate activity for the symmetry condition., Objectives Tourette syndrome (TS) is commonly comorbid with obsessive–compulsive disorder (OCD) and many phenomenological similarities exist between tics and obsessive–compulsive symptoms (OCS). Therefore, due to the clinical importance of comorbid OCD, the goal of this study was to investigate the neural substrates of OCS in TS using functional magnetic resonance imaging. Methods Forty patients with TS and 20 healthy controls underwent functional magnetic resonance imaging while viewing blocks of OCS-provoking pictures relating to washing, checking and symmetry symptoms, as well as generally disgusting and neutral scenes. Statistical comparisons were made between patients with moderate/severe OCS, absent/mild OCS and healthy controls. As well, within the entire TS patient group, significant associations with clinical measures were assessed for each of the provocation conditions. Results Group differences in the insula, sensorimotor cortex, supramarginal gyrus and visual processing regions were common among the checking, washing and disgust conditions. In the patient group, negative associations between OCS severity and activity in the supramarginal gyrus, inferior frontal gyrus, sensorimotor cortex, precuneus and visual processing regions were common among the provocation conditions. Tic severity was only associated with activity in the anterior cingulate cortex for the symmetry condition. Conclusion Our findings implicate areas previously reported to be involved in OCD, as well as areas not typically implicated in OCD, suggesting that the neurobiological profile of TS+OCD is intermediate to pure TS and pure OCD.

The purpose of this study was to determine the relationship between the organization of the brain connectome and cerebrovascular reactivity (CVR) in persons with white matter hyperintensities. Diffusion tensor and CVR mapping 3T MRI scans were acquired in 31 participants with white matter hyperintensities. In each participant, the connectome was assessed by reconstructing all white matter tracts with tractography and segmenting the whole brain into multiple regions. Graph theory analysis was performed to quantify how effectively tracts connected brain regions by measuring the global and local efficiency of the connectome. CVR in white matter and gray matter was correlated with the global and local efficiency of the connectome, while adjusting for age, gender, and gray matter volume. For comparison, white matter hyperintensity volume was also correlated with global and local efficiency. White matter CVR was positively correlated with the global efficiency (coefficient: 23.3, p = .005) and local efficiency (coefficient: 2850, p = .004) of the connectome. Gray matter CVR was positively correlated with the global efficiency (coefficient: 21.3, p

Objective:To compare the diffusion and perfusion MRI metrics of normal-appearing white matter (NAWM) with and without impaired cerebrovascular reactivity (CVR).Methods:Seventy-five participants with moderate to severe leukoaraiosis underwent blood oxygen level–dependent CVR mapping using a 3T MRI system with precise carbon dioxide stimulus manipulation. Several MRI metrics were statistically compared between areas of NAWM with positive and negative CVR using one-way analysis of variance with Bonferroni correction for multiple comparisons.Results:Areas of NAWM with negative CVR showed a significant reduction in fractional anisotropy by a mean (SD) of 3.7% (2.4), cerebral blood flow by 22.1% (8.2), regional cerebral blood volume by 22.2% (7.0), and a significant increase in mean diffusivity by 3.9% (3.1) and time to maximum by 10.9% (13.2) (p < 0.01), compared to areas with positive CVR.Conclusions:Impaired CVR is associated with subtle changes in the tissue integrity of NAWM, as evaluated using several quantitative diffusion and perfusion MRI metrics. These findings suggest that impaired CVR may contribute to the progression of white matter disease.

