Investigation of the neurovascular coupling in positive and negative BOLD responses in human brain at 7T

Decreases in stimulus-dependent blood oxygenation level dependent (BOLD) signal and their underlying neurovascular origins have recently gained considerable interest. In this study a multi-echo, BOLD-corrected vascular space occupancy (VASO) functional magnetic resonance imaging (fMRI) technique was used to investigate neurovascular responses during stimuli that elicit positive and negative BOLD responses in human brain at 7 T. Stimulus-induced BOLD, cerebral blood volume (CBV), and cerebral blood flow (CBF) changes were measured and analyzed in ‘arterial’ and ‘venous’ blood compartments in macro- and microvasculature. We found that the overall interplay of mean CBV, CBF and BOLD responses is similar for tasks inducing positive and negative BOLD responses. Some aspects of the neurovascular coupling however, such as the temporal response, cortical depth dependence, and the weighting between ‘arterial’ and ‘venous’ contributions, are significantly different for the different task conditions. Namely, while for excitatory tasks the BOLD response peaks at the cortical surface, and the CBV change is similar in cortex and pial vasculature, inhibitory tasks are associated with a maximum negative BOLD response in deeper layers, with CBV showing strong constriction of surface arteries and a faster return to baseline. The different interplays of CBV, CBF and BOLD during excitatory and inhibitory responses suggests different underlying hemodynamic mechanisms

Evidence that the negative BOLD response is neuronal in origin: a simultaneous EEG–BOLD–CBF study in humans

Unambiguous interpretation of changes in the BOLD signal is challenging because of the complex neurovascular coupling that translates changes in neuronal activity into the subsequent haemodynamic response. In particular, the neurophysiological origin of the negative BOLD response (NBR) remains incompletely understood. Here, we simultaneously recorded BOLD, EEG and cerebral blood flow (CBF) responses to 10 s blocks of unilateral median nerve stimulation (MNS) in order to interrogate the NBR. Both negative BOLD and negative CBF responses to MNS were observed in the same region of the ipsilateral primary sensorimotor cortex (S1/M1) and calculations showed that MNS induced a decrease in the cerebral metabolic rate of oxygen consumption (CMRO2) in this NBR region. The ∆CMRO2/∆CBF coupling ratio (n) was found to be significantly larger in this ipsilateral S1/M1 region (n = 0.91 ± 0.04, M = 10.45%) than in the contralateral S1/M1 (n = 0.65 ± 0.03, M = 10.45%) region that exhibited a positive BOLD response (PBR) and positive CBF response, and a consequent increase in CMRO2 during MNS. The fMRI response amplitude in ipsilateral S1/M1 was negatively correlated with both the power of the 8–13 Hz EEG mu oscillation and somatosensory evoked potential amplitude. Blocks in which the largest magnitude of negative BOLD and CBF responses occurred therefore showed greatest mu power, an electrophysiological index of cortical inhibition, and largest somatosensory evoked potentials. Taken together, our results suggest that a neuronal mechanism underlies the NBR, but that the NBR may originate from a different neurovascular coupling mechanism to the PBR, suggesting that caution should be taken in assuming the NBR simply represents the neurophysiological inverse of the PBR

Energetics and activation of the central nervous system by in vivo nuclear magnetic resonance

