Kâmil Uludağ

Modeling the hemodynamic response to brain activation

Neural activity in the brain is accompanied by changes in cerebral blood flow (CBF) and blood oxygenation that are detectable with functional magnetic resonance imaging (fMRI) techniques. In this paper, recent mathematical models of this hemodynamic response are reviewed and integrated. Models are described for: (1) the blood oxygenation level dependent (BOLD) signal as a function of changes in cerebral oxygen extraction fraction (E) and cerebral blood volume (CBV); (2) the balloon model, proposed to describe the transient dynamics of CBV and deoxy-hemoglobin (Hb) and how they affect the BOLD signal; (3) neurovascular coupling, relating the responses in CBF and cerebral metabolic rate of oxygen (CMRO(2)) to the neural activity response; and (4) a simple model for the temporal nonlinearity of the neural response itself. These models are integrated into a mathematical framework describing the steps linking a stimulus to the measured BOLD and CBF responses. Experimental results examining transient features of the BOLD response (post-stimulus undershoot and initial dip), nonlinearities of the hemodynamic response, and the role of the physiologic baseline state in altering the BOLD signal are discussed in the context of the proposed models. Quantitative modeling of the hemodynamic response, when combined with experimental data measuring both the BOLD and CBF responses, makes possible a more specific and quantitative assessment of brain physiology than is possible with standard BOLD imaging alone. This approach has the potential to enhance numerous studies of brain function in development, health, and disease.

An integrative model for neuronal activity-induced signal changes for gradient and spin echo functional imaging

Gradient and spin echo (GRE and SE, respectively) weighted magnetic resonance images report on neuronal activity via changes in deoxygenated hemoglobin content and cerebral blood volume induced by alterations in neuronal activity. Hence, vasculature plays a critical role in these functional signals. However, how the different blood vessels (e.g. arteries, arterioles, capillaries, venules and veins) quantitatively contribute to the functional MRI (fMRI) signals at each field strength, and consequently, how spatially specific these MRI signals are remain a source of discussion. In this study, we utilize an integrative model of the fMRI signals up to 16.4 T, exploiting the increasing body of published information on relevant physiological parameters. Through simulations, extra- and intravascular functional signal contributions were determined as a function of field strength, echo time (TE) and MRI sequence used. The model predicted previously reported effects, such as feasibility of optimization of SE but not the GRE approach to yield larger micro-vascular compared to macro-vascular weighting. In addition, however, micro-vascular effects were found to peak with increasing magnetic fields even in the SE approach, and further increases in magnetic fields imparted no additional benefits besides beyond the inherent signal-to-noise (SNR) gains. Furthermore, for SE, using a TE larger than the tissue T(2) enhances micro-vasculature signal relatively, though compromising SNR for spatial specificity. In addition, the intravascular SE MRI signals do not fully disappear even at high field strength as arteriolar and capillary contributions persist. The model, and the physiological considerations presented here can also be applied in contrast agent experiments and to other models, such as calibrated BOLD approach and vessel size imaging.

Coupling of cerebral blood flow and oxygen consumption during physiological activation and deactivation measured with fMRI.

The physiological basis of the blood oxygenation level dependent (BOLD) signal and its dependence on baseline cerebral blood flow (CBF) were investigated by comparing responses to a visual stimulus after physiological changes of the baseline. Eight human subjects were imaged with 3 and 4 T MRI scanners, and both BOLD signal and CBF were simultaneously measured. Subjects viewed a flickering radial checkerboard in a block design experiment, alternating between eyes open or closed during the off periods. Compared to a baseline state with eyes open in a darkened room, substantial deactivation (average change: 2.9 +/- 0.3% BOLD, 22 +/- 2.1% CBF) in the occipital cortex was observed when the eyes were closed. The absolute response during stimulation (average change: 4.4 +/- 0.4% BOLD, 36.3 +/- 3.1% CBF) was independent of the preceding resting condition. We estimated the fractional change in CBF to be approximately 2.2 +/- 0.15 times greater than the fractional change in metabolic rate of oxygen (CMRO2). The changes in CBF and CMRO2 were consistently linearly coupled during activation and deactivation with CBF changes being between approximately 60% and 150% compared to baseline with eyes open. Relative to an assumed baseline oxygen extraction fraction (OEF) of 40%, the estimated OEF decreased to 33 +/- 1.4% during activation and increased to 46 +/- 1.2% during rest with eyes closed. In conclusion, we found that simply closing the eyes creates a large physiological deactivation in the visual cortex, and provides a robust paradigm for studying baseline effects in fMRI. In addition, we propose a feed-forward model for neurovascular coupling which accounts for the changes in OEF seen following baseline changes, including both the current physiological perturbations as well as previously reported pharmacologically induced changes.

The Influence of Moderate Hypercapnia on Neural Activity in the Anesthetized Nonhuman Primate

Hypercapnia is often used as vasodilatory challenge in clinical applications and basic research. In functional magnetic resonance imaging (fMRI), elevated CO2 is applied to derive stimulus-induced changes in the cerebral rate of oxygen consumption (CMRO2) by measuring cerebral blood flow and blood-oxygenation-level–dependent (BOLD) signal. Such methods, however, assume that hypercapnia has no direct effect on CMRO2. In this study, we used combined intracortical recordings and fMRI in the visual cortex of anesthetized macaque monkeys to show that spontaneous neuronal activity is in fact significantly reduced by moderate hypercapnia. As expected, measurement of cerebral blood volume using an exogenous contrast agent and of BOLD signal showed that both are increased during hypercapnia. In contrast to this, spontaneous fluctuations of local field potentials in the beta and gamma frequency range as well as multiunit activity are reduced by ∼15% during inhalation of 6% CO2 (pCO2 = 56 mmHg). A strong tendency toward a reduction of neuronal activity was also found at CO2 inhalation of 3% (pCO2 = 45 mmHg). This suggests that CMRO2 might be reduced during hypercapnia and caution must be exercised when hypercapnia is applied to calibrate the BOLD signal.

Investigating the post-stimulus undershoot of the BOLD signal – A simultaneous fMRI and fNIRS study

Measuring the hemodynamic response with functional magnetic resonance imaging (fMRI) together with functional near-infrared spectroscopy (fNIRS) may overcome limitations of single-method approaches. Accordingly, we measured the event-related hemodynamic response with both imaging methods simultaneously in young subjects during visual stimulation. An intertrial interval of 60 s was chosen to include the prolonged post-stimulus undershoot of the blood oxygenation level dependent (BOLD) signal. During visual stimulation, the BOLD signal, oxy-, and total hemoglobin (Hb) increased, whereas deoxy-Hb decreased. The post-stimulus period was characterized by an undershoot of the BOLD signal, oxy-Hb, and an overshoot of deoxy-Hb. Total Hb as measured by fNIRS returned to baseline immediately after the end of stimulation. Results suggest that the post-stimulus events as measured by fNIRS are dominated by a prolonged high-level oxygen consumption in the microvasculature. The contribution of a delayed return of blood volume to the BOLD post-stimulus undershoot in post-capillary veins as suggested by the Balloon and Windkessel models remains ambiguous. Temporal changes in the BOLD signal were highly correlated with deoxy-Hb, with lower correlation values for oxy- and total Hb. Furthermore, data show that fNIRS covers the outer 1 cm of the brain cortex. These results were confirmed by simultaneous fMRI/fNIRS measurements during rest. In conclusion, multimodal imaging approaches may contribute to the understanding of neurovascular coupling.

The Cortical Site of Visual Suppression by Transcranial Magnetic Stimulation

In visual suppression paradigms, transcranial magnetic stimulation (TMS) applied approximately 90 ms after visual stimulus presentation over occipital visual areas can robustly interfere with visual perception, thereby most likely affecting feedback activity from higher areas (Amassian VE, Cracco RQ, Maccabee PJ, Cracco JB, Rudell A, Eberle L. 1989. Suppression of visual perception by magnetic coil stimulation of human occipital cortex. Electroencephalogr Clin Neurophysiol 74:458-462.). It is speculated that the observed effects might stem primarily from the disruption of V1 activity. This hypothesis, although under debate, argues in favor of a special role of V1 in visual awareness. In this study, we combine TMS, functional magnetic resonance imaging, and calculation of the induced electric field to study the neural correlates of visual suppression. For parafoveal visual stimulation in the lower right half of the visual field, area V2d is shown to be the likely TMS target based on its anatomical location close to the skull surface. Furthermore, isolated stimulation of area V3 also results in robust visual suppression. Notably, V3 stimulation does not directly affect the feedback from higher visual areas that is relayed mainly via V2 to V1. These findings support the view that intact activity patterns in several early visual areas (rather than merely in V1) are likewise important for the perception of the stimulus.

Comparison of pulsed arterial spin labeling encoding schemes and absolute perfusion quantification

Arterial spin labeling (ASL) using magnetic resonance imaging (MRI) is a powerful noninvasive technique to investigate the physiological status of brain tissue by measuring cerebral blood flow (CBF). ASL assesses the inflow of magnetically labeled arterial blood into an imaging voxel. In the last 2 decades, various ASL sequences have been proposed which differ in their ease of implementation and their sensitivity to artifacts. In addition, several quantification methods have been developed to determine the absolute value of CBF from ASL magnetization difference images. In this study, we evaluated three pulsed ASL sequences and three absolute quantification schemes. It was found that FAIR-QUIPSSII implementation of ASL yields 10-20% higher signal-to-noise ratio (SNR) and 18% higher CBF as compared with PICORE-Q2TIPS (with FOCI pulses) and PICORE-QUIPSSII (with BASSI pulses). In addition, quantification schemes employed can give rise to up to a 35% difference in CBF values. We conclude that, although all quantitative ASL sequences and CBF calibration methods should in principle result in the similar CBF values and image quality, substantial differences in CBF values and SNR were found. Thus, comparing studies using different ASL sequences and analysis algorithms is likely to result in erroneous intra- and intergroup differences. Therefore, (i) the same quantification schemes should consistently be used, and (ii) quantification using local tissue proton density should yield the most accurate CBF values because, although still requiring definitive demonstration in future studies, the proton density of blood is assumed to be very similar to the value of gray matter.

General overview on the merits of multimodal neuroimaging data fusion.

Multimodal neuroimaging has become a mainstay of basic and cognitive neuroscience in humans and animals, despite challenges to consider when acquiring and combining non-redundant imaging data. Multimodal data integration can yield important insights into brain processes and structures in addition to spatiotemporal resolution complementarity, including: a comprehensive physiological view on brain processes and structures, quantification, generalization and normalization, and availability of biomarkers. In this review, we discuss data acquisition and fusion in multimodal neuroimaging in the context of each of these potential merits. However, limitations - due to differences in the neuronal and structural underpinnings of each method - have to be taken into account when modeling and interpreting multimodal data using generative models. We conclude that when these challenges are adequately met, multimodal data fusion can create substantial added value for neuroscience applications making it an indispensable approach for studying the brain.

Direct measurement of oxygen extraction with fMRI using 6% CO2 inhalation

The blood-oxygenation-level-dependent (BOLD) signal is an indirect hemodynamic signal that is sensitive to cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen. Therefore, the BOLD signal amplitude and dynamics cannot be interpreted unambiguously without additional physiological measurements, and thus, there remains a need for a functional magnetic resonance imaging (fMRI) signal, which is more closely related to the underlying neuronal activity. In this study, we measured CBF with continuous arterial spin labeling, CBV with an exogenous contrast agent and BOLD combined with intracortical electrophysiological recording in the primary visual cortex of the anesthetized monkey. During inhalation of 6% CO2, it was observed that CBF and CBV are not further increased by a visual stimulus, although baseline CBF for 6% CO2 is below the maximal value of CBF. In contrast, the electrophysiological response to the stimulation was found to be preserved during hypercapnia. As a consequence, the simultaneously measured BOLD signal responds negatively to a visual stimulation for 6% CO2 inhalation in the same voxels responding positively during normocapnia. These observations suggest that the fMRI response to a sensory stimulus for 6% CO2 inhalation occurs in the absence of a hemodynamic response, and it therefore directly reflects oxygen extraction into the tissue.

Decreases in ADC observed in tissue areas during activation in the cat visual cortex at 9.4 T using high diffusion sensitization

Recent studies in the human visual cortex using diffusion-weighted functional magnetic resonance imaging (fMRI) have suggested that the apparent diffusion coefficient (ADC) decreases, in contrast to earlier studies that consistently reported ADC increases during neuronal activation. The changes, in either case, are hypothesized to provide the ability to improve the spatial specificity of fMRI over conventional blood-oxygenation-level-dependent (BOLD) methods. Most recently, the ADC decreases have been suggested as originating from transient cell swelling caused by either shrinkage of the extracellular space or some intracellular neuronal process that precedes the hemodynamic response. All of these studies have been conducted in humans and at lower magnetic fields, which can be limited by the signal-to-noise ratio (SNR). The low SNR can lead to significant partial-volume effects because of the lower spatial resolutions required to attain sufficient SNR in diffusion-weighted images. Human studies also have the potential confound of motion. At high magnetic fields and in animal model studies, these limitations are alleviated. At high fields, SNR increases, tissue signals are enhanced and signal changes inside the blood are significantly reduced compared to lower fields. In this work, we were able to measure a small but significant ADC decrease in tissue areas, in conjunction with brain activation in the cat visual cortex at 9.4 T when using highly diffusion-weighted images (b>1200 s/mm2) where intravascular effects are minimal. When using low b-values, delayed increases in the tissue ADC during activation were observed. No significant changes in ADC were observed in surface vessels for any diffusion weighting. Furthermore, we did not observe any temporal differences in the highly diffusion-weighted data compared to BOLD; however, although the changes may likely be vascular in nature, they are highly localized to the tissue areas.