BACKGROUND AND PURPOSE: The pathogenesis of leukoaraiosis has long been debated. This work addresses a less well-studied mechanism, cerebrovascular reactivity, which could play a leading role in the pathogenesis of this disease. Our aim was to evaluate blood flow dysregulation and its relation to leukoaraiosis. MATERIALS AND METHODS: Cerebrovascular reactivity, the change in the blood oxygen level–dependent 3T MR imaging signal in response to a consistently applied step change in the arterial partial pressure of carbon dioxide, was measured in white matter hyperintensities and their contralateral spatially homologous normal-appearing white matter in 75 older subjects (age range, 50–91 years; 40 men) with leukoaraiosis. Additional quantitative evaluation of regions of leukoaraiosis was performed by using diffusion (n = 75), quantitative T2 (n = 54), and DSC perfusion MRI metrics (n = 25). RESULTS: When we compared white matter hyperintensities with contralateral normal-appearing white matter, cerebrovascular reactivity was lower by a mean of 61.2% ± 22.6%, fractional anisotropy was lower by 44.9 % ± 6.9%, and CBF was lower by 10.9% ± 11.9%. T2 was higher by 61.7% ± 13.5%, mean diffusivity was higher by 59.0% ± 11.7%, time-to-maximum was higher by 44.4% ± 30.4%, and TTP was higher by 6.8% ± 5.8% (all P < .01). Cerebral blood volume was lower in white matter hyperintensities compared with contralateral normal-appearing white matter by 10.2% ± 15.0% (P = .03). CONCLUSIONS: Not only were resting blood flow metrics abnormal in leukoaraiosis but there is also evidence of reduced cerebrovascular reactivity in these areas. Studies have shown that reduced cerebrovascular reactivity is more sensitive than resting blood flow parameters for assessing vascular insufficiency. Future work is needed to examine the sensitivity of resting-versus-dynamic blood flow measures for investigating the pathogenesis of leukoaraiosis.

Objective: White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH. Methods: We examined 45 subjects (age range: 50-91; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood-oxygen-level-dependent MRI signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion-tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and one-year follow-up, with automated co-registration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the one-year period. Results: CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (P

Introduction: White matter hyper intensities (WMHs) on T2 FLAIR images, are associated with cognitive decline in older populations. WMHs exhibit diminished vascular reactivity compared to normal appearing white matter (Sam et al. AJNR 2016). We hypothesize that patients with WMHs have diminished cortical vascular reactivity compared to controls. Methods: 23 patients with WMHs and 21 controls were studied. Patient inclusion criteria were: no cortical infarcts, Fazekas Grade >= 2, no vascular stenoses >= 70%, and no history of cardio/pulmonary disease. MRI protocol and vasodilatory stimulus The 3T MRI protocol included a 1 mm isotopic T1 3D sequence and a 3.5 mm isotropic T2* BOLD sequence (30 msec echo time). Cerebrovascular reactivity ( CVR ) was measured using 2 step changes in end-tidal pCO2 (from 40 to 50mmHg) using a controlled gas delivery system (RespirAct TM ) during BOLD imaging. Recent work has shown an age invariant cortical response to this stimulus delivery method (McKetton et al Neuroimage 2018). Image Analysis CVR magnitude maps, expressed in %BOLD/mmHg, were generated by calculating the linear regression of the BOLD response with the pCO2. The BOLD response was fitted with an exponential function in order to measure its time characteristic TAU providing a measure of speed of vascular response. Maps were corrected for partial volume errors. (Figure 1A). Average CVR and TAU within frontal, occipital, parietal and temporal grey matter were calculated for all subjects. t-tests corrected for multiple comparisons were calculated between patients and controls. Results: CVR magnitude was lower and TAU longer in patients with WMHs compared to normal controls in all four lobes (p < 0.05) (Figure 1B). Conclusions: Patients with moderate to severe WMHs show diffuse impairment of vascular reactivity affecting the cerebral cortex even in the absence of significant large vessel steno-occlusive disease and in the absence of visible cortical disease on MRI.

