Functional magnetic resonance imaging (fMRI) has gained widespread use and critical importance as a tool for human brain imaging in both clinical and basic science settings. Despite its importance, the interpretation of the fMRI signal—particularly, its relation to neuronal activity—remains uncertain. The prevalent assumption is that the underlying brain hemodynamics reflect local neuronal activity and the resultant metabolic demand. An alternate hypothesis—forming the basis of the current proposal—states that the hemodynamic signal is not driven just by local metabolic demand. Rather, a significant component of the hemodynamic signal is due to temporal anticipation of expected events, independent of local neuronal activity. A corollary to this hypothesis is that the anticipatory hemodynamic signal is part of an arousal mechanism that prepares the brain for predicted events.
This hypothesis derives from a recent finding in our laboratory, using a novel brain imaging technique that measures cortical blood volume and blood oxygenation simultaneously. Using this technique, we have discovered a novel hemodynamic signal that is comparable in strength to stimulus-evoked responses, but is independent of local neuronal activity. When imaging V1 in alert behaving macaques engaged in a regular, periodic visual task, we find that V1 prepares for action by pumping in fresh arterial blood in temporal anticipation of the upcoming task. This preparatory hemodynamic signal is driven by a timing mechanism that entrains to the predicted onset of each trial of the periodic task. The signal is independent of visual stimulation and V1 spiking activity. It is seen even in complete darkness, and simultaneous electrode recordings show no trial-related spiking.
The signal is modality specific. When the monkeys perform a periodic auditory discrimination task rather than a visual task, V1 no longer shows the same periodic arterial pumping signal although it does show a BOLD-like oxygenation response. The V1 hemodynamic signal is accompanied by trial-linked changes in heart rate and pupillary dilation. This hitherto-unknown hemodynamic signal could be a rapid, trial-linked arousal mechanism with two components—one component that is present in all periodic tasks, entraining heart rate, pupil dilation and blood oxygenation, and another that entrains specifically to periodic visual tasks, engaging a periodic arterial pumping mechanism in V1.
This novel finding offers a remarkable example of a strong hemodynamic signal with possibly no local neuronal correlate. Studying this signal will give unique insights into the connections—or lack thereof—between neuroimaging signals and local neuronal activity. Further, the possible role of this signal as an arousal mechanism will give new insights into brain responses. Here we plan to characterize this signal and study its relation to neuronal activity and to fMRI using the following steps:
- Using simultaneous electrophysiology (multi-unit activity, LFP and EEG) and dual-wavelength optical imaging we will first confirm that our observed trial-related hemodynamic signal is not driven by local neuronal spiking. To test whether the trial-related signal is an anticipatory arousal mechanism we will then see if the cortical response to visual stimuli—i.e. V1 responsivity—is correlated with the amplitude of the trial-related signal.
- With fMRI in monkeys performing fixation tasks in a dark room, we will first confirm the presence of trial-related BOLD signals in V1. With whole-brain imaging we will also look for trial-related BOLD activity in other brain regions and for other task modalities. Further, we will image brain stem locations in an attempt to identify the source of the trial timing signal.
- We will measure fMRI responses in human subjects engaged in the same dark-room fixation task, to look for human correlates of the monkey results.
The results of this project are likely to have a major impact on our understanding of the brain. First, our findings could lead to a dramatic shift in the interpretation of the neuroimaging signal in terms of underlying neuronal activity. Second, this novel predictive hemodynamic signal could provide new insights into brain functioning and open up new channels of inquiry about the fine control of brain arousal states and their possible disorders.