fMRI spectral signatures of sleep

Sleep can be distinguished from wake by changes in brain electrical activity, typically assessed using electroencephalography (EEG). The hallmark of nonrapid-eye-movement (NREM) sleep is the shift from high-frequency, low-amplitude wake EEG to low-frequency, high-amplitude sleep EEG dominated by spindles and slow waves. Here we identified signatures of sleep in brain hemodynamic activity, using simultaneous functional MRI (fMRI) and EEG. We found that, at the transition from wake to sleep, fMRI blood oxygen level–dependent (BOLD) activity evolved from a mixed-frequency pattern to one dominated by two distinct oscillations: a low-frequency (<0.1 Hz) oscillation prominent in light sleep and correlated with the occurrence of spindles, and a high-frequency oscillation (>0.1 Hz) prominent in deep sleep and correlated with the occurrence of slow waves. The two oscillations were both detectable across the brain but exhibited distinct spatiotemporal patterns. During the falling-asleep process, the low-frequency oscillation first appeared in the thalamus, then the posterior cortex, and lastly the frontal cortex, while the high-frequency oscillation first appeared in the midbrain, then the frontal cortex, and lastly the posterior cortex. During the waking-up process, both oscillations disappeared first from the thalamus, then the frontal cortex, and lastly the posterior cortex. The BOLD oscillations provide local signatures of spindle and slow wave activity. They may be employed to monitor the regional occurrence of sleep or wakefulness, track which regions are the first to fall asleep or wake up at the wake–sleep transitions, and investigate local homeostatic sleep processes.

Traditionally, sleep is considered to be a global state that affects the whole brain uniformly and simultaneously. Correspondingly, brain activity during human sleep is typically measured using scalp electroencephalography (EEG). The hallmark of nonrapid-eye-movement (NREM) sleep is the shift from high-frequency, low-amplitude wake EEG to low-frequency, high-amplitude sleep EEG dominated by slow waves and spindles. Slow waves are associated with the near-synchronous transitions in large populations of neurons between depolarized up states of intense firing and hyperpolarized down states of silence (1). They are generated primarily in the cerebral cortex and affect virtually all cortical neurons, as well as neurons in several subcortical structures (2). By contrast, spindles are associated with cycles of depolarization and hyperpolarization triggered by the interactions between reticular thalamic nucleus and specific thalamic nuclei and amplified by the thalamo-cortico-thalamic circuits. Based on the prominence of slow waves and spindles, NREM sleep can be subdivided into transitional (N1), intermediate (N2), and deep (N3) sleep stages.Recently, the view of sleep as a global state has been overturned by the intracranial findings of local sleep and local wakefulness (3). During wakefulness, individual neurons were found to display brief periods of slow wave activity, accompanied by transient behavioral impairments (4). Conversely, during deep NREM sleep, subsets of brain regions were found to display wake-like activity (5), which was associated with dreaming (6). These findings establish that sleep-like and wakefulness-like states are not mutually exclusive, but can occur simultaneously in the same brain, with some neuronal populations showing one state and the rest the other. They highlight the importance to monitor the local state of individual neuronal populations, as opposed to the global state of the brain as a whole. However, EEG lacks both the spatial resolution and the brain coverage required for monitoring local neuronal state. It is difficult to identify the brain regions that generate the scalp EEG signal, where different source configurations can give rise to the same EEG topography. Moreover, the scalp and the intracranial EEG signals are both insensitive to neuronal activities in deep brain structures, making it difficult to monitor the neuronal state in these brain regions.Here we employed functional MRI (fMRI) to explore, with a full brain coverage and higher spatial resolution, local signatures of sleep in brain hemodynamic activity. We reasoned that the frequency content of fMRI blood oxygen level–dependent (BOLD) activity would show systematic changes from wake to sleep, reflecting the local groupings of spindles or slow waves by infra-slow fluctuations within the frequency range of brain hemodynamic activity. Our hypothesis builds upon previous reports of BOLD spectral changes from wake to sleep. Previous studies reported increases in low-frequency BOLD activity (<0.1 Hz) from wake to light sleep (7–9), as well as increases in higher-frequency BOLD activity (>0.1 Hz) from wake to propofol anesthesia (10). Although the relationships between these BOLD spectral changes and spindle or slow wave activity were not examined, it is interesting to note that propofol anesthesia can induce slow waves similar to those of NREM sleep (11), which might underlie the observed increase in high-frequency BOLD activity; moreover, the emergence of sleep spindles during child development (12) coincides with an increase in low-frequency BOLD activity (13). These studies hinted at a possible link between BOLD frequency content and spindle or slow wave activity. However, the exact link has remained unclear.Using simultaneous fMRI and EEG, we found that, during the transition from wake to sleep, fMRI BOLD activity evolved from a mixed-frequency pattern to one dominated by two distinct oscillations: a low-frequency oscillation (<0.1 Hz) prominent in light sleep and a higher-frequency oscillation (>0.1 Hz) in deep sleep. The time courses of low-frequency and high-frequency BOLD oscillation power correlated, respectively, with the time courses of spindle and slow wave activities. Moreover, the regional distributions and the onset, offset patterns of low-frequency and high-frequency BOLD oscillation were similar to those of spindle and slow wave activity. By providing local signatures of spindle and slow wave activity, these two BOLD oscillations may be employed to monitor the local neuronal state and detect local sleep or local wakefulness.     

