Cerebral blood flow and behavioural effects of caffeine in habitual and non-habitual consumers of caffeine: A near infrared spectroscopy study

Caffeine has been shown to modulate cerebral blood flow, with little evidence of tolerance to these effects following habitual use. However, previous studies have focused on caffeine levels much higher than those found in dietary servings and have compared high caffeine consumers with low consumers rather than 'non-consumers'. The current placebo-controlled double-blind, balanced-crossover study employed near infrared spectroscopy to monitor pre-frontal cerebral-haemodynamics at rest and during completion of tasks that activate the pre-frontal cortex. Twenty healthy young habitual and non-habitual consumers of caffeine received 75mg caffeine or placebo. Caffeine significantly decreased cerebral blood flow but this was subject to a significant interaction with consumption status, with no significant effect being shown in habitual consumers and an exaggerated effect in non-habitual consumers. These findings suggest that caffeine, at levels typically found in a single dietary serving, is able to modulate cerebral blood flow but these effects are subject to tolerance

Exploring the effects of acute partial sleep restriction and subsequent caffeine ingestion on neurovascular coupling and cognitive function

Longitudinal, cross-sectional, and acute experimental research demonstrate that a short sleep duration is associated with an increased risk of both cardiovascular and cerebrovascular disease. Chronic habitual short sleep duration is associated with an increased dementia risk, however a quarter of the population fail to meet sleep duration guidelines. It is thought that alterations in cerebrovascular function precede symptoms of cognitive decline and dementia. Currently, no evidence exists on measures of cerebrovascular function, such as neurovascular coupling (NVC), and habitual sleep across the lifespan. The association of chronic poor sleep and dementia is likely due to the repeated exposure to a poor night’s sleep. Therefore, there is value in performing controlled, interventional work to understand the acute responses to a single night of sleep restriction. Furthermore, following a night of poor sleep, individuals commonly consume caffeine to increase alertness, but caffeine is known to simultaneously reduce brain blood flow. It is unknown how caffeine affects cerebrovascular function in a sleep restricted state. The purpose of this thesis was therefore to explore 1) the impact of one night of partial sleep restriction on NVC and, 2) whether caffeine ingestion affects NVC after partial sleep restriction in young healthy adults. NVC was determined using transcranial Doppler ultrasound (TCD) to measure blood velocity through the posterior cerebral artery (PCAv) during a visual search task. TCD was also used to measure blood velocity through the middle cerebral artery (MCAv) during cognitive function tests, both of which were assessed before and after normal sleep and partial sleep restriction, and following caffeine ingestion. This study found that NVC was unaltered following partial sleep restriction, and that the magnitude of the NVC response was unchanged after caffeine ingestion in both the rested and sleep restricted state. However, both absolute PCAv and MCAv were lower after caffeine, though this response did not differ between normal and restricted sleep. This study was the first to examine the effects of partial sleep restriction and subsequent caffeine ingestion on a measure of cerebrovascular function. However, sleep restriction was only studied in the form of a 50% sleep restriction, with sleep taking place in the second half of the night. Future research should explore whether the relationship between sleep and NVC is dependent on how sleep is accrued throughout the night, for example fragmented/broken sleep

Investigating the field-dependence of the Davis model: Calibrated fMRI at 1.5, 3 and 7 T

Gas calibrated fMRI in its most common form uses hypercapnia in conjunction with the Davis model to quantify relative changes in the cerebral rate of oxygen consumption (CMRO2) in response to a functional stimulus. It is most commonly carried out at 3 T but, as 7 T research scanners are becoming more widespread and the majority of clinical scanners are still 1.5 T systems, it is important to investigate whether the model used remains accurate across this range of field strengths. Ten subjects were scanned at 1.5, 3 and 7 T whilst performing a bilateral finger-tapping task as part of a calibrated fMRI protocol, and the results were compared to a detailed signal model. Simulations predicted an increase in value and variation in the calibration parameter M with field strength. Two methods of defining experimental regions of interest (ROIs) were investigated, based on (a) BOLD signal and (b) BOLD responses within grey matter only. M values from the latter ROI were in closer agreement with theoretical predictions; however, reassuringly, ROI choice had less impact on CMRO2 than on M estimates. Relative changes in CMRO2 during motor tasks at 3 and 7 T were in good agreement but were over-estimated at 1.5 T as a result of the lower signal to noise ratio. This result is encouraging for future studies at 7 T, but also highlights the impact of imaging and analysis choices (such as ASL sequence and ROI definition) on the calibration parameter M and on the calculation of CMRO2

