Gulf War Illness (GWI) is a medically unexplained illness that is classified by two common case criteria including the CDC chronic multisymptom illness definition and Kansas GWI criteria. It occurred among veterans who served in the Persian Gulf War from August, 1990 to February, 1991. Because of its complex chronic symptoms and multiple potential causes the neuropathological mechanisms and/or successfully clinical treatments for it remain elusive. Those in the theater of this war experienced exposures to many neurotoxicants, suggesting an association between GWI and neurologic dysfunction. In order to better understand the underlying cause of GWI, we have chosen to explore cerebral blood flow. Our hypothesis is that abnormal cerebral blood flow is associated with GWI and ultimately neurological dysfunction. By conducting a comprehensive evaluation of cerebral blood flow we will be able to determine if it has a role in Gulf War Illness. Historically, several techniques have been used to measure cerebral blood flow. Arterial spin labeling (ASL) has been widely used in research as a non-invasive and non-ionizing technique, which has the least adverse effects on the participants. An ASL subtype called pseudo-continuous arterial spin labeling (PCASL) has become a favorable technique in ASL research because it combines the advantages of continuous arterial spin labeling (CASL) and pulsed arterial spin labeling (PASL). PCASL can quantify the absolute cerebral blood flow without the exogenous contrast agents. The cost of PCASL is relatively low as most scanner can run this sequence without additional hardware. It provides higher label efficiency (to CASL) and greater signal-to-noise ratio (to PASL). We utilized the data from an ongoing study with 114 GW veterans study participants aged from 42 to 80. Their regional cerebral blood flow was scanned using a 3T Philips Achieva MRI scanner. Asltoolbox (Wang et al., 2016) was used to calculate the cerebral blood flow, and Freesurfer v6.0 was used to do the co-registration and quantification. The analysis of demographic data suggested that the presence of hypertension was the only variables that made differences between control and GWI case groups (p = 0.02). General linear models indicated that alternations of cerebral blood flow were not a component of GWI at least using CMI definition. Whether cerebral blood flow associates with GWI is still pending on further studies with utilizing a more refined case definition.

Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL18, 69.96.7 years) and subjects with mild cognitive impairment (MCI15, 74.98.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL17, MCI7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (0.41, P0.049) and global cortical (0.46, P0.02) vasoreactivity to hypercapnia (VRh). The FCRP-VRh relationships were most pronounced in the MCI group: hippocampus (0.77, P=0.04); global cortex (0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR h was lower in MCI than in NL subjects (Z2.0, P=0.047). This difference persisted after age and FCRP correction (F 3,20 4.6, P0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR h is more sensitive to vascular burden than either resting CBF or brain volume.

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Ketone monoester (KME) supplements are one exogenous ketone intervention which has demonstrated benefits to multiple facets of brain health, including cerebral blood flow (CBF) and cognition. However, it is unknown how KME impact CBF and cognition acutely, and whether the size of KME dose differentially impacts these outcomes. Higher KME doses lower blood pH and arterial CO2 (PaCO2), which are important regulators of CBF. We hypothesized that high-dose KME ingestion would lower CBF via acidosis-induced compensatory reductions in PaCO2, whereas low-dose KME ingestion would enhance CBF, mirroring past findings from other exogenous ketone interventions. Changes in cognitive function were also hypothesized to parallel CBF responses. Twenty young adults (age=23±3 years; BMI=23.4±2.2 kg/m2) participated. In a double-blinded, counterbalanced, crossover design, participants completed 3 separate conditions: 1) high-dose KME (0.6 g/kg); 2) low-dose KME (0.3 g/kg); or 3) placebo. Outcome measures were assessed at fasting baseline, 45-, and 120-min post-ingestion. CBF was assessed using Duplex ultrasound of the internal carotid and vertebral arteries. End-tidal CO2 (PETCO2) was measured using a gas analyzer, to approximate PaCO2. Hippocampal-dependent function was assessed using the lure discrimination index (LDI) and recognition memory score (REC) from the mnemonic similarity task. Over a 2-hour period post-ingestion, low- and high-dose KME lowered CBF to a different extent relative to baseline (45-min (low-dose, high-dose): ∆10.4%, ∆14.0%; 120-min (low-dose, high-dose): ∆6.2%, ∆18.6%; P < 0.001). These reductions were mirrored by dose-dependent reductions in PETCO2 and changes in CBF were positively correlated with changes in PETCO2 (P < 