An approach to probe some neural systems interaction by functional MRI at neural time scale down to milliseconds

In this paper, we demonstrate an approach by which some evoked neuronal events can be probed by functional MRI (fMRI) signal with temporal resolution at the time scale of tens of milliseconds. The approach is based on the close relationship between neuronal electrical events and fMRI signal that is experimentally demonstrated in concurrent fMRI and electroencephalographic (EEG) studies conducted in a rat model with forepaw electrical stimulation. We observed a refractory period of neuronal origin in a two-stimuli paradigm: the first stimulation pulse suppressed the evoked activity in both EEG and fMRI signal responding to the subsequent stimulus for a period of several hundred milliseconds. When there was an apparent site-site interaction detected in the evoked EEG signal induced by two stimuli that were primarily targeted to activate two different sites in the brain, fMRI also displayed signal amplitude modulation because of the interactive event. With visual stimulation using two short pulses in the human brain, a similar refractory phenomenon was observed in activated fMRI signals in the primary visual cortex. In addition, for interstimulus intervals shorter than the known latency time of the evoked potential induced by the first stimulus ( approximately 100 ms) in the primary visual cortex of the human brain, the suppression was not present. Thus, by controlling the temporal relation of input tasks, it is possible to study temporal evolution of certain neural events at the time scale of their evoked electrical activity by noninvasive fMRI methodology.     

Ipsilateral cortical fMRI responses after peripheral nerve damage in rats reflect increased interneuron activity

In the weeks following unilateral peripheral nerve injury, the deprived primary somatosensory cortex (SI) responds to stimulation of the ipsilateral intact limb as demonstrated by functional magnetic resonance imaging (fMRI) responses. The neuronal basis of these responses was studied by using high-resolution fMRI, in vivo electrophysiological recordings, and juxtacellular neuronal labeling in rats that underwent an excision of the forepaw radial, median, and ulnar nerves. These nerves were exposed but not severed in control rats. Significant bilateral increases of fMRI responses in SI were observed in denervated rats. In the healthy SI of the denervated rats, increases in fMRI responses were concordant with increases in local field potential (LFP) amplitude and an increased incidence of single units responding compared with control rats. In contrast, in the deprived SI, increases in fMRI responses were associated with a minimal change in LFP amplitude but with increased incidence of single units responding. Based on action potential duration, juxtacellular labeling, and immunostaining results, neurons responding to intact forepaw stimulation in the deprived cortex were identified as interneurons. These results suggest that the increases in fMRI responses in the deprived cortex reflect increased interneuron activity.     