Stefano Pascarella, Mario Compiani, Staderin

Cortical lamina-dependent blood volume changes in human brain at 7T

Cortical layer-dependent high (sub-millimeter) resolution functional magnetic resonance imaging (fMRI) in human or animal brain can be used to address questions regarding the functioning of cortical circuits, such as the effect of different afferent and efferent connectivities on activity in specific cortical layers. The sensitivity of gradient echo (GE) blood oxygenation level-dependent (BOLD) responses to large draining veins reduces its local specificity and can render the interpretation of the underlying laminar neural activity impossible. The application of the more spatially specific cerebral blood volume (CBV)-based fMRI in humans has been hindered by the low sensitivity of the noninvasive modalities available. Here, a vascular space occupancy (VASO) variant, adapted for use at high field, is further optimized to capture layer-dependent activity changes in human motor cortex at sub-millimeter resolution. Acquired activation maps and cortical profiles show that the VASO signal peaks in gray matter at 0.8–1.6 mm depth, and deeper compared to the superficial and vein-dominated GE-BOLD responses. Validation of the VASO signal change versus well-established iron-oxide contrast agent based fMRI methods in animals showed the same cortical profiles of CBV change, after normalization for lamina-dependent baseline CBV. In order to evaluate its potential of revealing small lamina-dependent signal differences due to modulations of the input-output characteristics, layer-dependent VASO responses were investigated in the ipsilateral hemisphere during unilateral finger tapping. Positive activation in ipsilateral primary motor cortex and negative activation in ipsilateral primary sensory cortex were observed. This feature is only visible in high-resolution fMRI where opposing sides of a sulcus can be investigated independently because of a lack of partial volume effects. Based on the results presented here, we conclude that VASO offers good reproducibility, high sensitivity and lower sensitivity than GE-BOLD to changes in larger vessels, making it a valuable tool for layer-dependent fMRI studies in humans

Oxygen Polarography in the Awake Macaque: Bridging BOLD fMRI and Electrophysiology

Blood oxygen level dependent (BOLD) fMRI is the predominant method for evaluating human brain activity. This technique identifies brain activity by measuring blood oxygen changes associated with neural activity. Although clearly related, the nature of the relationship between BOLD fMRI identified brain activity and electrophysiologically measured neural activity remains unclear. Direct comparison of BOLD fMRI and electrophysiology has been severely limited by the technical challenges of combining the two techniques. Microelectrode electrophysiology in non-human primates is an excellent model for studying neural activity related to high order brain function similar to that commonly studied with BOLD fMRI in humans, i.e. attention, working memory, engagement. This thesis discusses the development of, validation of, and first results obtained using a new multi-site oxygen polarographic recording system in the awake macaques as a surrogate for BOLD fMRI. Oxygen polarography measures tissue oxygen which is coupled to blood oxygen. This tool offers higher resolution than BOLD fMRI and can be more readily combined with electrophysiology. Using this new tool we evaluated local field potential and oxygen responses to an engaging visual stimulus in two distinct brain systems. In area V3, a key region in the visual system and representative of stimulus driven sensory cortex, we show increased tissue oxygen and local field potential power in response to visual stimulus. In area 23 of the posterior cingulate cortex (PCC), a hub of the default-mode network we show decreased oxygen and local field potential in response to the same stimulus. The default-mode network is a set of brain regions identified in humans whose BOLD fMRI activity is higher at rest than during external engagement, arguing that they sub-serve a function that is engaged as the default-mode in humans. Our results provide new evidence of default-mode network activity in the macaque similar to that seen in humans, provide evidence that the BOLD identified default-mode suppression reflects neural suppression and overall support a strong relationship between neural activity and BOLD fMRI. However, we also note that the LFP responses in both regions show substantial nuances that cannot be seen in the oxygen response and suggest response complexity that is invisible with fMRI. Further the nature of the relationship between LFP and oxygen differs between regions. Our multi-site technique also allows us to evaluate inter-regional interaction of ongoing oxygen fluctuations. Inter-regional correlation of BOLD fMRI fluctuations is commonly used as an index of functional connectivity and has provided new insight into behaviorally relevant aspects of the brains organization and its disruption in disease. Here we demonstrate that we can measure the same inter-regional correlation using oxygen polarography. We utilize the increased resolution of our technique to investigate the frequency structure of the signals driving the correlation and find that inter-regional correlation of oxygen fluctuations appears to depend on a rhythmic mechanism operating at ~0.06 Hz

Multimodal imaging of human brain activity: rational, biophysical aspects and modes of integration

Until relatively recently the vast majority of imaging and electrophysiological studies of human brain activity have relied on single-modality measurements usually correlated with readily observable or experimentally modified behavioural or brain state patterns. Multi-modal imaging is the concept of bringing together observations or measurements from different instruments. We discuss the aims of multi-modal imaging and the ways in which it can be accomplished using representative applications. Given the importance of haemodynamic and electrophysiological signals in current multi-modal imaging applications, we also review some of the basic physiology relevant to understanding their relationship