Nearly everybody has seen maps of brain activity generated by functional MRI (fMRI). This method, which at its core measures blood flow-based magnetic effects on water molecules, allows researchers to map out areas of the brain based on sensory responses, motor actions, and even complex cognitive thoughts. It has, for the first time, allowed for a routine interrogation and precise localization of human brain activity during cognitive tasks. The success of fMRI in unveiling new and important properties of human brain function is undebatable, and the resulting images have had the consequence of informing the public about the brains circuits and raising interest in neuroscience more generally. Always lurking in the background, however, has been the simple fact that fMRI does not measure neural activity but only regional blood flow, whichto the extent that it is consistently coupled with neural activitycan act as a surrogate or marker for underlying electrical signals. One of the long-term goals in our laboratory is to understand the vexing relationship between hemodynamic fMRI activity and electrical neural activity. Optimistic views of this problem in the past have considered this relationship as possibly being a straightforward conversion: When given an fMRI response pattern, is there a well-defined measure of electrical activity that corresponds to it? Unfortunately, much evidence suggests that this simple translation cannot be valid, since the local coupling between blood flow and neurons is highly dependent on stimuli, contexts, and behavioral states. Moreover, given the mismatch in the dimensionality of the signals (there are roughly one million cells in a single fMRI voxel), the prospect of any one-to-one mapping seems fruitless. Nonetheless, there is much to be learned about the relationship of neurons, their various forms of electrical responses, and the local control of blood flow that indicates activity in the fMRI scanner. In the laboratory, we have focused on targeted and practical questions, leaving more specific neurovascular coupling questions (such as how neural firing leads to the local perfusion of capillaries) to other laboratories. Our studies focus on two points: first, the diversity of neural spiking activity within a single voxel, and second, the relationship of large-scale functional MRI networks to local and remote neural activity in the brain. In one project, we discovered that neurons from within a single voxel were highly varied in their responses to naturalistic movies. Important from the perspective of the basis of the fMRI signal, we further found the local blood flow activity followed only a small proportion (16%) of 150 neurons tightly packed within a single voxel < 1mm3 (Park et al., Neuron 2017). The time courses of these special neurons closely matched both the local field potential (LFP) signal and the vascular response, suggesting that they may have a particular importance for local vascular control. This result may help explain why there is often a discrepancy between local spiking activity on the one hand and LFP and fMRI activity on the other, a point we have previously made in the laboratory (Maier et al. Nature Neuroscience 2008). In another collaborative paper published this year, we similarly found fMRI activity that, although robust, seemed a mismatch compared to previously single-unit results from corresponding brain areas (Kaskan et al., 2017). These findings, while challenging for simple interpretations, gradually shape our understanding of how to interpret fMRI results. Using a rather different approach, we have undertaken several studies to explore the manner in which brain arousal is expressed, both in its electrical and fMRI responses, and also controlled by arousal structures such as the basal forebrain. Last April we published findings from our investigation of the manner in which brain arousal is simultaneously reflected in behavioral, electrophysiological, and fMRI measures (Chang et al., 2016). Specifically, we found that behavioral changes in arousal, matched by corresponding changes in the cortical field potentials, were yoked to hemodynamic fluctuations in an identified multicomponent network, or template, that could be used to read out the arousal state of an animal at each point in time. This study has important implications for the enormous number of human fMRI studies of functional connectivity, which attempt to quantify the functional relationship between areas based on the correlation of their signals. In a subsequent study employing a more causal manipulation, we have examined the effects of reversibly inactivating the basal forebrain using pharmacological agents (Turchi, Chang, et al., , in preparation). The basal forebrain is a small region that is the origin of many long-range anatomical projections that reach virtually the entire cerebral cortex. Our initial experiments, inactivating portions of this structure in animals undergoing fMRI testing, suggest that the basal forebrain is centrally involved in regulating spontaneous signals throughout the telencephalon. Its effect is particularly pronounced during transitions of arousal, gauged by eye opening and closure. Finally, through collaboration (Liu X et al., manuscript under review), we have also found evidence that the basal forebrain orchestrates important aspects of arousal fluctuations in the human brain. Together, these studies paint a new picture of spontaneous brain activity that consists of two rather different components: the first global component is orchestrated regionally by the basal forebrain long-range projections, whereas the second local component is more strongly determined by other factors, including but not limited to anatomical projections.
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