Critical Changes in Cortical Neuronal Interactions in Anesthetized and Awake Rats.

BACKGROUND: Neuronal interactions are fundamental for information processing, cognition, and consciousness. Anesthetics reduce spontaneous cortical activity; however, neuronal reactivity to sensory stimuli is often preserved or augmented. How sensory stimulus-related neuronal interactions change under anesthesia has not been elucidated. In this study, the authors investigated the visual stimulus-related cortical neuronal interactions during stepwise emergence from desflurane anesthesia. METHODS: Parallel spike trains were recorded with 64-contact extracellular microelectrode arrays from the primary visual cortex of chronically instrumented, unrestrained rats (N = 6) at 8, 6, 4, and 2% desflurane anesthesia and wakefulness. Light flashes were delivered to the retina by transcranial illumination at 5- to 15-s randomized intervals. Information theoretical indices, integration and interaction complexity, were calculated from the probability distribution of coincident spike patterns and used to quantify neuronal interactions before and after flash stimulation. RESULTS: Integration and complexity showed significant negative associations with desflurane concentration (N = 60). Flash stimulation increased integration and complexity at all anesthetic levels (N = 60); the effect on complexity was reduced in wakefulness. During stepwise withdrawal of desflurane, the largest increase in integration (74%) and poststimulus complexity (35%) occurred before reaching 4% desflurane concentration-a level associated with the recovery of consciousness according to the rats' righting reflex. CONCLUSIONS: Neuronal interactions in the cerebral cortex are augmented during emergence from anesthesia. Visual flash stimuli enhance neuronal interactions in both wakefulness and anesthesia; the increase in interaction complexity is attenuated as poststimulus complexity reaches plateau. The critical changes in cortical neuronal interactions occur during transition to consciousness.

Comparison of randomized multifocal mapping and temporal phase mapping of visual cortex for clinical use.

fMRI is becoming an important clinical tool for planning and guidance of surgery to treat brain tumors, arteriovenous malformations, and epileptic foci. For visual cortex mapping, the most popular paradigm by far is temporal phase mapping, although random multifocal stimulation paradigms have drawn increased attention due to their ability to identify complex response fields and their random properties. In this study we directly compared temporal phase and multifocal vision mapping paradigms with respect to clinically relevant factors including: time efficiency, mapping completeness, and the effects of noise. Randomized, multifocal mapping accurately decomposed the response of single voxels to multiple stimulus locations and made correct retinotopic assignments as noise levels increased despite decreasing sensitivity. Also, multifocal mapping became less efficient as the number of stimulus segments (locations) increased from 13 to 25 to 49 and when duty cycle was increased from 25% to 50%. Phase mapping, on the other hand, activated more extrastriate visual areas, was more time efficient in achieving statistically significant responses, and had better sensitivity as noise increased, though with an increase in systematic retinotopic mis-assignments. Overall, temporal phase mapping is likely to be a better choice for routine clinical applications though random multifocal mapping may offer some unique advantages for selected applications.

Monosynaptic functional connectivity in cerebral cortex during wakefulness and under graded levels of anesthesia.

The balance between excitation and inhibition is considered to be of significant importance for neural computation and cognitive function. Excitatory and inhibitory functional connectivity in intact cortical neuronal networks in wakefulness and graded levels of anesthesia has not been systematically investigated. We compared monosynaptic excitatory and inhibitory spike transmission probabilities using pairwise cross-correlogram (CCG) analysis. Spikes were measured at 64 sites in the visual cortex of rats with chronically implanted microelectrode arrays during wakefulness and three levels of anesthesia produced by desflurane. Anesthesia decreased the number of active units, the number of functional connections, and the strength of excitatory connections. Connection probability (number of connections per number of active unit pairs) was unaffected until the deepest anesthesia level, at which a significant increase in the excitatory to inhibitory ratio of connection probabilities was observed. The results suggest that the excitatory-inhibitory balance is altered at an anesthetic depth associated with unconsciousness.

Determination of low-pass filter cutoff frequencies for high-rate biomechanical signals obtained using videographic analysis.