Magnetic resonance imaging of resting cerebral oxygen metabolism : applications in Alzheimer’s disease

The BOLD contrast employed in functional MRI studies is an ambiguous signal composed of changes in blood flow, blood volume and oxidative metabolism. In situations where the vasculature and metabolism may have been affected, such as in aging and in certain diseases, the dissociation of the more physiologically-specific components from the BOLD signal becomes crucial. The latest generation of calibrated functional MRI methods allows the estimation of both resting blood flow and absolute oxygen metabolism. The work presented here is based on one such proof-of-concept approach, dubbed QUO2, whereby taking into account, within a generalized model, both arbitrary changes in blood flow and blood O2 content during a combination of hypercapnia and hyperoxia breathing manipulations, yields voxel-wise estimates of resting oxygen extraction fraction and oxidative metabolism. In the first part of this thesis, the QUO2 acquisition protocol and data analysis were revisited in order to enhance the temporal stability of individual blood flow and BOLD responses, consequently improving reliability of the model-derived estimates. Thereafter, an assessment of the within and between-subject variability of the optimized QUO2 measurements was performed on a group of healthy volunteers. In parallel, an analysis was performed of the sensitivity of the model to different sources of random and systematic errors, respectively due to errors in measurements and choice of assumed parameters values. Moreover, the various impacts of the oxygen concentration administered during the hyperoxia manipulation were evaluated through a simulation and experimentally, indicating that a mild hyperoxia was beneficial. Finally, the influence of Alzheimer’s disease in vascular and metabolic changes was explored for the first time by applying the QUO2 approach in a cohort of probable Alzheimer’s disease patients and age-matched control group. Voxel-wise and region-wise differences in resting blood flow, oxygen extraction fraction, oxidative metabolism, transverse relaxation rate constant R2* and R2* changes during hypercapnia were identified. A series of limitations along with recommended solutions was given with regards to the delayed transit time, the susceptibility artifacts and the challenge of performing a hypercapnia manipulation in cohorts of elderly and Alzheimer’s patients.Le contraste BOLD employé dans les études d’imagerie par résonance magnétique fonctionnelle (IRMf) provient d’une combinaison ambigüe de changements du flux sanguin cérébral, du volume sanguin ainsi que du métabolisme oxydatif. Dans un contexte où les fonctions vasculaires ou métaboliques du cerveau ont pu être affectées, tel qu’avec l’âge ou certaines maladies, il est crucial d’effectuer une décomposition du signal BOLD en composantes physiologiquement plus spécifiques. La dernière génération de méthodes d’IRMf calibrée permet d’estimer à la fois le flux sanguin cérébral et le métabolisme oxydatif au repos. Le présent travail est basé sur une telle technique, appelée QUantitative O2 (QUO2), qui, via un model généralisé, prend en considération les changements du flux sanguin ainsi que ceux en concentrations sanguine d’O2 durant des périodes d’hypercapnie et d’hyperoxie, afin d’estimer, à chaque voxel, la fraction d’extraction d’oxygène et le métabolisme oxydatif au repos. Dans la première partie de cette thèse, le protocole d’acquisition ainsi que la stratégie d’analyse de l’approche QUO2 ont été revus afin d’améliorer la stabilité temporelle des réponses BOLD et du flux sanguin, conséquemment, afin d’accroître la fiabilité des paramètres estimés. Par la suite, une évaluation de la variabilité intra- et inter-sujet des différentes mesures QUO2 a été effectuée auprès d’un groupe de participants sains. En parallèle, une analyse de la sensibilité du model à différentes sources d’erreurs aléatoires (issues des mesures acquises) et systématiques (dues aux assomptions du model) a été réalisée. De plus, les impacts du niveau d’oxygène administré durant les périodes d’hyperoxie ont été évalués via une simulation puis expérimentalement, indiquant qu’une hyperoxie moyenne était bénéfique. Finalement, l’influence de la maladie d’Alzheimer sur les changements vasculaires et métaboliques a été explorée pour la première fois en appliquant le protocole QUO2 à une cohorte de patients Alzheimer et à un groupe témoin du même âge. Des différences en terme de flux sanguin, fraction d’oxygène extraite, métabolisme oxydatif, et taux de relaxation transverse R2* au repos comme en réponse à l’hypercapnie, ont été identifiées au niveau du voxel, ainsi qu’au niveau de régions cérébrales vulnérables à la maladie d’Alzheimer. Une liste de limitations accompagnées de recommandations a été dressée en ce qui a trait au temps de transit différé, aux artéfacts de susceptibilité magnétique, de même qu’au défi que représente l’hypercapnie chez les personnes âgées ou atteintes de la maladie d’Alzheimer