0.001, R2 = 0.219). Despite reductions in CBF, both LDI (P = 0.619) and REC (P = 0.651) were unchanged in the KME conditions. These findings provide a foundational characterization of the acute effects of KME dose on CBF and cognition, which will inform potential therapeutic recommendations on KME for brain health. / Thesis / Master of Science (MSc) / In addition to being an alternative energy source used during fasting or when consuming low amounts of carbohydrates, ketone bodies may act as signals that impact various aspects of brain health. Recent studies suggest that supplementating with a drink that contains ketones is an alternative way to increase ketones in your blood, without dietary modifications. We investigated whether one-time ingestion of a ketone supplement (KME) affects brain blood flow and cognition, as well as whether the size of KME dose differentially impacts these outcomes. Our results show that KME ingestion lowers brain blood flow, to a different extent depending on the dose that was ingested. Despite this, there was no change in memory performance from taking this ketone supplement. These findings were important in demonstrating how KME ingestion impacts the brain, and will inform future guidelines on its potential use for protecting and/or improving brain health.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Cerebral autoregulation is an intrinsic physiological response that maintains a constant cerebral blood flow (CBF) despite dynamic changes in the systemic blood pressure. Autoregulation is achieved through changes in the resistance of the small blood vessels in the brain through reflexive vasodilatation and vasoconstriction. Cerebrovascular reactivity (CVR) is a measure of this response. CVR is defined as a change in CBF in response to a given vasodilatory stimulus. CVR therefore potentially reflects the vasodilatory reserve capacity of the cerebral vasculature to maintain a constant cerebral blood flow. A decrease in CVR (which is interpreted as a reduction in the vasodilatory reserve capacity) in the vascular territory downstream of a larger stenosed supply artery correlates strongly with the risk of a hemodynamic stroke. As a result, the use of CVR studies to evaluate the state of the cerebral autoregulatory capacity has clinical utility. Application of CVR studies in the clinical scenario depends on a thorough understanding of the normal response. The goal of this thesis therefore was to map CVR throughout the brain in normal healthy individuals using Blood Oxygen Level Dependant functional Magnetic Resonance Imaging (BOLD MRI) as an index to CBF and precisely controlled changes in end-tidal partial pressure of carbon dioxide (PETCO2) as the global flow stimulus.

Die Grundlage der modernen funktionellen Bildgebung des Gehirns mit der BOLD-fMRT ist die neurovaskuläre Kopplung. Sie ist in ihren Mechanismen wenig verstanden und führt zu einem komplexen Zusammenspiel von Blutfluß, Blutvolumen und Oxygenierung. Die Aufklärung der Blutflußantwort mit ihren Auswirkungen auf die Meßsignale ist für eine genaue Interpretation des BOLD-Signals kritisch. Zudem stellt sich seit einigen Jahren die Frage, ob es bei funktioneller Aktivierung aufgrund eines vermehrten neuronalen Sauerstoffverbrauchs zu einer frühen Deoxygenierung kommt. Diese könnte sich als initialer BOLD-Abfall für eine hochauflösende Bildgebung eignen. Ein Vergleich von optischen Methoden und funktioneller Magnetresonanztomographie am gleichen Stimulationsmodell kann diesen Fragen nachgehen. Wir haben die kortikale Blutflußantwort auf somatosensorische Stimulation der Ratte mit den optischen Methoden Optical Imaging und Imaging Spectroscopy sowie mit BOLD-fMRT und blutvolumengewichteter MION-fMRT gemessen. Bei der Stimulation eines einzelnen Whisker-Haares grenzte sich die entsprechende kortikale Kolumne über eine optische Abschwächung ab. Spektroskopisch zeigte sich, daß diesem Signal eine initiale Blutvolumenzunahme zugrundeliegt. Eine Lambert-Beer-Analyse, die die differentiellen Pfadlängen des Lichtes im streuenden Gewebe vernachlässigt, konnte die gemessenen Spektren nicht linear anpassen. Mit einer Annäherung errechnete sie einen artifiziellen Anstieg des Deoxy-Hb in der frühen Antwort. Die quantifizierte Lambert-Beer-Analyse unter Einschluß der differentiellen Pfadlängen konnte die gemessenen Spektren linear anpassen. Im berechneten Konzentrationsverlauf stieg Oxy-Hb zum Stimulationsbeginn an, Deoxy-Hb blieb zunächst auf dem Ruhewert und fiel dann ab. Diese Verzögerung lag im Bereich der kapillären Transitzeit. Die spektroskopisch gemessene frühe Antwort fand sich auch in der Messung der Antwort auf Vorderpfotenstimulation. Zum Vergleich wurden fMRT-Messungen an diesem Stimulationsmodell herangezogen. Die MION-fMRT erfaßte einen initialen Anstieg des plasmatischen Blutvolumens (pCBV), das BOLD-Signal delta-R2* eine verzögerte Hyperoxygenierung. Die Hyperoxygenierung im weiteren Verlauf der Blutflußantwort zeigte in Imaging Spectroscopy und fMRT einen linearen Zusammenhang mit