Coupling of the cortical hemodynamic response to cortical and thalamic neuronal activity

Accurate interpretation of functional MRI (fMRI) signals requires knowledge of the relationship between the hemodynamic response and the neuronal activity that underlies it. Here we address the question of coupling between pre- and postsynaptic neuronal activity and the hemodynamic response in rodent somatosensory (Barrel) cortex in response to single-whisker deflection. Using full-field multiwavelength optical imaging of hemoglobin oxygenation and electrophysiological recordings of spiking activity and local field potentials, we demonstrate that a point hemodynamic measure is influenced by neuronal activity across multiple cortical columns. We demonstrate that the hemodynamic response is a spatiotemporal convolution of the neuronal activation. Therefore, positive hemodynamic response in one cortical column might be explained by neuronal activity not only in that column but also in the neighboring columns. Thus, attempts at characterizing the neurovascular relationship based on point measurements of electrophysiology and hemodynamics may yield inconsistent results, depending on the spatial extent of neuronal activation. The finding that the hemodynamic signal observed at a given location is a function of electrophysiological activity over a broad spatial region helps explain a previously observed increase of local vascular response beyond the saturation of local neuronal activity. We also demonstrate that the oxy- and total-hemoglobin hemodynamic responses can be well approximated by space-time separable functions with an antagonistic center-surround spatial pattern extending over several millimeters. The surround "negative" hemodynamic activity did not correspond to observable changes in neuronal activity. The complex spatial integration of the hemodynamic response should be considered when interpreting fMRI data.     

Quantitative basis for neuroimaging of cortical laminae with calibrated functional MRI

Layer-specific neurophysiologic, hemodynamic, and metabolic measurements are needed to interpret high-resolution functional magnetic resonance imaging (fMRI) data in the cerebral cortex. We examined how neurovascular and neurometabolic couplings vary vertically in the rat’s somatosensory cortex. During sensory stimulation we measured dynamic layer-specific responses of local field potential (LFP) and multiunit activity (MUA) as well as blood oxygenation level-dependent (BOLD) signal and cerebral blood volume (CBV) and blood flow (CBF), which in turn were used to calculate changes in oxidative metabolism (CMR_O2) with calibrated fMRI. Both BOLD signal and CBV decreased from superficial to deep laminae, but these responses were not well correlated with either layer-specific LFP or MUA. However, CBF changes were quite stable across laminae, similar to LFP. However, changes in CMR_O2 and MUA varied across cortex in a correlated manner and both were reduced in superficial lamina. These results lay the framework for quantitative neuroimaging across cortical laminae with calibrated fMRI methods.The most recognizable features of the cerebral cortex across phyla are the layers (i.e., laminae) representing different cell types that project and connect to create networks, both in the horizontal and vertical directions of the cortex (1). Functional MRI (fMRI) with high-field magnets has been used to image this complex heterogeneous system of connections across cortical laminae. Given the complexity of the blood oxygenation level-dependent (BOLD) signal (2), quantitative assessment of neurophysiologic, hemodynamic, and metabolic responses across cortical laminae is needed to interpret high-resolution fMRI data in terms of neural activity. Because synaptic density (1) and commensurate electrical and chemical activities vary across cortical layers (3, 4), it is hypothesized that hemodynamic and metabolic responses would also vary. However, there are limited results on layer-specific variations in these parameters.High magnetic fields have improved BOLD sensitivity and specificity (5), whereas other MRI developments have allowed cerebral blood volume (CBV) and flow (CBF) measurements to calibrate fMRI signal so that changes in cerebral metabolic rate of oxygen consumption (CMR_O2) can be calculated with a biophysical model of BOLD (6). These multimodal fMRI techniques in conjunction with other related magnetic resonance spectroscopy methods have allowed quantitative insights into the molecular and cellular bases of neurovascular and neurometabolic couplings (7).In vivo recordings of neural activity with metal microelectrodes depict fluctuations of extracellular voltage, where the high- and low-frequency components, respectively, reflect multiunit activity (MUA) and local field potential (LFP) in a region (8). MUA is believed to reflect the output spiking activity of an ensemble of neurons because it reveals action potentials of large pyramidal neurons, whereas LFP reflects the synaptic input of a particular region because it depicts the weighted sum of changing membrane potentials along dendritic branches and soma (9, 10).To interpret the functional organization of the mammalian cerebral cortex from high-resolution fMRI data, the relation of the BOLD signal to underlying neural activities and hemodynamic or metabolic responses is needed at the laminar level. Although many animal studies have contributed to our knowledge about fMRI and its relation to multimodal functional responses (9–16), these past reports have focused primarily on dynamic correlations of signals in a specific cortical region. Here we measured the degree to which neurovascular and neurometabolic couplings vary in the vertical direction of the rat’s primary somatosensory cortex. Briefly, our results show that during sensory stimulation transcortical BOLD and CBV response patterns are uncoupled with both neural activity measures across cortical laminae, whereas neurometabolic coupling of MUA vs. CMR_O2 and neurovascular coupling of LFP vs. CBF have different spatial distributions in the superficial lamina.     