The effect of caffeine on working memory load-­related brain activation in middle-­aged males

Klaassen, E. B., De Groot, R. H. M., Evers, E. A. T., Snel, J., Veerman, E. C. I., Ligtenberg, A. J. M., Jolles, J., & Veltman, D. J. (2013). The effect of caffeine on working memory load-related brain activation in middle-aged male. Neuropharmacology, 64, 160-167. doi:10.1016/j.neuropharm.2012.06.026Caffeine is commonly consumed in an effort to enhance cognitive performance. However, little is known about the usefulness of caffeine with regard to memory enhancement, with previous studies showing inconsistent effects on memory performance. We aimed to determine the effect of caffeine on working memory (WM) load-related activation during encoding, maintenance and retrieval phases of a WM maintenance task using functional magnetic resonance imaging (fMRI). 20 healthy, male, habitual caffeine consumers aged 40 to 61 years were administered 100 mg of caffeine in a double-blind placebo-controlled crossover design. Participants were scanned in a non-withdrawn state following a workday during which caffeinated products were consumed according to individual normal use (range = 145 – 595 mg). Acute caffeine administration was associated with increased load-related activation compared to placebo in the left and right dorsolateral prefrontal cortex during WM encoding, but decreased load-related activation in the left thalamus during WM maintenance. These findings are indicative of an effect of caffeine on the fronto-parietal network involved in the top-down cognitive control of WM processes during encoding and an effect on the prefrontal cortico-thalamic loop involved in the interaction between arousal and the top-down control of attention during maintenance. Therefore, the effects of caffeine on WM may be attributed to both a direct effect of caffeine on WM processes, as well as an indirect effect on WM via arousal modulation. Behavioral and fMRI results were more consistent with a detrimental effect of caffeine on WM at higher levels of WM load, than caffeine-related WM enhancement

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

Traumatic Brain Injury Induced Cerebral Blood Flow Changes - A Potential Role For Caffeine

Traumatic brain injury (TBI) is a global health problem with significant socio-economic costs. Closed head TBIs are one of the major causes of physical disability and cognitive disorder in young adults and a leading cause of death in children. Alteration in cerebral blood flow due to an impaired autoregulation is one of the most common consequences of TBI. However, studies related to understanding the temporal changes in CBF following TBI in experimental models are limited. The few available studies report acute reduction in CBF following TBI; knowledge related to CBF changes at sub-acute periods extending to 7 days after TBI is still not known. Furthermore, reduction in CBF has been associated with unfavorable neurological outcome and can render the brain vulnerable to secondary damage. However, thus far no effective interventions that can restore or have shown the potential to restore are available. A few available studies have demonstrated that caffeine acts as a neuroprotectant in several neurological disorders acting through diverse mechanisms. It has been postulated that caffeine may offer neuroprotection by restoring or maintaining adequate CBF following TBI. Thus, studying these CBF changes following TBI and its potential modulation by caffeine pre-treatment forms the central theme of this research. We investigated the CBF changes in male Sprague Dawley rats at 4hrs, 24 hrs, 3 days and 7 days following closed head injury, with and without caffeine (chronic and acute) pretreatment. TBI was induced using the Marmarou impact acceleration device (2 m height, 450 g weight). Rats subjected to TBI showed reduced regional and global CBF at 4hrs and 7 days following TBI. In contrast, rats that underwent chronic caffeine (1.5 g/L) pretreatment for 3 weeks did not show apparent changes in regional and global CBF following TBI, indicating a potential benefit after TBI. Acute caffeine treatment (150 mg/kg, i.p. injection 30 minutes before TBI) showed significant reductions in CBF at 4 hrs post-TBI, further deteriorating the cerebral perfusion. Furthermore, chronic caffeine pretreated rats demonstrated significantly reduced surface righting duration following TBI, compared to acute caffeine treated rats subjected to TBI and rats subjected to TBI without caffeine treatment. Therefore, chronic caffeine treatment may be beneficial in offering a degree of neuroprotection against TBI. This study was able to support the hypothesis that chronic caffeine can restore or optimize CBF following TBI and this optimization may be related to the ensuring positive outcomes such as reduced surface righting duration. This may form the stepping stone for further studies on beneficial effects of caffeine in TBI

Magnetic resonance imaging of the cerebral metabolic rate of oxygen (CMRO₂)

