Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies

Blood oxygenation level dependent (BOLD) contrast fMRI is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breathhold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue, and the peri-infarct tissue, both sub-acutely (~two weeks) and chronically (~four months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared to the controls may be confounded by a reduced CVR, longitudinal grouplevel BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity

Neuropharmacological Investigation Of Stress And Nicotine Self-Administration Among Current Cigarette Smokers

ABSTRACT NEUROPHARMACOLOGICAL INVESTIGATION OF STRESS AND NICOTINE SELF-ADMINISTRATION AMONG CURRENT CIGARETTE SMOKERS by ERIC ANDREW WOODCOCK August 2017 Advisor: Dr. Mark K. Greenwald Major: Neuroscience (Translational) Degree: Doctor of Philosophy Nicotine use, especially cigarette smoking, is a significant public health problem. Existing pharmacotherapies attenuate nicotine craving and withdrawal symptoms. However, the majority of patients relapse within the first year of treatment. Treatment studies indicate a commonly cited precipitant to smoking relapse is stress. Pharmacotherapies do not attenuate, and may exacerbate, the effects of acute stress. Experimental studies (preclinical and clinical) indicate that acute stress potentiates drug-seeking behavior across drugs of abuse. Despite a robust literature linking acute stress and substance use, neurobiological mechanisms remain poorly understood. A more complete understanding of the neurobiological effects of acute stress on brain function may facilitate development of novel interventions. Adjunctive stress-blunting medications may improve the effectiveness of existing pharmacotherapies. The present study investigated the effects of pharmacological stress-induction among cigarette smokers. Non-treatment-seeking cigarette smokers were recruited locally and screened for psychiatric, medical, and neuroimaging contraindications. Using a double-blind, placebo-controlled within-subject random cross-over design, participants (N = 21) completed two oral-dosing experimental sessions: active (yohimbine [YOH] 54mg + hydrocortisone [HYD] 10mg) and placebo (YOH 0mg + HYD 0mg) stress. Prior research indicated that YOH+HYD is a robust pharmacological stress-induction technique that stimulates the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal (HPA) axis systems, increases circulating levels of noradrenaline and cortisol (two primary stress hormones), and potentiates drug-seeking behavior. Throughout each experimental session, subjective and physiological effects were measured. In addition, participants completed a 60min magnetic resonance imaging (MRI) scan which consisted of three task paradigms: 1) letter 2-back, 2) smoking cued letter N-back, and 3) breath-hold challenge. Participants completed a working memory paradigm (letter 2-back) during proton functional magnetic resonance spectroscopy (1H fMRS). Left dorsolateral prefrontal cortex (dlPFC) neurochemistry was evaluated during letter 2-back task performance. Next, participants completed a cued N-back paradigm that consisted of images (cigarette smoking or neutral) centered behind capitalized letters across three levels of N-back task difficulty: 0-, 1-, and 2-back. Finally, participants were instructed (visually) to control their breathing across three phases: ‘normal’ breathing, paced breathing (3s in/3s out), and breath-hold challenge (11s). After the MRI scan, participants completed a choice progressive ratio task. Across 11 independent choice trials, participants could earn one cigarette puff (preferred brand) or money ($0.25) via behavioral responding. Each successive unit earned (puffs or money, independently) was associated with a higher response requirement (progressive ratio schedule). At the end of the 30min task, participants smoked the exact number of cigarette puffs earned and/or were provided the amount of money earned. Number of puffs earned and smoked was a direct measure of nicotine-seeking and self-administration behavior (nicotine motivation). Participants were compensated for their time. Results indicated that oral pretreatment with YOH+HYD increased biomarkers of a physiological stress response: systolic and diastolic blood pressure, heart rate, saliva cortisol and α-amylase (indirect biomarker of noradrenaline levels), relative to placebo. YOH+HYD potentiated nicotine-seeking and self-administration behavior (controlling for nicotine dependence level), relative to placebo. Appetitive and relief-motivated cigarette craving, nicotine withdrawal symptoms, negative affect, and anxiety levels increased throughout each session, but did not differ by experimental session (active vs. placebo stress). Similarly, positive affect decreased throughout each session, but did not as a function of stress. 1H fMRS indicated that letter 2-back performance increased left dlPFC glutamate (GLU) levels relative to interleaved fixation cross rest (indicative of task engagement) during the placebo, but not active stress, session. Further, YOH+HYD impaired letter 2-back response accuracy, relative to placebo. Across N-back levels (0-, 1-, and 2-back), fMRI indicated more robust neural activation across ‘reward’-associated brain regions in response to smoking images (\u3e neutral images) during placebo, relative to active stress. Results demonstrated YOH+HYD induced a sustained physiological stress response (ANS and HPA axis) and potentiated nicotine-seeking and self-administration. YOH+HYD attenuated dlPFC task engagement and impaired response accuracy during a well-established working memory task. These findings provide experimental support for a plausible neurobiological mechanism through which acute stress may potentiate nicotine self-administration. Acute stress-impaired dlPFC function may potentiate nicotine self-administration and, among abstinence-motivated individuals, precipitate smoking relapse. Prior research demonstrated dlPFC function is associated with a host of cognitive processes (e.g. delayed gratification, self-control, decision making, etc.) associated with prolonged smoking abstinence. Future studies are needed to confirm this hypothesis, investigate dose-response relationships, and evaluate the efficacy of stress-blunting medications in combination with existing pharmacotherapies for smoking cessation