Diffuse brain injury (DBI) commonly results from blunt impact followed by sudden head rotation, wherein severity is a function of rotational kinematics. A noninvasive in vivo rat model was designed to further investigate this relationship. Due to brain mass differences between rats and humans, rotational acceleration magnitude indicative of rat DBI ( approximately 350 krad/s(2)) has been estimated as approximately 60 times greater than that of human DBI ( approximately 6 krad/s(2)). Prior experimental testing attempted to use standard transducers such as linear accelerometers to measure loading kinematics. However, such measurement techniques were intrusive to experimental model operation. Therefore, initial studies using this experimental model obtained rotational displacement data from videographic images and implemented a finite difference differentiation (FDD) method to obtain rotational velocity and acceleration. Unfortunately, this method amplified high-frequency, low-amplitude noise, which interfered with signal magnitude representation. Therefore, a coherent average technique was implemented to improve the measurement of rotational kinematics from videographic images, and its results were compared with those of the previous FDD method. Results demonstrated that the coherent method accurately determined a low-pass filter cutoff frequency specific to pulse characteristics. Furthermore, noise interference and signal attenuation were minimized compared with the FDD technique.

Isoflurane disrupts anterio-posterior phase synchronization of flash-induced field potentials in the rat.

Consciousness presumes a set of integrated functions such as sensory processing, attention, and interpretation, and may depend upon both local and long-range phase synchronization of neuronal activity in cerebral cortex. Here we investigated whether volatile anesthetic isoflurane at concentrations that produce loss of consciousness (LOC) disrupts long-range anterio-posterior and local anterior synchronization of neuronal activity in the rat. In six rats, deep electrodes were chronically implanted in the primary visual cortex (V1) and in two areas of the motor cortex (M1 and M2) for recording of intracortical event-related potentials (ERP). Thirty discrete flashes were presented at random interstimulus intervals of 15-45 s, and ERPs were recorded at stepwise increasing isoflurane concentrations of 0-1.1%. Neuronal synchronization was estimated using wavelet coherence computed from the ERP data band-pass filtered at 5-50 Hz. We found that (1) in the waking state, long-range anterio-posterior coherence in 5-25 Hz and 25-50 Hz frequency bands was significantly higher than local anterior coherence; (2) anterio-posterior coherence in both 5-25 Hz and 26-50 Hz bands was significantly reduced by isoflurane in a concentration-dependent manner; (3) local anterior coherence was not affected by isoflurane at any of the concentrations studied. These findings suggest that a disruption of long-range anterio-posterior rather than local anterior synchronization of neuronal activity precedes the anesthetic-induced loss of consciousness.

Ischemia reperfusion dysfunction changes model-estimated kinetics of myofilament interaction due to inotropic drugs in isolated hearts.

BACKGROUND: The phase-space relationship between simultaneously measured myoplasmic [Ca2+] and isovolumetric left ventricular pressure (LVP) in guinea pig intact hearts is altered by ischemic and inotropic interventions. Our objective was to mathematically model this phase-space relationship between [Ca2+] and LVP with a focus on the changes in cross-bridge kinetics and myofilament Ca2+ sensitivity responsible for alterations in Ca2+-contraction coupling due to inotropic drugs in the presence and absence of ischemia reperfusion (IR) injury. METHODS: We used a four state computational model to predict LVP using experimentally measured, averaged myoplasmic [Ca2+] transients from unpaced, isolated guinea pig hearts as the model input. Values of model parameters were estimated by minimizing the error between experimentally measured LVP and model-predicted LVP. RESULTS: We found that IR injury resulted in reduced myofilament Ca2+ sensitivity, and decreased cross-bridge association and dissociation rates. Dopamine (8 microM) reduced myofilament Ca2+ sensitivity before, but enhanced it after ischemia while improving cross-bridge kinetics before and after IR injury. Dobutamine (4 microM) reduced myofilament Ca2+ sensitivity while improving cross-bridge kinetics before and after ischemia. Digoxin (1 microM) increased myofilament Ca2+ sensitivity and cross-bridge kinetics after but not before ischemia. Levosimendan (1 microM) enhanced myofilament Ca2+ affinity and cross-bridge kinetics only after ischemia. CONCLUSION: Estimated model parameters reveal mechanistic changes in Ca2+-contraction coupling due to IR injury, specifically the inefficient utilization of Ca2+ for contractile function with diastolic contracture (increase in resting diastolic LVP). The model parameters also reveal drug-induced improvements in Ca2+-contraction coupling before and after IR injury.