BACKGROUND AND PURPOSE: Changes in cerebrovascular reactivity can be used to assess disease progression and response to therapy but require discrimination of pathology from normal test-to-test variability. Such variability is due to variations in methodology, technology, and physiology with time. With uniform test conditions, our aim was to determine the test-to-test variability of cerebrovascular reactivity in healthy subjects and in patients with known cerebrovascular disease. MATERIALS AND METHODS: Cerebrovascular reactivity was the ratio of the blood oxygen level–dependent MR imaging response divided by the change in carbon dioxide stimulus. Two standardized cerebrovascular reactivity tests were conducted at 3T in 15 healthy men (36.7 ± 16.1 years of age) within a 4-month period and were coregistered into standard space to yield voxelwise mean cerebrovascular reactivity interval difference measures, composing a reference interval difference atlas. Cerebrovascular reactivity interval difference maps were prepared for 11 male patients. For each patient, the test-retest difference of each voxel was scored statistically as z-values of the corresponding voxel mean difference in the reference atlas and then color-coded and superimposed on the anatomic images to create cerebrovascular reactivity interval difference z-maps. RESULTS: There were no significant test-to-test differences in cerebrovascular reactivity in either gray or white matter (mean gray matter, P = .431; mean white matter, P = .857; paired t test) in the healthy cohort. The patient cerebrovascular reactivity interval difference z-maps indicated regions where cerebrovascular reactivity increased or decreased and the probability that the changes were significant. CONCLUSIONS: Accounting for normal test-to-test differences in cerebrovascular reactivity enables the assessment of significant changes in disease status (stability, progression, or regression) in patients with time.

Purpose To evaluate the relationship between both dynamic and steady-state measures of cerebrovascular reactivity (CVR) and the progression of age-related white matter disease. Methods Blood oxygen level-dependent (BOLD) MRI CVR scans were acquired from forty-five subjects (age range: 50–90 years, 25 males) with moderate to severe white matter disease, at baseline and one-year follow-up. To calculate the dynamic (τ) and steady-state (ssCVR) components of the BOLD signal response, the PETCO2 signal waveform was convolved with an exponential decay function. The τ corresponding to the best fit between the convolved PETCO2 and BOLD signal defined the speed of response, and the slope of the regression between the convolved PETCO2 and BOLD signal defined ssCVR. ssCVR and τ were compared between normal-appearing white matter (NAWM) that remains stable over time and NAWM that progresses to white matter hyperintensities (WMHs). Results In comparison to contralateral NAWM, NAWM that progressed to WMH had significantly lower ssCVR values by mean (SD) 46.5 (7.6)%, and higher τ values by 31.9 (9.6)% (both P, Highlights • Vascular responses are slower in normal white matter that progresses to disease. • Steady-state cerebrovascular reactivity is reduced in normal white matter that progresses to disease. • Cerebrovascular dysregulation occurs before development of leukoaraiosis.

We define cerebral vascular reactivity (CVR) as the ratio of the change in blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) signal (S) to an increase in blood partial pressure of CO2 (PCO2): % Δ S/Δ PCO2 mm Hg. Our aim was to further characterize CVR into dynamic and static components and then study 46 healthy subjects collated into a reference atlas and 20 patients with unilateral carotid artery stenosis. We applied an abrupt boxcar change in PCO2 and monitored S. We convolved the PCO2 with a set of first-order exponential functions whose time constant τ was increased in 2-second intervals between 2 and 100 seconds. The τ corresponding to the best fit between S and the convolved PCO2 was used to score the speed of response. Additionally, the slope of the regression between S and the convolved PCO2 represents the steady-state CVR (ssCVR). We found that both prolongations of τ and reductions in ssCVR (compared with the reference atlas) were associated with the reductions in CVR on the side of the lesion. τ and ssCVR are respectively the dynamic and static components of measured CVR.

The frontotemporal cortical network is associated with behaviours such as impulsivity and aggression. The health of the uncinate fasciculus (UF) that connects the orbitofrontal cortex (OFC) with the anterior temporal lobe (ATL) may be a crucial determinant of behavioural regulation. Behavioural changes can emerge after repeated concussion and thus we used MRI to examine the UF and connected gray matter as it relates to impulsivity and aggression in retired professional football players who had sustained multiple concussions. Behaviourally, athletes had faster reaction times and an increased error rate on a go/no-go task, and increased aggression and mania compared to controls. MRI revealed that the athletes had (1) cortical thinning of the ATL, (2) negative correlations of OFC thickness with aggression and task errors, indicative of impulsivity, (3) negative correlations of UF axial diffusivity with error rates and aggression, and (4) elevated resting-state functional connectivity between the ATL and OFC. Using machine learning, we found that UF diffusion imaging differentiates athletes from healthy controls with significant classifiers based on UF mean and radial diffusivity showing 79–84 % sensitivity and specificity, and 0.8 areas under the ROC curves. The spatial pattern of classifier weights revealed hot spots at the orbitofrontal and temporal ends of the UF. These data implicate the UF system in the pathological outcomes of repeated concussion as they relate to impulsive behaviour. Furthermore, a support vector machine has potential utility in the general assessment and diagnosis of brain abnormalities following concussion.

Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.

Objectives: To examine structural integrity loss in the fornix from 5–30 months after moderate and severe traumatic brain injury (TBI) using diffusion tensor imaging.Methods: MRIs were prospectively undertaken in 29 adults with moderate and severe TBI at two time points. Fractional anisotropy (FA) was calculated for the fornix (column/body, right crux and left crux) at 5 and 30 months post-injury.Results: Paired t-tests revealed significant FA reductions with large effect sizes across time in the column/body, p

Introduction: Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) during manipulation of inhaled carbon dioxide (CO2) can be used to measure cerebrovascular reactivity (CVR) and map regions of exhausted cerebrovascular reserve. These regions exhibit a reduced or negative BOLD response to inhaled CO2. In this study, we sought to clarify the mechanism behind the negative BOLD response by investigating its time delay (TD). Dynamic susceptibility contrast (DSC) MRI with the injection of a contrast agent was used as the gold standard in order to provide measurement of the blood arrival time to which CVR TD could be compared. We hypothesize that if negative BOLD responses are the result of a steal phenomenon, they should be synchronized with positive BOLD responses from healthy brain tissue, even though the blood arrival time would be delayed. Methods: On a 3-tesla MRI system, BOLD CVR and DSC images were collected in a group of 19 patients with steno-occlusive cerebrovascular disease. For each patient, we generated a CVR magnitude map by regressing the BOLD signal with the end-tidal partial pressure of CO2 (PETCO2), and a CVR TD map by extracting the time of maximum cross-correlation between the BOLD signal and PETCO2. In addition, a blood arrival time map was generated by fitting the DSC signal with a gamma variate function. ROI masks corresponding to varying degrees of reactivity were constructed. Within these masks, the mean CVR magnitude, CVR TD and DSC blood arrival time were extracted and averaged over the 19 patients. CVR magnitude and CVR TD were then plotted against DSC blood arrival time. Results: The results show that CVR magnitude is highly correlated to DSC blood arrival time. As expected, the most compromised tissues with the longest blood arrival time have the lowest (most negative) CVR magnitude. However, CVR TD shows a noncontinuous relationship with DSC blood arrival time. CVR TD is well correlated to DSC blood arrival time (p < 0.0001) for tissue of positive reactivity, but fails to maintain this trend for tissue of negative reactivity. Regions with negative reactivity have similar CVR TD than healthy regions. Conclusion: These results support the hypothesis that negative reactivity is the result of a steal phenomenon, lowering the BOLD signal as soon as healthier parts of the brain start to react and augment their blood flow. BOLD CVR MRI is capable of identifying this steal distribution, which has particular diagnostic significance as it represents an actual reduction in flow to already compromised tissue.

Variability in blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals reflects the moment-by-moment fluctuations in resting-state fMRI (rs-fMRI) activity within specific areas of the brain. Regional BOLD signal variability was recently proposed to serve an important functional role in the efficacy of neural systems because of its relationship to behavioural performance in aging and cognition studies. We previously showed that individuals who better cope with pain have greater fluctuations in interregional functional connectivity, but it is not known whether regional brain signal variability is a mechanism underlying pain coping. We tested the hypothesis that individual pain sensitivity and coping is reflected by regional fMRI BOLD signal variability within dynamic pain connectome-brain systems implicated in the pain experience. We acquired resting-state fMRI and assessed pain threshold, suprathreshold temporal summation of pain, and the impact of pain on cognition in 80 healthy right-handed individuals. We found that regional BOLD signal variability: (1) inversely correlated with an individual's temporal summation of pain within the ascending nociceptive pathway (primary and secondary somatosensory cortex), default mode network, and salience network; (2) was correlated with an individual's ability to cope with pain during a cognitive interference task within the periaqueductal gray, a key opiate-rich brainstem structure for descending pain modulation; and (3) provided information not captured from interregional functional connectivity. Therefore, regional BOLD variability represents a pain metric with potential implications for prediction of chronic pain resilience vs vulnerability.

Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a technique used to infer neuronal activity from the observed changes in blood flow. Cerebrovascular reactivity (CVR) is the ability of arterioles to increase blood flow in response to vasodilatory stimulus. We hypothesize that in areas of disease where there is exhausted vascular reserve and impaired CVR there will be diminished blood flow response following neuronal activation, and that these areas would appear as false-negative tests on BOLD fMRI.Patients with steno-occlusive disease and unilateral hemodynamic impairment received a standardized hypercapnic stimuli while being imaged with BOLD fMRI to generate CVR maps. These were compared to traditional BOLD fMRI maps of neuronal activation in the motor cortex in response to a motor task.Neuronal activation from the motor task was found to be linearly correlated with CVR (n = 11 patients, R = 0.82). Regions with positive (normal) CVR showed positive activation on BOLD fMRI, while regions with negative CVR had attenuated neuronal activation on BOLD fMRI.In areas with cerebrovascular disease where CVR is impaired, there is uncoupling of neuronal activation and blood flow that confounds traditional BOLD fMRI. CVR mapping is a noninvasive MRI-based imaging technique that can provide information about the vascular reactivity of the brain that is important to consider when interpreting traditional BOLD fMRI studies.2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2017;46:1448-1455.

White matter hyperintensities (WMH) observed on neuroimaging of elderly individuals are associated with cognitive decline and disability. However, the pathogenesis of WMH remains poorly understood. We observed that regions of reduced cerebrovascular reactivity (CVR) in the white matter of young individuals correspond to the regions most susceptible to WMH in the elderly. This finding prompted us to consider that reduced CVR may play a role in the pathogenesis of WMH. We hypothesized that reduced CVR precedes development of WMH.We examined 45 subjects (age range = 50-91 years; 25 males) with moderate-severe WMH, and measured their baseline CVR using the blood oxygen level-dependent magnetic resonance imaging signal response to a standardized step change in the end-tidal partial pressure of carbon dioxide. Diffusion tensor imaging and transverse relaxation time (T2) relaxometry were performed at baseline and 1-year follow-up, with automated coregistration between time points. Baseline fractional anisotropy (FA), mean diffusivity (MD), T2, and CVR were measured in areas that progressed from normal-appearing white matter (NAWM) to WMH over the 1-year period.CVR and FA values in baseline NAWM that progressed to WMH were lower by mean (standard deviation) = 26.5% (23.2%) and 11.0% (7.2%), respectively, compared to the contralateral homologous NAWM that did not progress (p 0.001). T2 and MD were higher by 8.7% (7.9%) and 17.0% (8.5%), respectively, compared to the contralateral homologous NAWM (p 0.001).Areas of reduced CVR precede the progression from NAWM to WMH, suggesting that hemodynamic impairment may contribute to the pathogenesis and progression of age-related white matter disease. Ann Neurol 2016;80:277-285.

Background and Purpose— The purpose of this study was to evaluate in symptomatic moyamoya patients the effect of surgical revascularization on impaired cerebrovascular reactivity (CVR) and its relationship to clinical outcome. Methods— Brain revascularization was performed using a direct superficial temporal artery to middle cerebral artery bypass or indirect encephalo-dural–arterial synangiosis. CVR was measured pre- and 3 months postoperatively using blood oxygen level-dependent MRI during iso-oxic hypercapnic changes in end-tidal carbon dioxide. Outcomes were assessed by MRI, clinical examination, and modified Rankin Scale scores. Results— Fifty-five hemispheres were revascularized in 39 patients (superficial temporal artery to middle cerebral artery in 47, encephalo-dural–arterial synangiosis in 8). Surgery reversed CVR impairment in 52 hemispheres (94.5%) and in 36 of 39 patients (92.3%; Fisher exact test, P P Conclusions— Cerebral revascularization surgery is a safe and effective treatment for reversing preoperative CVR defects and may prevent recurrence of preoperative symptoms. Moreover, CVR measurements may be useful in long-term follow-up and for predicting bypass patency.