Synchronized delta oscillations correlate with the resting-state functional MRI signal

Synchronized low-frequency spontaneous fluctuations of the functional MRI (fMRI) signal have recently been applied to investigate large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations remain largely unknown. To this end, electrophysiological recordings and resting-state fMRI measurements were conducted in alpha-chloralose-anesthetized rats. Using a seed-voxel analysis strategy, region-specific, anesthetic dose-dependent fMRI resting-state functional connectivity was detected in bilateral primary somatosensory cortex (S1FL) of the resting brain. Cortical electroencephalographic signals were also recorded from bilateral S1FL; a visual cortex locus served as a control site. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in the gamma bands, the resting-state fMRI signal correlates with the power coherence in low-frequency bands, particularly the delta band. These data indicate that hemodynamic fMRI signal differentially registers specific electrical oscillatory frequency band activity, suggesting that fMRI may be able to distinguish the ongoing from the evoked activity of the brain.     

Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal

Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with “upstream” propagation of vasodilation toward the cortical surface along the diving arterioles and “downstream” propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the “initial dip” was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.     

Consistent resting-state networks across healthy subjects

Functional MRI (fMRI) can be applied to study the functional connectivity of the human brain. It has been suggested that fluctuations in the blood oxygenation level-dependent (BOLD) signal during rest reflect the neuronal baseline activity of the brain, representing the state of the human brain in the absence of goal-directed neuronal action and external input, and that these slow fluctuations correspond to functionally relevant resting-state networks. Several studies on resting fMRI have been conducted, reporting an apparent similarity between the identified patterns. The spatial consistency of these resting patterns, however, has not yet been evaluated and quantified. In this study, we apply a data analysis approach called tensor probabilistic independent component analysis to resting-state fMRI data to find coherencies that are consistent across subjects and sessions. We characterize and quantify the consistency of these effects by using a bootstrapping approach, and we estimate the BOLD amplitude modulation as well as the voxel-wise cross-subject variation. The analysis found 10 patterns with potential functional relevance, consisting of regions known to be involved in motor function, visual processing, executive functioning, auditory processing, memory, and the so-called default-mode network, each with BOLD signal changes up to 3%. In general, areas with a high mean percentage BOLD signal are consistent and show the least variation around the mean. These findings show that the baseline activity of the brain is consistent across subjects exhibiting significant temporal dynamics, with percentage BOLD signal change comparable with the signal changes found in task-related experiments.     

Cerebral energetics and spiking frequency: the neurophysiological basis of fMRI

Functional MRI (fMRI) is widely assumed to measure neuronal activity, but no satisfactory mechanism for this linkage has been identified. Here we derived the changes in the energetic component from the blood oxygenation level-dependent (BOLD) fMRI signal and related it to changes in the neuronal spiking frequency in the activated voxels. Extracellular recordings were used to measure changes in cerebral spiking frequency (Deltanu/nu) of a neuronal ensemble during forepaw stimulation in the alpha-chloralose anesthetized rat. Under the same conditions localized changes in brain energy metabolism (DeltaCMR(O2)/CMR(O2)) were obtained from BOLD fMRI data in conjunction with measured changes in cerebral blood flow (DeltaCBF/CBF), cerebral blood volume (DeltaCBV/CBV), and transverse relaxation rates of tissue water (T(2)(*) and T(2)) by MRI methods at 7T. On stimulation from two different depths of anesthesia DeltaCMR(O2)/CMR(O2) approximately Deltanu/nu. Previous (13)C magnetic resonance spectroscopy studies, under similar conditions, had shown that DeltaCMR(O2)/CMR(O2) was proportional to changes in glutamatergic neurotransmitter flux (DeltaV(cyc)/V(cyc)). These combined results show that DeltaCMR(O2)/CMR(O2) approximately DeltaV(cyc)/V(cyc) approximately Deltanu/nu, thereby relating the energetic basis of brain activity to neuronal spiking frequency and neurotransmitter flux. Because DeltaCMR(O2)/CMR(O2) had the same high spatial and temporal resolutions of the fMRI signal, these results show how BOLD imaging, when converted to DeltaCMR(O2)/CMR(O2), responds to localized changes in neuronal spike frequency.     

Total neuroenergetics support localized brain activity: implications for the interpretation of fMRI

In alpha-chloralose-anesthetized rats, changes in the blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signal (DeltaS/S), and the relative spiking frequency of a neuronal ensemble (Deltanu/nu) were measured in the somatosensory cortex during forepaw stimulation from two different baselines. Changes in cerebral oxygen consumption (DeltaCMR(O2)/CMR(O2)) were derived from the BOLD signal (at 7T) by independent determinations in cerebral blood flow (DeltaCBF/CBF) and volume (DeltaCBV/CBV). The spiking frequency was measured by extracellular recordings in layer 4. Changes in all three parameters (CMR(O2), nu, and S) were greater from the lower baseline (i.e., deeper anesthesia). For both baselines, DeltaCMR(O2)/CMR(O2) and Deltanu/nu were approximately one order of magnitude larger than DeltaS/S. The final values of CMR(O2) and nu reached during stimulation were approximately the same from both baselines. If only increments were required to support functions then their magnitudes should be independent of the baseline. In contrast, if particular magnitudes of activity were required, then sizes of increments should inversely correlate with the baseline (being larger from a lower baseline). The results show that particular magnitudes of activity support neural function. The disregard of baseline activity in fMRI experiments by differencing removes a large and necessary component of the total activity. Implications of these results for understanding brain function and fMRI experiments are discussed.     

Three-dimensional functional magnetic resonance imaging of human brain on a clinical 1.5-T scanner.

Functional magnetic resonance imaging (fMRI) is a tool for mapping brain function that utilizes neuronal activity-induced changes in blood oxygenation. An efficient three-dimensional fMRI method is presented for imaging brain activity on conventional, widely available, 1.5-T scanners, without additional hardware. This approach uses large magnetic susceptibility weighting based on the echo-shifting principle combined with multiple gradient echoes per excitation. Motor stimulation, induced by self-paced finger tapping, reliably produced significant signal increase in the hand region of the contralateral primary motor cortex in every subject tested.     

Transients may occur in functional magnetic resonance imaging without physiological basis

Functional magnetic resonance imaging (fMRI) has revolutionized the study of human brain activity, in both basic and clinical research. The commonly used blood oxygen level dependent (BOLD) signal in fMRI derives from changes in oxygen saturation of cerebral blood flow as a result of brain activity. Beyond the traditional spatial mapping of stimulus–activation correspondences, the detailed waveforms of BOLD responses are of high interest. Especially intriguing are the transient overshoots and undershoots, often, although inconclusively, attributed to the interplay between changes in cerebral blood flow and volume after neuronal activation. While physically simulating the BOLD response in fMRI phantoms, we encountered prominent transient deflections, although the magnetic field inside the phantom varied in a square-wave manner. Detailed analysis and modeling indicated that the transients arise from activation-related partial misalignment of the imaging slices and depend heavily on measurement parameters, such as the time between successive excitations. The results suggest that some transients encountered in normal fMRI recordings may be spurious, potentially compromising the physiological interpretation of BOLD signal overshoots and undershoots.     

Optogenetic-guided cortical plasticity after nerve injury

Peripheral nerve injury causes sensory dysfunctions that are thought to be attributable to changes in neuronal activity occurring in somatosensory cortices both contralateral and ipsilateral to the injury. Recent studies suggest that distorted functional response observed in deprived primary somatosensory cortex (S1) may be the result of an increase in inhibitory interneuron activity and is mediated by the transcallosal pathway. The goal of this study was to develop a strategy to manipulate and control the transcallosal activity to facilitate appropriate plasticity by guiding the cortical reorganization in a rat model of sensory deprivation. Since transcallosal fibers originate mainly from excitatory pyramidal neurons somata situated in laminae III and V, the excitatory neurons in rat S1 were engineered to express halorhodopsin, a light-sensitive chloride pump that triggers neuronal hyperpolarization. Results from electrophysiology, optical imaging, and functional MRI measurements are concordant with that within the deprived S1, activity in response to intact forepaw electrical stimulation was significantly increased by concurrent illumination of halorhodopsin over the healthy S1. Optogenetic manipulations effectively decreased the adverse inhibition of deprived cortex and revealed the major contribution of the transcallosal projections, showing interhemispheric neuroplasticity and thus, setting a foundation to develop improved rehabilitation strategies to restore cortical functions.     

The effect of a serotonin-induced dissociation between spiking and perisynaptic activity on BOLD functional MRI

The relationship of the blood oxygen-level-dependent (BOLD) signal to its underlying neuronal activity is still poorly understood. Combined physiology and functional MRI experiments suggested that local field potential (LFP) is a better predictor of the BOLD signal than multiunit activity (MUA). To further explore this relationship, we simultaneously recorded BOLD and electrophysiological activity while inducing a dissociation of MUA from LFP activity with injections of the neuromodulator BP554 into the primary visual cortex of anesthetized monkeys. BP554 is a 5-HT1A agonist acting primarily on the membrane of efferent neurons by potassium-induced hyperpolarization. Its infusion in visual cortex reliably reduced MUA without affecting either LFP or BOLD activity. This finding suggests that the efferents of a neuronal network pose relatively little metabolic burden compared with the overall presynaptic and postsynaptic processing of incoming afferents. We discuss implications of this finding for the interpretation of BOLD activity.     

Initial localization of the memory trace for a basic form of learning.

Electrophysiological recording of neuronal unit activity during paired training trials from various regions of the ipsilateral cerebellum in rabbits well trained in the classically conditioned eyelid/nictitating membrane response have revealed both stimulus-evoked responses and responses that form an amplitude/temporal model of the learned behavioral response. Ablation of the ipsilateral, lateral cerebellum completely and permanently abolished the behavioral conditioned response in well-trained animals but had no effect at all on the unconditioned reflex response. In marked contrast, conditioned responses were easily trained in the eye contralateral to the cerebellar lesion. We suggest that at least part of the essential neuronal plasticity that codes the learned response may be localized to the cerebellum.     

Negative blood oxygenation level dependent homunculus and somatotopic information in primary motor cortex and supplementary motor area

A crucial attribute in movement encoding is an adequate balance between suppression of unwanted muscles and activation of required ones. We studied movement encoding across the primary motor cortex (M1) and supplementary motor area (SMA) by inspecting the positive and negative blood oxygenation level-dependent (BOLD) signals in these regions. Using periodic and event-related experiments incorporating the bilateral/axial movements of 20 body parts, we report detailed mototopic imaging maps in M1 and SMA. These maps were obtained using phase-locked analysis. In addition to the positive BOLD, significant negative BOLD was detected in M1 but not in the SMA. The negative BOLD spatial pattern was neither located at the ipsilateral somatotopic location nor randomly distributed. Rather, it was organized somatotopically across the entire homunculus and inversely to the positive BOLD, creating a negative BOLD homunculus. The neuronal source of negative BOLD is unclear. M1 provides a unique system to test whether the origin of negative BOLD is neuronal, because different arteries supply blood to different regions in the homunculus, ruling out blood-stealing explanations. Finally, multivoxel pattern analysis showed that positive BOLD in M1 and SMA and negative BOLD in M1 contain somatotopic information, enabling prediction of the moving body part from inside and outside its somatotopic location. We suggest that the neuronal processes underlying negative BOLD participate in somatotopic encoding in M1 but not in the SMA. This dissociation may emerge because of differences in the activity of these motor areas associated with movement suppression.     

Laminar specificity of functional MRI onset times during somatosensory stimulation in rat

The blood oxygenation level-dependent (BOLD) response to somatosensory stimulation was measured in alpha-chloralose-anesthetized rats. BOLD fMRI was obtained at 40-ms temporal resolution and spatial resolution of 200 x 200 x 2,000 microm(3) by using a gated activation paradigm in an 11.7 T MRI. Results show a consistent heterogeneity of fMRI onset times and amplitudes. The earliest onset time (0.59 +/- 0.17 s, n = 9) corresponded anatomically to layer IV, with superficial and deeper layers starting significantly later (1.27 +/- 0.43 s in layers I-III, and 1.11 +/- 0.45 s in layer VI). The amplitude of BOLD signal changes also varied with the cortical depth from the pial surface. Changes in the supragranular layers (8.3%) were 44% bigger than changes in the intermediate layers (5.5%), located only approximately 700 microm below, and 144% larger than the bottom layer (3.5%), located approximately 1.4 mm below the pial surface. The data presented demonstrate that BOLD signal changes have distinct amplitude and temporal characteristics, which vary spatially across cortical layers.     

Impaired renorenal reflexes in spontaneously hypertensive rats

In normotensive Sprague-Dawley rats stimulation of renal mechanoreceptors and chemoreceptors by increasing ureteral pressure and retrograde ureteropelvic perfusion with 0.9 M NaCl results in a contralateral inhibitory renorenal reflex response with contralateral diuresis and natriuresis. Since efferent renal nerve activity is increased in spontaneously hypertensive rats (SHR) and renal denervation delays the onset of hypertension in SHR in association with increased diuresis and natriuresis, the present study was undertaken to examine whether renorenal reflexes were altered in SHR compared with normotensive Wistar-Kyoto rats (WKY). In WKY mean arterial pressure was 113 +/- 2 mm Hg and remained unchanged during renal mechanoreceptor and chemoreceptor stimulation. Increasing ureteral pressure 35 mm Hg increased ipsilateral afferent renal nerve activity 4.5 +/- 1.7 resets/min, decreased contralateral efferent renal nerve activity 3.2 +/- 0.8 resets/min, and increased contralateral urine flow rate 33 +/- 4% and urinary sodium excretion 49 +/- 8%. Similarly, retrograde ureteropelvic perfusion with 0.9 M NaCl increased ipsilateral afferent renal nerve activity 2.5 +/- 0.6 resets/min, decreased contralateral efferent renal nerve activity 2.4 +/- 1.1 resets/min, and increased contralateral urine flow rate 39 +/- 5% and urinary sodium excretion 38 +/- 8%. Stimulating renal mechanoreceptors and chemoreceptors to the same extent in SHR failed to increase ipsilateral afferent renal nerve activity, decrease contralateral efferent renal nerve activity, and produce a contralateral diuresis and natriuresis. It is concluded that renorenal reflexes are impaired in SHR. Failure of ipsilateral afferent renal nerve activity to increase during renal mechanoreceptor and chemoreceptor stimulation indicates a peripheral defect at the level of the renal sensory receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-course of Changes in Activation Among Facial Nerve Injury: A Functional Imaging Study

Patients suffering different intervals of facial nerve injury were investigated by functional magnetic resonance imaging to study changes in activation within cortex.Forty-five patients were divided into 3 groups based on intervals of facial nerve injury. Another 16 age and sex-matched healthy participants were included as a control group. Patients and healthy participants underwent task functional magnetic resonance imaging (eye blinking and lip pursing) examination.Functional reorganization after facial nerve injury is dynamic and time-dependent. Correlation between activation in sensorimotor area and intervals of facial nerve injury was significant, with a Pearson correlation coefficient of −0.951 (P < 0.001) in the left sensorimotor area and a Pearson correlation coefficient of 0.333 (P = 0.025) in the right sensorimotor area.Increased activation in integration areas, such as supramarginal gyrus and precunes lobe, could be detected in the early-middle stage of facial dysfunction compared with normal individuals. Decreased activation in sensorimotor area contralateral to facial nerve injury could be found in late stage of facial dysfunction compared with normal individuals. Dysfunction in the facial nerve has devastating effects on the activity of sensorimotor areas, whereas enhanced intensity in the sensorimotor area ipsilateral to the facial nerve injury in middle stage of facial dysfunction suggests the possible involvement of interhemispheric reorganization. Behavioral or brain stimulation technique treatment in this stage could be applied to alter reorganization within sensorimotor area in the rehabilitation of facial function, monitoring of therapeutic efficacy, and improvement in therapeutic intervention along the course of recovery.     

Early fMRI responses to somatosensory and optogenetic stimulation reflect neural information flow

Blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to localize brain functions. To further advance understanding of brain functions, it is critical to understand the direction of information flow, such as thalamocortical versus corticothalamic projections. For this work, we performed ultrahigh spatiotemporal resolution fMRI at 15.2 T of the mouse somatosensory network during forepaw somatosensory stimulation and optogenetic stimulation of the primary motor cortex (M1). Somatosensory stimulation induced the earliest BOLD response in the ventral posterolateral nucleus (VPL), followed by the primary somatosensory cortex (S1) and then M1 and posterior thalamic nucleus. Optogenetic stimulation of excitatory neurons in M1 induced the earliest BOLD response in M1, followed by S1 and then VPL. Within S1, the middle cortical layers responded to somatosensory stimulation earlier than the upper or lower layers, whereas the upper cortical layers responded earlier than the other two layers to optogenetic stimulation in M1. The order of early BOLD responses was consistent with the canonical understanding of somatosensory network connections and cannot be explained by regional variabilities in the hemodynamic response functions measured using hypercapnic stimulation. Our data demonstrate that early BOLD responses reflect the information flow in the mouse somatosensory network, suggesting that high-field fMRI can be used for systems-level network analyses.

Blood oxygenation level–dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to localize brain regions and networks associated with sensation, perception, and behavior (1–3). Different functional brain regions are connected through feedforward and feedback, ascending and descending, or bottom-up and top-down projections within the network (4). Therefore, it is critical to determine the direction of information flow to better understand brain functions. However, BOLD fMRI response, which is sensitive to vascular density and baseline physiological parameters (5), varies among brain regions and subjects (6, 7). For example, a region with large draining veins has a BOLD fMRI response that is delayed by a few seconds compared with a region that contains only capillaries within the parenchyma (8–10). Consequently, it has been argued that the order of neural events that occur within a few to tens of milliseconds of one another can be biased in fMRI dynamics due to regionally variable hemodynamic response functions (HRFs) (11).One ultimate goal of fMRI research is to demonstrate the causality and temporal sequences of neural events in humans (12). Because the contribution of capillaries to BOLD fMRI increases with the magnetic field strength, we hypothesized that early hemodynamic responses at ultrahigh fields would reflect the timing of neural activation. During forepaw somatosensory stimulation in rats, the earliest fMRI response was observed in the thalamocortical (TC) input layer 4 (L4) within the primary somatosensory cortex (S1) (13–16), suggesting that early fMRI signals reflect synaptic input. However, differences in the BOLD onset responses between layers or regions could be related to differences in their HRFs. Thus, a systematic study of different neural processing orders is crucial to determine whether the onset times of BOLD fMRI responses indeed follow the order of neural events in functional interconnected regions that include thalamic nuclei with potentially different HRFs.To investigate whether early BOLD response timing reflects the direction of neural information flow, we performed high spatiotemporal–resolution fMRI at an ultrahigh magnetic field of 15.2 T while conducting somatosensory stimulation, optogenetic stimulation, and a vascular challenge in lightly anesthetized mice. Forepaw somatosensory stimulation induced significant BOLD fMRI responses across multiple interconnected brain regions, including the ventral posterolateral nucleus (VPL), the posterior complex of the thalamic nucleus (PO), S1, and the primary motor cortex (M1) (17), among which the expected information flow is VPL → S1 → M1 (18, 19). To investigate whether the early BOLD responses were reversed when the activation sequence was reversed, we performed optogenetic stimulation of excitatory neurons in M1. In addition, to investigate whether the differences in onset times among brain regions were driven by different HRFs, we used hypercapnic challenge–induced vasodilation as a vascular control condition (20, 21). The dynamic characteristics of the BOLD responses were compared among the active somatosensory regions and among the cortical layers of S1. We found that the order of onset times among the active regions and layers clearly coincided with the known sequence of neural activation, indicating that early BOLD fMRI responses can be used to identify the direction of neural information flow.