ICA-based denoising strategies in breath-hold induced cerebrovascular reactivity mapping with multi echo BOLD fMRI

Available online 6 March 2021.Performing a BOLD functional MRI (fMRI) acquisition during breath-hold (BH) tasks is a non-invasive, robust method to estimate cerebrovascular reactivity (CVR). However, movement and breathing-related artefacts caused by the BH can substantially hinder CVR estimates due to their high temporal collinearity with the effect of interest, and attention has to be paid when choosing which analysis model should be applied to the data. In this study, we evaluate the performance of multiple analysis strategies based on lagged general linear models applied on multi- echo BOLD fMRI data, acquired in ten subjects performing a BH task during ten sessions, to obtain subject-specific CVR and haemodynamic lag estimates. The evaluated approaches range from conventional regression models, i.e. including drifts and motion timecourses as nuisance regressors, applied on single-echo or optimally-combined data, to more complex models including regressors obtained from multi-echo independent component analysis with different grades of orthogonalization in order to preserve the effect of interest, i.e. the CVR. We compare these models in terms of their ability to make signal intensity changes independent from motion, as well as the reliability as measured by voxelwise intraclass correlation coefficients of both CVR and lag maps over time. Our results reveal that a conservative independent component analysis model applied on the optimally-combined multi-echo fMRI signal offers the largest reduction of motion-related effects in the signal, while yielding reliable CVR amplitude and lag estimates, although a conventional regression model applied on the optimally-combined data results in similar estimates. This work demonstrates the usefulness of multi-echo based fMRI acquisitions and independent component analysis denoising for precision mapping of CVR in single subjects based on BH paradigms, fostering its potential as a clinically-viable neuroimaging tool for individual patients. It also proves that the way in which data-driven regressors should be incorporated in the analysis model is not straight-forward due to their complex interaction with the BH-induced BOLD response.This research was supported by the European Union’s Horizon 2020 research and innovation program ( Marie Sk ł odowska-Curie grant agreement No. 713673 ), a fellowship from La Caixa Foundation (ID 100010434 , fellowship code LCF/BQ/IN17/11620063 ), the Spanish Ministry of Economy and Competitiveness ( Ramon y Cajal Fellowship, RYC-2017- 21845 ), the Spanish State Research Agency (BCBL “Severo Ochoa ”excellence accreditation, SEV- 2015-490 ), the Basque Govern- ment ( BERC 2018-2021 and PIBA_2019_104 ), the Spanish Ministry of Science, Innovation and Universities (MICINN; PID2019-105520GB-100 and FJCI-2017-31814 ), and the Eunice Kennedy Shriver National Insti- tute of Child Health and Human Development of the National Institutes of Health under award number K12HD073945

Measuring vascular reactivity with breath-holds after stroke: a method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies

Blood oxygenation level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath-hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task-related BOLD signal changes. Three methods of analyzing the breath-hold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue and the peri-infarct tissue, both sub-acutely (∼2 weeks) and chronically (∼4 months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri-infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared with the controls may be confounded by a reduced CVR, longitudinal group-level BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath-hold-based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity

Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease

BACKGROUND AND PURPOSE: There is a critical need for a reliable and clinically feasible imaging technique that can enable prognostication and selection for revascularization surgery in children with Moyamoya disease. Blood oxygen level-dependent MR imaging assessment of cerebrovascular reactivity, using voluntary breath-hold hypercapnic challenge, is one such simple technique. However, its repeatability and reliability in children with Moyamoya disease are unknown. The current study sought to address this limitation. MATERIALS AND METHODS: Children with Moyamoya disease underwent dual breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging of cerebrovascular reactivity in the same MR imaging session. Within-day, within-subject repeatability of cerebrovascular reactivity estimates, derived from the blood oxygen level-dependent signal, was computed. Estimates were associated with demographics and intellectual function. Interrater reliability of a qualitative and clinically applicable scoring scheme was assessed. RESULTS: Twenty children (11 males; 12.1 ± 3.3 years) with 30 MR imaging sessions (60 MR imaging scans) were included. Repeatability was "good" on the basis of the intraclass correlation coefficient (0.70 ± 0.19). Agreement of qualitative scores was "substantial" (κ = 0.711), and intrarater reliability of scores was "almost perfect" (κ = 0.83 and 1). Younger participants exhibited lower repeatability (P = .027). Repeatability was not associated with cognitive function (P > .05). However, abnormal cerebrovascular reactivity was associated with slower processing speed (P = .015). CONCLUSIONS: Breath-hold hypercapnic challenge blood oxygen level-dependent MR imaging is a repeatable technique for the assessment of cerebrovascular reactivity in children with Moyamoya disease and is reliably interpretable for use in clinical practice. Standardization of such protocols will allow further research into its application for the assessment of ischemic risk in childhood cerebrovascular disease