Objective: To characterize the relationship between cerebrovascular reactivity (CVR) and white matter (WM) diffusion in patients with internal carotid artery (ICA) occlusive disease.Methods: In this exploratory observational study, 41 patients with severe stenosis or occlusion of the extracranial ICA and 12 healthy control subjects underwent CVR mapping using the fMRI response to hypercapnia. Conventional anatomic and diffusion-weighted MRI sequences were used to calculate maps of the apparent diffusion coefficient (ADC) and to exclude areas of previous ischemic injury. In all subjects, ADC was compared between WM with positive and negative CVR. In 27 patients with unilateral ICA involvement, ADC and CVR were compared between ipsilateral and contralateral WM while covarying for relevant clinical risk factors.Results: In patients with bilateral disease and in the ipsilateral hemisphere of patients with unilateral disease, negative CVR was associated with increased WM ADC (p Conclusions: CVR impairment is associated with ADC elevation in normal-appearing WM of patients with severe stenosis or occlusion of the extracranial ICA. This finding is consistent with the presence of early, low-grade ischemic injury. Neurology (R) 2011;77:431-438

Background and Purpose— Chronic deficiencies in regional blood flow lead to cerebral cortical thinning without evidence of gross tissue loss at the same time as potentially negatively impacting on neurological and cognitive performance. This is most pronounced in patients with severe occlusive cerebrovascular disease in whom affected brain areas exhibit “steal physiology,” a paradoxical reduction of cerebral blood flow in response to a global vasodilatory stimulus intended to increase blood flow. We tested whether surgical brain revascularization that eliminates steal physiology can reverse cortical thinning. Methods— We identified 29 patients from our database who had undergone brain revascularization with pre- and postoperative studies of cerebrovascular reactivity using blood oxygen(ation) level-dependent MRI and whose preoperative study exhibited steal physiology without MRI-evident structural abnormalities. Cortical thickness in regions corresponding to steal physiology, and where applicable corresponding areas in the normal hemisphere, were measured using Freesurfer software. Results— At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere (n=30). Mean cortical thickness in the revascularized regions increased by 5.1% (from 2.40±0.03 to 2.53±0.03; P Conclusions— Successful regional revascularization and reversal of steal physiology is followed by restoration of cortical thickness.

Background and Purpose— Cerebrovascular reactivity (CVR) is an indicator of cerebral hemodynamics. In adults with cerebrovascular disease, impaired CVR has been shown to be associated with an increased risk of stroke. In children, however, CVR studies are not common. This may be due to the difficulties and risks associated with current CVR study methodologies. We have previously described the application of precise control of end-tidal carbon dioxide partial pressure for CVR studies in adults. Our aim is to report initial observations of CVR studies that were performed as part of a larger observational study regarding investigations in pediatric patients with cerebral vascular disease. Methods— Thirteen patients between the ages of 10 and 16 years (10 with a diagnosis of Moyamoya vasculopathy and 3 with confirmed, or suspected, intracranial vascular stenosis) underwent angiography, MRI, and functional blood oxygen level-dependent MRI mapping of CVR to hypercapnia. The results of the CVR study were then related to both the structural imaging and clinical status. Results— Sixteen blood oxygen level-dependent MRI CVR studies were performed successfully in 13 consecutive patients. Twelve of the 13 patients with angiographic abnormalities also had CVR deficits in the corresponding downstream vascular territories. CVR deficits were also seen in 8 of 9 symptomatic patients and 2 of the asymptomatic patients. Noteably, in patients with abnormalities on angiography, the reductions in CVR extended beyond the ischemic lesions identified with MR structural imaging into normal-appearing brain parenchyma. Conclusions— This is the first case series reporting blood oxygen level-dependent MRI CVR in children with cerebrovascular disease. CVR studies performed so far provide information regarding hemodynamic compromise, which complements traditional clinical assessment and structural imaging.