der Dauer der Stimulation. Dabei korrelierte die delta-R2* stark mit der spektroskopisch gemessenen Deoxy-Hb-Konzentration. Auch die Antwort auf das Stimulationsende stellte sich als von der Stimulationsdauer abhängig heraus und wurde als vaskuläres Speicherphänomen interpretiert. BOLD und Deoxy-Hb zeigten beide eine Hypooxygenierung nach dem Stimulationsende. pCBV und das spektroskopisch gemessene korpuskuläre Blutvolumen, cCBV, verhielten sich nach dem Stimulationsende spiegelbildlich. Die pCBV-Zunahme bildete sich nur allmählich zurück, während das cCBV steil unter seinen Ruhewert abfiel. Im Laufe der Messung nahm das cCBV wieder zu und erreichte seinen Ruhewert zeitgleich mit dem pCBV. Eine vermehrte Volumenspeicherung als Folge venöser Streßrelaxation und eine Verschiebung des Hämatokrits aufgrund des Fahraeus-Lindquist-Effekts werden als Grund für diese Veränderungen in Betracht gezogen. Die experimentellen Daten belegen, daß optische und magnetresonanztomographische Methoden korrespondierende Signale von Oxygenierung und Blutvolumen messen. Eine frühe Deoxygenierung wurde nicht gemessen. Allerdings zeigte sich die frühe Komponente der Blutvolumenzunahme an die initiale Kapillarnetzfüllung einer kortikalen Kolumne gebunden. Ihre Detektion mit der fMRT bietet eine Perspektive auf dem Weg zu einer hochauflösenden funktionellen Bildgebung des Gehirns. / Neurovascular coupling forms the basis of modern functional brain imaging with BOLD-fMRI. Its mechanisms are poorly understood as it leads to a complex interaction of blood flow, blood volume and oxygenation. The investigation of the blood flow response with its influences on measured signals is critical for the exact interpretation of the BOLD-Signal. In addition to that, the question on whether or not an increase in oxygen consumption during functional activation leads to an early deoxygenation is not resolved yet. This early deoxygenation could cause an initial BOLD decrease suitable for high resolution imaging. A comparison of optical methods and functional magnetic resonance imaging on the same stimulation model can help to answer these questions. We have measured the cortical blood flow response on somatosensory stimulation of the rat with the optical methods Optical Imaging and Imaging Spectroscopy and with BOLD-fMRI and blood volume weighted MION-fMRI. During stimulation of a single whisker vibrissa the corresponding cortical column delineated itself as an area of increased optical attenuation. A spectroscopical analysis showed an initial blood volume increase responsible for this signal. A Lambert-Beer-Analysis that ignored the differential pathlength of light in scattering tissue could not fit the measured spectra. The result of its closest approximation showed an artificial increase of deoxy-Hb during the early response. The quantified Lambert-Beer-Analysis with inclusion of differential pathlengths succeeded in fitting the measured spectra. The calculated concentration time course showed an increase of oxy-Hb at stimulus onset with deoxy-Hb staying at baseline values and then decreasing. This delay was as long as the capillary mean transit time. The spectroscopically measured early response was also found when measuring the response to forepaw stimulation. For comparison, fMRI measurements on this stimulation model were done. MION-fMRI detected an early increase of plasmatic blood volume (pCBV), the BOLD-Signal delta-R2* a delayed hyperoxygenation. The time course of the hyperoxygenation during the blood flow response showed a linear relationship with the stimulus duration in Imaging Spectroscopy and fMRI. The delta-R2* correlated strongly with spectroscopically measured concentration changes of deoxy-Hb. In addition to that, the response on the stimulus offset was dependent on the stimulus duration. It was interpreted as a vascular storage phenomenon. Both BOLD and deoxy-Hb showed a hypooxygenation after stimulus offset. pCBV and the spectroscopically measured corpuscular blood volume, cCBV, showed mirroring signals after stimulus offset. While pCBV returned to baseline values gradually, cCBV fell below baseline values immediately. During the further measurement cCBV increased and returned to baseline values at the same time as pCBV. To explain this, an increased volume storage due to venous stress relaxation and a hematocrit shift due to the Fahraeus-Lindquist effect are taken into consideration. The experimental data proves that optical and fMRI methods measure corresponding signals of oxygenation and blood volume. An early deoxygenation was not seen. However, the early component of the blood volume increase seems to be restricted to the initial filling of the capillary net supplying a cortical column. Its detection with fMRI offers a perspective on the way to high resolution functional imaging of the brain.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21669号 / 医博第4475号 / 新制||医||1035(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 古川 壽亮, 教授 宮本 享 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM