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The mammalian neocortex exhibits a stereotypical laminar organization, with feedforward inputs arriving primarily into layer 4, local computations shaping response selectivity in layers 2/3, and outputs to other brain areas emanating via layers 2/3, 5 and 6. It cannot be assumed a priori that these signatures of laminar differences in neuronal circuitry are reflected in hemodynamic signals that form the basis of functional magnetic resonance imaging (fMRI). Indeed, optical imaging of single-vessel functional responses has highlighted the potential limits of using vascular signals as surrogates for mapping the selectivity of neural responses. Therefore, before fMRI can be employed as an effective tool for studying critical aspects of laminar processing, validation with single-vessel resolution is needed. The primary visual cortex (V1) in cats, with its precise neuronal functional micro-architecture, offers an ideal model system to examine laminar differences in stimulus selectivity across imaging modalities. Here we used cerebral blood volume weighted (wCBV) fMRI to examine if layer-specific orientation-selective responses could be detected in cat V1. We found orientation preference maps organized tangential to the cortical surface that typically extended across depth in a columnar fashion. We then examined arterial dilation and blood velocity responses to identical visual stimuli by using two- and three- photon optical imaging at single-vessel resolution-which provides a measure of the hemodynamic signals with the highest spatial resolution. Both fMRI and optical imaging revealed a consistent laminar response pattern in which orientation selectivity in cortical layer 4 was significantly lower compared to layer 2/3. This systematic change in selectivity across cortical layers has a clear underpinning in neural circuitry, particularly when comparing layer 4 to other cortical layers., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Many brain diseases have been linked to abnormal oxygen metabolism and blood perfusion; nevertheless, there is still a lack of robust diagnostic tools for directly imaging cerebral metabolic rate of oxygen (CMRO(2)) and cerebral blood flow (CBF), as well as the oxygen extraction fraction (OEF) that reflects the balance between CMRO(2) and CBF. This study employed the recently developed in vivo (17)O MR spectroscopic imaging to simultaneously assess CMRO(2), CBF and OEF in the brain using a preclinical middle cerebral arterial occlusion mouse model with a brief inhalation of (17)O-labeled oxygen gas. The results demonstrated high sensitivity and reliability of the noninvasive (17)O-MR approach for rapidly imaging CMRO(2), CBF and OEF abnormalities in the ischemic cortex of the MCAO mouse brain. It was found that in the ischemic brain regions both CMRO(2) and CBF were substantially lower than that of intact brain regions, even for the mildly damaged brain regions that were unable to be clearly identified by the conventional MRI. In contrast, OEF was higher in the MCAO affected brain regions. This study demonstrates a promising (17)O MRI technique for imaging abnormal oxygen metabolism and perfusion in the diseased brain regions. This (17)O MRI technique is advantageous because of its robustness, simplicity, noninvasiveness and reliability: features that are essential to potentially translate it to human patients for early diagnosis and monitoring of treatment efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Despite the essential role of the brain energy generated from ATP hydrolysis in supporting cortical neuronal activity and brain function, it is challenging to noninvasively image and directly quantify the energy expenditure in the human brain. In this study, we applied an advanced in vivo(31)P MRS imaging approach to obtain regional cerebral metabolic rates of high-energy phosphate reactions catalyzed by ATPase (CMR(ATPase)) and creatine kinase (CMR(CK)), and to determine CMR(ATPase) and CMR(CK) in pure gray mater (GM) and white mater (WM), respectively. It was found that both ATPase and CK rates are three times higher in GM than WM; and CMR(CK) is seven times higher than CMR(ATPase) in GM and WM. Among the total brain ATP consumption in the human cortical GM and WM, 77% of them are used by GM in which approximately 96% is by neurons. A single cortical neuron utilizes approximately 4.7 billion ATPs per second in a resting human brain. This study demonstrates the unique utility of in vivo(31)P MRS imaging modality for direct imaging of brain energy generated from ATP hydrolysis, and provides new insights into the human brain energetics and its role in supporting neuronal activity and brain function., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To investigate whether individuals' ongoing neuronal activity at resting state can affect their response to brain stimulation, fMRI BOLD signals were imaged from the human visual cortex of fifteen healthy subjects in the absence and presence of visual stimulation. It was found that the temporal correlation strength but not amplitude of baseline BOLD signal fluctuations acquired under the eyes-fixed condition is positively correlated with the amplitude of stimulus-evoked BOLD responses across subjects. Moreover, the spatiotemporal correlations of baseline BOLD signals imply a coherent network covering the visual system, which is topographically indistinguishable from the "resting-state visual network" observed under the eyes-closed condition. The overall findings suggest that the synchronization of ongoing brain activity plays an important role in determining stimulus-evoked brain activity even at an early stage of the sensory system. The tight relationship between baseline BOLD correlation and stimulus-evoked BOLD amplitude provides an essential basis for understanding and interpreting the large inter-subject BOLD variability commonly observed in numerous fMRI studies and potentially for improving group fMRI analysis. This study highlights the importance to integrate the information from both resting-state coherent networks and task-evoked neural responses for a better understanding of how the brain functions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In this work, we exploited the superior capability of high-resolution functional magnetic resonance imaging (fMRI) for functional mapping of ocular dominance layer (ODL) in the cat lateral geniculate nucleus (LGN). The stimulus-evoked neuronal activities in the LGN ODLs associated with contralateral- and ipsilateral-eye visual inputs were successfully differentiated and mapped using both blood-oxygenation-level dependent (BOLD)-weighted and cerebral blood volume (CBV)-weighted fMRI methods. The morphology of mapped LGN ODLs was in remarkable consistency with histology findings in terms of ODL shape, orientation, thickness and eye-dominance. Compared with the BOLD signal, the CBV signal provides higher reproducibility and better spatial resolvability for function mapping of LGN because of improved contrast-to-noise ratio and point-spread function. The capability of fMRI for non-invasively imaging the functional sub-units of ODL in a small LGN overcomes the limitation of conventional neural-recording approach, and it opens a new opportunity for studying critical roles of LGN in brain function and dysfunction at the fine scale of ocular dominance layer., (2010 Elsevier Inc. All rights reserved.)

The relationship between the blood-oxygenation-level dependent (BOLD) signal and its underlying neuronal activity is still inconclusive. The task of completely understanding this relationship has been encumbered not only by the complexity of neuronal responses, but also by nonlinear characteristics of the vascular response that are not correlated to neural activity. Repeated stimuli inducing replicable neural responses led to successively smaller BOLD amplitudes and delayed BOLD onset latencies when inter-stimulus intervals (ISIs) are shorter than 4-6 s, indicating significant nonlinearity between the BOLD signal and the underlying neuronal activity. We have provided evidence that large-vessel BOLD contributions could be the source of the nonlinearity (Zhang, N., Zhu, X.H., Chen, W., 2008b. Investigating the source of BOLD nonlinearity in human visual cortex in response to paired visual stimuli. Neuroimage 43, 204-212). By utilizing the spin-echo (SE) BOLD fMRI method at high magnetic fields to suppress large-vessel BOLD contributions, we found that the BOLD signal from the micro-vascular activity is replicable in response to replicated neuronal activities even at ISIs as short as approximately 1 s, suggesting that the micro-vascular BOLD activity is essentially a linear system. These results indicate that micro-vascular BOLD signals should provide an accurate estimate of the amplitude of neuronal activity changes. Consequently, the findings are important in understanding and resolving the controversy in the neurovascular coupling relationship. In addition, the difference in BOLD response times between macro- and micro-vascular activities demonstrated herein will have a significant impact on functional connectivity and causality studies. Moreover, SE fMRI at high fields, due to its capability of accurately representing the strength of neural activity as well as its previously shown high spatial specificity to activated brain regions, is an ideal choice for mapping brain function and quantifying the stimulus-evoked brain activity noninvasively.

Several studies have demonstrated significant nonlinearity in the blood-oxygenation-level-dependent (BOLD) signal. Completely understanding the nature of this nonlinear behavior is important in the interpretation of the BOLD signal. However, this task is hindered by the uncertainty of the source of BOLD nonlinearity which could come from neuronal and/or vascular origin. The obscurity of this issue not only impedes accurate modeling of BOLD nonlinearity, but also limits generalization of the conclusions regarding BOLD nonlinearity. To examine this issue, we eliminated nonlinear contributions from the neuronal response and selectively study BOLD nonlinearity under only the vascular effect by employing a paired-stimulus paradigm composed of two ultra-short visual stimuli separated by a variable inter-stimulus interval (ISI). ISIs chosen were long enough (> or = 1s) to ensure invariant neuronal activity to all stimuli. Under this circumstance, we still observed significant nonlinearity in the BOLD signal reflected by a progressive recovery of BOLD response to the second stimuli as ISI gets longer and delayed BOLD onset latency. These nonlinear behaviors identified in the BOLD signal originate entirely from the vascular responses as the neuronal responses to all stimuli are identical. More importantly, we found that BOLD nonlinearity became much less significant after we removed activated pixels from large vessels. These finds reveal that the dominant component, if not all, of the source of BOLD nonlinearity comes from large-vessel hemodynamic response. They also suggest a possible mechanism to improve the spatial specificity of gradient-echo BOLD signal for fMRI mapping based on the characteristics of vascular refractoriness.

To date there is still no proper neuroimaging methods suitable for noninvasively providing both detailed spatial and temporal information of neural interaction across large-scale brain networks. This limitation has impeded the advance of neuroscience research. In an attempt to overcome this challenge, Ogawa et al. applied a paired-stimulus paradigm, which is composed of a pair of stimuli separated by a variable inter-stimulus interval (ISI), to decode temporal information of neural interaction from amplitude modulation of the blood-oxygenation-level-dependent (BOLD) responses elicited by the neural interaction pursued [Ogawa, S., Lee, T.-M., Stepnoski, R., Chen, W., Zhu, X.H., Ugurbil, K., 2000. An approach to probe neural systems interaction by functional MRI at neural time scale down to milliseconds. Proc. Natl. Acad Sci. U S A 97, 11026-11031.]. Although application of this paradigm has been demonstrated in a few publications, most of them only focused on investigating cortico-cortical interaction. Considering the vital roles that cortico-thalamic networks play in brain communication and function, extending the applicability of this method to studying cortico-thalamic neural interaction should be significant. In this study, we applied the paired-visual-stimulus paradigm to simultaneously measure the BOLD amplitude modulations as a function of ISI in the lateral geniculate nucleus (LGN) and primary visual cortex (V1) in the cat brain. The results reveal that both V1 and LGN BOLD responses were significantly suppressed when the visual system was within the refractory period at ISI

Stimulus-response compatibility (SRC) is a general term describing the relationship between a triggering stimulus and its associated motor response. The relationship between stimulus and response can be manipulated at the level of the set of stimulus and response characteristics (set-level) or at the level of the mapping between the individual elements of the stimulus and response sets (element-level). We used functional magnetic resonance imaging (fMRI) to investigate the effects of SRC on functional activation in cortical motor areas. Using behavioral tasks to separately evaluate set- and element-level compatibility, and their interaction, we measured the volume of functional activation in 11 cortical motor areas, in the anterior frontal cortex, and in the superior temporal lobe. Element-level compatibility effects were associated with significant activation in the pre-supplementary motor area (preSMA), the dorsal (PMd) and ventral (PMv) premotor areas, and the parietal areas (inferior, superior, intraparietal sulcus, precuneus). The activation was lateralized to the right hemisphere for most of the areas. Set-level compatibility effects resulted in significant activation in the inferior frontal gyri, anterior cingulate and cingulate motor areas, the PMd, PMv, preSMA, the parietal areas (inferior, superior, intraparietal sulcus, precuneus), and in the superior temporal lobe. Activation in the majority of these areas was lateralized to the left hemisphere. Finally, there was an interaction between set and element-level compatibility in the middle and superior frontal gyri, in an area co-extensive with the dorsolateral prefrontal cortex, suggesting that this area provided the neural substrate for common processing stages, such as working memory and attention, which are engaged when both levels of SRC are manipulated at once., (Copyright 2001 Academic Press.)