The clinimetric properties of blood oxygen level‒dependent (BOLD) magnetic resonance imaging (MRI) for assessment of musculoskeletal changes have been poorly investigated. The study objectives were to assess the interframework reliability of data acquisition of BOLD MRI and to test its convergent validity in chronic arthritis in a rabbit model of inflammatory arthritis as compared with corresponding clinical and laboratory measures.One of the knees of 12 New Zealand male white rabbits was injected with a 1% carrageenin solution, and the contralateral (control) one was not. Twelve rabbits were euthanized on day 28 of arthritis (chronic arthritis). Clinical (joint diameters), laboratory (serum amyloid A concentration), and BOLD MRI measurements were obtained on days 0, 1, and 28 of arthritis. Twenty paradigms of data acquisition and analysis were applied.The most reliable MRI parameters set, regardless of threshold values used for data analysis, was spiral technique (level 1), 40 ms of echo time (level 2), 60 seconds of on_ and off_ paradigm (level 3) and carbogen mixture of gases (95% O2 + 5% CO2) (level 4). With regard to construct validity, BOLD imaging correlated moderately (r = -.54, P.0001) with knee diameters, and weakly (r = -.35, P = .01) with laboratory indices (high threshold for analysis).BOLD MRI has a substantial or excellent interframework reliability for assessment of arthritic rabbit knees; however, it correlates only moderately or poorly with clinical and laboratory measures. Nevertheless, this study supports further validation of BOLD MRI for assessment of soft tissue changes in a rabbit model of arthritis.

BACKGROUND AND PURPOSE: CVR is a measure of cerebral hemodynamic impairment. A recently validated technique quantifies CVR by using a precise CO(2) vasodilatory stimulus and BOLD MR imaging. Our aim was to determine whether preoperative CO(2) BOLD CVR predicts the hemodynamic effect of ECIC bypass surgery in patients with intracranial steno-occlusive disease. MATERIALS AND METHODS: Twenty-five patients undergoing ECIC bypass surgery for treatment of intracranial stenosis or occlusion were recruited. CVR was measured preoperatively and postoperatively and expressed as %ΔBOLD MR signal intensity per mm Hg ΔPetCO(2). Using normative data from healthy subjects, we stratified patients on the basis of preoperative CVR into 3 groups: normal CVR, reduced CVR, and negative (paradoxical) CVR. Wilcoxon 2-sample tests (2-sided, α = 0.05) were used to determine whether the 3 groups differed with respect to change in CVR following bypass surgery. RESULTS: The group with normal preoperative CVR demonstrated no significant change in CVR following bypass surgery (mean, 0.22% ± 0.05% to 0.22% ± 0.01%; P = .881). The group with reduced preoperative CVR demonstrated a significant improvement following bypass surgery (mean, 0.08% ± 0.05% to 0.21 ± 0.08%; P < .001), and the group with paradoxical preoperative CVR demonstrated the greatest improvement (mean change, −0.04% ± 0.03% to 0.27% ± 0.03%; P = .028). CONCLUSIONS: Preoperative measurement of CVR by using CO(2) BOLD MR imaging predicts the hemodynamic effect of ECIC bypass in patients with intracranial steno-occlusive disease. The technique is potentially useful for selecting patients for surgical revascularization.

We report fMRI findings in 3 asymptomatic cases of agenesis of the corpus callosum, the largest white matter bundle in the brain, which is responsible for interhemispheric transfer of information. Sensory information was presented to 1 hemisphere, and the patients had to generate a motor response governed by the contralateral hemisphere. Enhanced ipsilateral motor pathways have been suggested as a compensation method for people with agenesis of the corpus callosums; our functional magnetic resonance imaging data did not support this theory.