Cerebrovascular reactivity alterations due to subconcussive repetitive head trauma in asymptomatic high school football players

Chronic neurological damage as a result of chronic repetitive head trauma is a major concern for football athletes today. Repetitive concussions have been linked to many neurological disorders. Recently, it has been reported that repetitive subconcussive events can contribute to long-term neurodegeneration. For these reasons, it is important to understand the effect repetitive subconcussive head trauma has on brain health in young athletes. Past research has demonstrated that cerebrovascular reactivity (CVR), an important mediator of cerebrovascular regulation, is impaired following mild traumatic brain injury (mTBI). This impairment increases susceptibility to secondary injury following mTBI. In this study, Breath-Hold (BH) task based functional Magnetic Resonance Imaging (fMRI) was used to track CVR changes in asymptomatic high school football athletes across three competition seasons. Athletes in the first competition season had higher exposure to head impacts than the athletes during the second and the third seasons. Baseline scans were acquired before the start of the season, and follow-up scans were obtained during and after the season to track the potential changes in CVR as a result of experienced trauma. Noncollision-sport athletes were scanned over two sessions as controls during the first and third competition season. CVR decreased significantly in football athletes during the first half of their season in the first completion season but not in any other competition seasons. Controls did not show any significant changes in CVR. The results suggest that athletes getting higher exposure to head impacts in short duration of time drives cerebrovascular changes that may place athletes at higher risk of getting injured. These results also indicate that the brain may not be able to adapt quickly to abrupt increases in contact activity (as associated with the beginning of practice and competition), transiently increasing risk for symptomatic injury

Effects of Thresholding on Voxel-Wise Correspondence of Breath-Hold and Resting-State Maps of Cerebrovascular Reactivity

Functional magnetic resonance imaging for presurgical brain mapping enables neurosurgeons to identify viable tissue near a site of operable pathology which might be at risk of surgery-induced damage. However, focal brain pathology (e.g., tumors) may selectively disrupt neurovascular coupling while leaving the underlying neurons functionally intact. Such neurovascular uncoupling can result in false negatives on brain activation maps thereby compromising their use for surgical planning. One way to detect potential neurovascular uncoupling is to map cerebrovascular reactivity using either an active breath-hold challenge or a passive resting-state scan. The equivalence of these two methods has yet to be fully established, especially at a voxel level of resolution. To quantitatively compare breath-hold and resting-state maps of cerebrovascular reactivity, we first identified threshold settings that optimized coverage of gray matter while minimizing false responses in white matter. When so optimized, the resting-state metric had moderately better gray matter coverage and specificity. We then assessed the spatial correspondence between the two metrics within cortical gray matter, again, across a wide range of thresholds. Optimal spatial correspondence was strongly dependent on threshold settings which if improperly set tended to produce statistically biased maps. When optimized, the two CVR maps did have moderately good correspondence with each other (mean accuracy of 73.6%). Our results show that while the breath-hold and resting-state maps may appear qualitatively similar they are not quantitatively identical at a voxel level of resolution

Lag-Optimized Blood Oxygenation Level Dependent Cerebrovascular Reactivity Estimates Derived From Breathing Task Data Have a Stronger Relationship With Baseline Cerebral Blood Flow

