Time-dependent effects of hyperoxia on the BOLD fMRI signal in primate visual cortex and LGN

Hyperoxia is present in many anaesthesia protocols used in animal blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. However, little data exist on the influence of hyperoxia on the magnitude of stimulus-induced relative changes in BOLD fMRI signal (ΔBOLD). No study to date has investigated these effects in a time-resolved manner, although cerebral vasoregulation offers sites for a time-dependent interaction of hyperoxia and ΔBOLD. Here we investigated time-dependent effects of an inspiratory oxygen fraction of 90. We tightly clamped end tidal CO2 and body temperature and recorded physiological parameters relevant to rCBF in (fentanyl/isoflurane) anaesthetized monkeys while using visual stimulation to elicit ΔBOLD. To clarify whether changes in ΔBOLD arose from changes in baseline blood oxygenation or rather altered neuronal or vascular reactivity, we directly measured changes in rCBV using monocrystalline ion oxide nanoparticles (MION) as contrast agent. In visual cortex we found a biphasic modulation of stimulus-induced ΔBOLD under hyperoxia: We observed first a significant decrease in ΔBOLD by − 24 for data averaged over the time interval of 0–180 min post onset of hyperoxia followed by a subsequent recovery to baseline. rCBV response amplitudes were decreased by 21 in the same time interval (0–180 min). In the LGN, we neither found a significant modulation of ΔBOLD nor of MION response amplitude. The cerebrovascular effects of hyperoxia may, therefore, be regionally specific and cannot be explained by a deoxyhemoglobin dilution model accounting for plasma oxygenation without assuming altered neuronal activity or altered neurovascular coupling

Cortical Layer-Dependent Hemodynamic Regulation Investigated by Functional Magnetic Resonance Imaging

Functional magnetic resonance imaging (fMRI) is currently one of the most widely used non-invasive neuroimaging modalities for mapping brain activation. Techniques such as blood oxygenation level dependent (BOLD) fMRI or cerebral blood volume (CBV)-weighted fMRI are based on the assumption that hemodynamic responses are tightly regulated by neural activity. However, the relationship between fMRI responses and neural activity is still unclear. To investigate this relationship, the unique properties of temporal frequency tuning of primary visual cortex neurons was used as a model since it can be used to separate the neural input and output activities of this area. During moving grating stimuli of 1, 2, 10 and 20 Hz temporal frequencies, two fMRI studies, areal and laminar studies, were conducted with different spatial resolution in a 9.4-T Varian spectrometer. In areal studies, BOLD fMRI was able to detect the difference in tuning properties between area 17 (A17), area 18 (A18) and lateral geniculate nucleus. In A17, the BOLD tuning curve seemed to reflect the local field potential (LFP) low frequency band (<12 Hz) rather than spiking activity and LFP gamma band (25-90 Hz). In laminar studies, a high spatial resolution protocol was adopted to resolve the different cortical layers in A17. In addition to BOLD fMRI, CBV-weighted fMRI was performed to eliminate the contamination from the superficial draining veins. These results showed that BOLD and CBV tuning curves do not reflect the underlying spiking activity or the LFP activity at infragranular layers (the bottom layer of three cortical layers). This implies that the hemodynamic response may not be regulated on a laminar level. Therefore, caution should be taken when interpreting BOLD responses as the sole indicator of different aspects of neural activity in areal and laminar scales

Oxygen challenge MRI: development of a novel technique and application to acute stroke patients

The treatment of hyperacute ischaemic stroke has been revolutionised by the concept of potentially salvageable tissue – the ‘ischaemic penumbra’. However, current therapeutic practice is to administer thrombolytic therapy with recombinant tissue plasminogen activator after exclusion of intra-cerebral haemorrhage, with ‘time since onset’ used as a surrogate marker for the presence or absence of the ischaemic penumbra. The ability to identify the penumbra on an individual basis would enable bespoke treatment plans on the basis of underlying pathophysiology. The most commonly employed penumbral image technique is multi-modal magnetic resonance imaging (MRI) to identify a region of perfusion-diffusion mismatch. However, this approach remains to be validated. Moreover, a systematic review presented as an appendix to this thesis highlights the marked heterogeneity for its application. This thesis focusses on the development of a novel MRI technique (Oxygen Challenge) and is the first to report findings from human acute ischaemic stroke. The rationale for this technique is that it is sensitive to deoxyhaemoglobin, which is produced as a consequence of oxidative metabolism. It therefore has the potential to discriminate tissue compartments based on metabolic activity. For this study, 35 subjects with acute ischaemic stroke were imaged with transient hyperoxia (Oxygen Challenge) applied during continuous T2*-weighted MRI. Exploratory analyses suggested the following; •Oxygen Challenge precipitates a T2*-weighted signal increase in healthy tissue •This signal increase is partly dependent on the underlying cerebral blood volume, as suggested by univariate and multivariate analyses •In general, higher concentrations of oxygen precipitate greater T2*-weighted signal increases, but oxygen may influence T2*-weighted signal intensity in a bi-modal manner •The signal changes in operationally defined infarct core are attenuated, suggesting a metabolic influence on Oxygen Challenge results •Signal increases in the hyperacute perfusion-diffusion mismatch region were sometimes exaggerated, consistent with increased oxygen extraction fraction. However, small volumes of tissue acquired from only a few subjects limited definitive conclusions in this study •Oxygen Challenge may detect regions of crossed cerebellar diaschsis, although further confirmation is required •Maps of ‘percentage signal change’ allowed rapid evaluation of whole brain Oxygen Challenge data •Improvements in signal-to-noise ratio are required before this technique can be applied in clinical practice. On the basis of these data it is concluded that the technique is encouraging and further validation is warranted