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student submitted PDF version of thesis.Includes bibliographical references (p. 120-128).Oxygen consumption is an essential process of the functioning brain. The rate at which the brain consumes oxygen is known as the cerebral metabolic rate of oxygen (CMRO₂). CMRO₂ is intimately related to brain health and function, and will change in settings of disease and functional activation. Accurate CMRO₂ measurement will enable detailed investigation of neuropathology and facilitate our understanding of the brain's underlying functional architecture. Despite the importance of CMRO₂ in both clinical and basic neuroscience settings, a robust CMRO₂ mapping technique amenable to functional and clinical MRI has not been established. To address this issue, a novel method called QUantitative Imaging of eXtraction of Oxygen and TIssue Consumption, or QUIXOTIC, is introduced. The key innovation in QUIXOTIC is the use of velocity-selective spin labeling to isolate MR signal exclusively from post-capillary venular blood on a voxel-by-voxel basis. This isolated signal can be related to venular oxygen saturation, oxygen extraction fraction, and ultimately CMRO₂. This thesis first explores fundamental theory behind the QUIXOTIC technique, including design of a novel MRI pulse sequence, explanation of the principal sequence parameters, and results from initial human experiences. A human trial follows, in which QUIXOTIC is used to measure cortical gray matter CMRO₂ in ten healthy volunteers.(cont.) QUIXOTIC-measured CMRO₂ is found to be within the expected physiological range and is comparable to values reported by other techniques. QUIXOTIC is then applied to evaluate CMRO₂ response to carbon-dioxide-induced hypercapnia in awake humans. In this study, CMRO₂ is observed to decrease in response to mild hypercapnia. Finally, pilot studies that show feasibility of QUIXOTIC-based functional MRI (fMRI) and so-called "turbo" QUIXOTIC are presented and discussed.by Divya Sanam Bolar.Ph.D

DEVELOPMENT OF MRI TECHNIQUES FOR MEASURING CEREBRAL BLOOD VOLUME, BLOOD FLOW, AND BLOOD OXYGENATION WITHIN A SINGLE SCAN

Functional MRI (fMRI) is commonly performed using the blood-oxygenation-level-dependent (BOLD) approach, which is sensitive to ensemble changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO2). In order to understand and quantify the BOLD fMRI signal, it is essential to design multi-modal fMRI approaches that are sensitized to these individual hemodynamic parameters, and to further determine the oxygen metabolism. This dissertation aims to develop and improve current quantitative fMRI techniques to detect relaxation times T2*, cerebral blood volume (CBV), cerebral blood flow (CBF), blood oxygenation level hemodynamics, oxygen extraction fraction (OEF), and CMRO2 during neuronal activation in a time efficient manner. Total and extravascular R2* values in the parenchyma in human visual cortex are measured by combining multi-echo BOLD and vascular-space-occupancy (VASO) fMRI with visual stimulation at 7T. The VASO method is expected to suppress the intravascular signals in the microvessels. Both the absolute parenchymal extravascular R2* and R2* changes (ΔR2*) upon activation are determined, and the ratio of extravascular ΔR2* to total ΔR2* is calculated, confirming a predominant contribution from the extravascular component of the BOLD effect at 7T. Parenchymal OEF during stimulation is also estimated based on these measurements, the value of which is consistent with those reported at lower field strengths. While normally in most of the quantitative fMRI approaches, BOLD, CBV, and CBF measurements are separately performed to estimate CMRO2 dynamics, the ability to acquire these physiological parameters simultaneously would be very useful to improve image acquisition efficiency, and more importantly reduce the sensitivity to temporal variations due to factors such as subject head motion, task performance, and physiologic fluctuations between the fMRI experiments. A large portion of this dissertation is devoted to design single-scan approaches to detect changes in the multi-modal hemodynamic signals. First, a novel 3D whole-brain MRI pulse sequence, dubbed 3D VASO-FAIR, is proposed to detect CBV and CBF responses in a single scan. Second, a new 3D acquisition strategy that extends VASO-FAIR and incorporates a 3D T2-preparation gradient-echo (GRE) BOLD method is implemented to simultaneously measure BOLD, CBV, and CBF reactivity during functional stimulation. Compared to individually performed multi-modal fMRI scans, similar image quality, activation patterns, relative signal changes (ΔS/S), tSNRs and CNRs can be achieved using the proposed combined sequences. Finally, based on the BOLD, CBV, and CBF responses obtained from the combined sequence, the oxygen metabolism alterations (OEF and CMRO2) are quantified