Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is widely used in neuroscience to study brain activity. However, BOLD fMRI does not measure neuronal activity directly but depends on cerebral blood flow (CBF), cerebral blood volume (CBV), and cerebral metabolic rate of oxygen (CMRO(2)) consumption. Using fMRI, CBV, CBF, neuronal recordings, and CMRO(2) modeling, we investigated how the signals are related during seizures in rats. We found that increases in hemodynamic, neuronal, and metabolic activity were associated with positive BOLD signals in the cortex, but with negative BOLD signals in hippocampus. Our data show that negative BOLD signals do not necessarily imply decreased neuronal activity or CBF, but can result from increased neuronal activity, depending on the interplay between hemodynamics and metabolism. Caution should be used in interpreting fMRI signals because the relationship between neuronal activity and BOLD signals may depend on brain region and state and can be different during normal and pathological conditions.

Energetics of resting and evoked fMRI signals were related to localized ensemble firing rates () measured by electrophysiology in rats. Two different unstimulated, or baseline, states were established by anesthesia. Halothane and ␣-chloralose established baseline states of high and low energy, respectively, in which forepaw stimulation excited the contralateral primary somatosensory cortex (S1). With ␣-chloralose, forepaw stimulation induced strong and reproducible fMRI activations in the contralateral S1, where the ensemble firing was dominated by slow signaling neurons (SSN; range of 1-13 Hz). Under halothane, weaker and less reproducible fMRI activations were observed in the contralateral S1 and elsewhere in the cortex, but ensemble activity in S1 was dominated by rapid signaling neurons (RSN; range of 13-40 Hz). For both baseline states, the RSN activity (i.e., higher frequencies, including the ␥ band) did not vary upon stimulation, whereas the SSN activity (i.e., ␣ band and lower frequencies) did change. In the high energy baseline state, a large majority of total oxidative energy [cerebral metabolic rate of oxygen consumption (CMR O2)] was devoted to RSN activity, whereas in the low energy baseline state, it was roughly divided between SSN and RSN activities. We hypothesize that in the high energy baseline state, the evoked changes in fMRI activation in areas beyond S1 are supported by rich intracortical interactions represented by RSN. We discuss implications for interpreting fMRI data where stimulus-specific ⌬CMR O2 is generally small compared with baseline CMR O2.awake ͉ behavior ͉ calibrated fMRI ͉ glucose ͉ glutamate N oninvasive NMR and electrophysiological methods offer considerably different spatiotemporal results that presumably reflect the same cerebral activity. Localized energy consumption of neuronal and glial populations in MRI voxels has been evaluated (1), initially from 13 C MRS (2) and more recently from calibration of functional MRI (fMRI) (3). In vivo electrophysiological measurements of neuronal activity, from single neurons or large ensembles (4), are considered the gold standard of cerebral activity (5). Can measurements from these dissimilar techniques provide complementary insights into the working brain?A promising convergence between these apparently different results relies on a universal thermodynamic principle, the fundamental relationship between the work done and the energy expended. Cerebral energy comes almost exclusively from glucose oxidation (6). Recent results have shown that the cerebral metabolic rate of oxygen consumption (CMR O2 ) is almost completely dedicated to supporting work associated with synaptic activity (7,8). Changes in CMR O2 from calibrated fMRI (9) are linear with changes in firing rates of a representative neuronal ensemble in the same voxel (10). This basic work/ energy relationship has been extended by in vivo investigations (11, 12) that relate imaging energetics to the underlying neuronal activities.Neuroimaging methods localize changes of task-i...

SUMMARY Impaired consciousness in temporal lobe seizures has a major negative impact on quality of life. The prevailing view holds that this disorder impairs consciousness by seizure spread to the bilateral temporal lobes. We propose instead that seizures invade subcortical regions and depress arousal, causing impairment through decreases rather than through increases in activity. Using functional magnetic resonance imaging in a rodent model, we found increased activity in regions known to depress cortical function including lateral septum and anterior hypothalamus. Importantly, we found suppression of intralaminar thalamic and brainstem arousal systems and suppression of the cortex. At a cellular level, we found reduced firing of identified cholinergic neurons in the brainstem pedunculopontine tegmental nucleus and basal forebrain. Finally, we used enzyme-based amperometry to demonstrate reduced cholinergic neurotransmission in both cortex and thalamus. Decreased subcortical arousal is a novel mechanism for loss of consciousness in focal temporal lobe seizures.