Published: 15 June 2022Cerebrovascular reactivity (CVR), an important indicator of cerebrovascular health, is commonly studied with the Blood Oxygenation Level Dependent functional MRI (BOLD-fMRI) response to a vasoactive stimulus. Theoretical and empirical evidence suggests that baseline cerebral blood flow (CBF) modulates BOLD signal amplitude and may influence BOLD-CVR estimates. We address how acquisition and modeling choices affect the relationship between baseline cerebral blood flow (bCBF) and BOLD-CVR: whether BOLD-CVR is modeled with the inclusion of a breathing task, and whether BOLD-CVR amplitudes are optimized for hemodynamic lag effects. We assessed between-subject correlations of average GM values and within-subject spatial correlations across cortical regions. Our results suggest that a breathing task addition to a resting-state acquisition, alongside lag-optimization within BOLD-CVR modeling, can improve BOLD-CVR correlations with bCBF, both between- and within-subjects, likely because these CVR estimates are more physiologically accurate. We report positive correlations between bCBF and BOLD-CVR, both between- and within-subjects. The physiological explanation of this positive correlation is unclear; research with larger samples and tightly controlled vasoactive stimuli is needed. Insights into what drives variability in BOLD-CVR measurements and related measurements of cerebrovascular function are particularly relevant when interpreting results in populations with altered vascular and/or metabolic baselines or impaired cerebrovascular reserve.This work was supported by the Center for Translational Imaging at Northwestern University. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health [K12HD073945]. KZ was supported by an NIH-funded training program [T32EB025766]. SM was supported by the European Union’s Horizon 2020 research and innovation program [Marie Skłodowska-Curie grant agreement No. 713673] and a fellowship from La Caixa Foundation [ID 100010434, fellowship code LCF/BQ/IN17/11620063]. CC-G was supported by the Spanish Ministry of Economy and Competitiveness [Ramon y Cajal Fellowship, RYC2017-21845], the Basque Government [BERC 2018-2021 and PIBA_2019_104], and the Spanish Ministry of Science, Innovation and Universities [MICINN; PID2019- 105520GB-100]

Using physiological MRI to estimate dynamic cerebral autoregulation metrics: functional MRI feasibility study

Cerebral autoregulation is the homeostatic mechanism that maintains sufficient cerebral circulation despite changes in the perfusion pressure. Dynamic CA refers to the changes that occur in CBF within the first few seconds after an acute MAP change. Assessment of the CA impairment plays important role in the prognosis of many cerebrovascular diseases such as stroke, sub-arachnoid haemorrhage, as well as traumatic brain injury and neurodegenerative disorders. This thesis investigates the feasibility of using physiological MRI to estimate dynamic cerebral autoregulation (dCA) metrics. In particular, this thesis has an emphasis on measuring beat-to-beat arterial blood pressure inside the scanner to provide better understanding of the physiological aspects of dCA. Further, continuous blood pressure (BP) measures in response to different non invasive BP fluctuating methods are acquired to evaluate the reliability of these methods to induce response changes. Blood Oxygen Level Dependent (BOLD) fMRI method was used to estimate the expected variations of tissue oxygenation during induced dCA changes in healthy volunteers. The non invasive arterial blood pressure measurements were acquired using MR compatible arterial blood pressure monitoring device (NIBP-MRI/Caretaker; Biopac®). Further, sudden release of inflated thigh-cuffs (TCR) and inspiratory breath-hold (iBH) methods were used in the scanner to induce dynamic autoregulatory changes. These two methods were investigated in a pilot study, to evaluate the reliability prior to the MR study by comparing BP measurements obtained outside the scanner using non invasive methods. This pilot study included monitoring BP changes in response to four types of non invasive BP fluctuating methods. The reliability of NIBP/MRI Caretaker device was examined by comparing the BP response changes with the simultaneously acquired BP data from Finometer plethysmographic device. The cerebral autoregulation metrics were estimated by calculating the rate of regulation (RoR) following dynamic BP fluctuating events. Rate of regulation defines the rate at which the BOLD signal changes depending on MAP changes at a particular time. Further, the tissue specific regulation parameters were obtained for grey matter (GM), white matter (WM) and water shed areas (WS). The effect of iBH method on cerebral blood flow (CBF) and velocity (CBFV) was explored in a preliminary study by quantitative measures using time resolved 4D PC MRI angiography in two subjects. The mean arterial blood pressure (MAP) changes in response to TCR and iBH method were comparable. The fMRI data demonstrated BOLD signal amplitude change in response to the induced fast MAP changes. The GM and WS areas showed similar rates of regulation, and these were nominally higher than WM RoR in both TCR and iBH methods. Further, the 4D PC MRI data suggested 29% CBF-increase in response to 33% iBH in four minutes acquisition time. The acquired non invasive arterial BP measures concurrent with the BOLD signal amplitude response, allowed deriving the rate of regulation as a metric of dCA. It is not known whether this information is clinically relevant to gauge the haemodynamic risk association to cerebrovascular disease. However, BOLD signal change and CBF changes after iBH are confounded by the extent to which the CO2 gradually accumulate in response to iBH and causes an overshoot in the CBF response-change. In conclusion, the presented study indicates the feasibility of using physiological MRI to measure dCA in response to non-invasively induced MAP changes. Estimation of the dCA metrics could be improved by using advanced data fitting methods as well as controlling for physiological parameters such as PECO2