Ischemia-reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts.

Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca2+ concentration ([Ca2+]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca2+] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37 degrees C, 1.25 mM CaCl2). [Ca2+] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca2+-contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 microM) worsened, whereas dopamine (8 microM) improved Ca2+-contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 microM) improved Ca2+-contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 microM) did not alter Ca2+-contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca2+ flux before and after ischemia. Dynamic indexes based on LVP-[Ca2+] diagrams (area, shape, position) can be used to identify and measure alterations in Ca2+-contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.

Volatile anesthetics disrupt frontal-posterior recurrent information transfer at gamma frequencies in rat.

We seek to understand neural correlates of anesthetic-induced unconsciousness. We hypothesize that cortical integration of sensory information may underlie conscious perception and may be disrupted by anesthetics. A critical role in frontal-posterior interactions has been proposed, and gamma (20-60 Hz) oscillations have also been assigned an essential role in consciousness. Here we investigated whether general anesthetics may interfere with the exchange of information encoded in gamma oscillations between frontal and posterior cortices. Bipolar electrodes for recording of event-related potentials (ERP) were chronically implanted in the primary visual cortex, parietal association and frontal association cortices of six rats. Sixty light flashes were presented every 5s, and ERPs were recorded at increasing concentrations of halothane or isoflurane (0-2%). Information exchange was estimated by transfer entropy, a novel measure of directional information transfer. Transfer entropy was calculated from 1-s wavelet-transformed ERPs. We found that (1) feedforward transfer entropy (FF-TE) and feedback transfer entropy (FB-TE) were balanced in conscious-sedated state; (2) anesthetics at concentrations producing unconsciousness augmented both FF-TE and FB-TE at 30 Hz but reduced them at 50 Hz; (3) reduction at 50 Hz was more pronounced for FB-TE, especially between frontal and posterior regions; (4) at high concentrations, both FF-TE and FB-TE at all frequencies were at or below conscious-sedated baseline. Our findings suggest that inhalational anesthetics preferentially impair frontal-posterior FB information transfer at high gamma frequencies consistent with the postulated role of frontal-posterior interactions in consciousness.

Microfocal X-ray computed tomography post-processing operations for optimizing reconstruction volumes of stented arteries during 3D computational fluid dynamics modeling.

Restenosis caused by neointimal hyperplasia (NH) remains an important clinical problem after stent implantation. Restenosis varies with stent geometry, and idealized computational fluid dynamics (CFD) models have indicated that geometric properties of the implanted stent may differentially influence NH. However, 3D studies capturing the in vivo flow domain within stented vessels have not been conducted at a resolution sufficient to detect subtle alterations in vascular geometry caused by the stent and the subsequent temporal development of NH. We present the details and limitations of a series of post-processing operations used in conjunction with microfocal X-ray CT imaging and reconstruction to generate geometrically accurate flow domains within the localized region of a stent several weeks after implantation. Microfocal X-ray CT reconstruction volumes were subjected to an automated program to perform arterial thresholding, spatial orientation, and surface smoothing of stented and unstented rabbit iliac arteries several weeks after antegrade implantation. A transfer function was obtained for the current post-processing methodology containing reconstructed 16 mm stents implanted into rabbit iliac arteries for up to 21 days after implantation and resolved at circumferential and axial resolutions of 32 and 50 microm, respectively. The results indicate that the techniques presented are sufficient to resolve distributions of WSS with 80% accuracy in segments containing 16 surface perturbations over a 16 mm stented region. These methods will be used to test the hypothesis that reductions in normalized wall shear stress (WSS) and increases in the spatial disparity of WSS immediately after stent implantation may spatially correlate with the temporal development of NH within the stented region.

Volatile anesthetics enhance flash-induced gamma oscillations in rat visual cortex.

BACKGROUND: The authors sought to understand neural correlates of anesthetic-induced unconsciousness. Cortical gamma oscillations have been associated with neural processes supporting conscious perception, but the effect of general anesthesia on these oscillations is controversial. In this study, the authors examined three volatile anesthetics, halothane, isoflurane, and desflurane, and compared their effects on flash-induced gamma oscillations in terms of equivalent concentrations producing the loss of righting reflex (1 minimum alveolar concentration for the loss of righting [MAC(LR)]). METHODS: Light flashes were presented every 5 s for 5 min, and event-related potentials were recorded from primary visual cortex of 15 rats with a chronically implanted bipolar electrode at increasing anesthetic concentrations (0-2.4 MAC(LR)). Early cortical response was obtained by averaging poststimulus (0-100 ms) potentials filtered at 20-60 Hz across 60 trials. Late (100-1,000 ms) gamma power was calculated using multitaper power spectral technique. Wavelet decomposition was used to determine spectral and temporal distributions of gamma power. RESULTS: The authors found that (1) halothane, isoflurane, and desflurane enhanced the flash-evoked early cortical response in a concentration-dependent manner; (2) the effective concentration for this enhancement was the lowest for isoflurane, intermediate for halothane, and the highest for desflurane when compared at equal fractions of the concentration that led to a loss of righting; (3) the power of flash-induced late (> 100 ms) gamma oscillations was augmented at intermediate concentrations of all three anesthetic agents; and (4) flash-induced gamma power was not reduced below waking baseline even in deep anesthesia. CONCLUSIONS: These findings suggest that a reduction in flash-induced gamma oscillations in rat visual cortex is not a unitary correlate of anesthetic-induced unconsciousness.

How inotropic drugs alter dynamic and static indices of cyclic myoplasmic [Ca2+] to contractility relationships in intact hearts.

The authors examined effects of positive (dopamine and digoxin) and negative (nifedipine and lidocaine) inotropic interventions on the instantaneous cyclic relationship between myoplasmic [Ca2+] and simultaneously developed left ventricular pressure (LVP) in intact guinea pig hearts. Novel indices were developed to quantify this relationship based on (1) transient [Ca2+] and LVP signal morphology, ie, maxima and minima, peak derivatives, beat areas, durations, and ratios of indices of LVP to [Ca2+]; (2) temporal delay; and (3) LVP versus [Ca2+] loop morphology, ie, orientation, size, hysteresis, position, shape, and duration. These analyses were used to assess the cost of phasic [Ca2+] for contraction and relaxation over one beat after inotropic intervention. It was found that dopamine and digoxin increased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike dopamine, digoxin did not decrease relaxation response time. Nifedipine and lidocaine decreased contractile and relaxation responsiveness to phasic [Ca2+], cumulative Ca2+, and net Ca2+ flux. Unlike lidocaine, nifedipine decreased net available Ca2+ and Ca2+ influx. Positive inotropic agents increased [Ca2+]-LVP loop area and hysteresis and resulted in a more vertically oriented loop. Nifedipine and lidocaine decreased these loop indices and lidocaine exhibited greater loop hysteresis than did nifedipine. These novel indices provide a quantitative assessment of myoplasmic [Ca2+] handling for cardiac contractile function.

Simultaneous ERP and fMRI of the auditory cortex in a passive oddball paradigm.

Infrequent occurrences of a deviant sound within a sequence of repetitive standard sounds elicit the automatic mismatch negativity (MMN) event-related potential (ERP). The main MMN generators are located in the superior temporal cortex, but their number, precise location, and temporal sequence of activation remain unclear. In this study, ERP and functional magnetic resonance imaging (fMRI) data were obtained simultaneously during a passive frequency oddball paradigm. There were three conditions, a STANDARD, a SMALL deviant, and a LARGE deviant. A clustered image acquisition technique was applied to prevent contamination of the fMRI data by the acoustic noise of the scanner and to limit contamination of the electroencephalogram (EEG) by the gradient-switching artifact. The ERP data were used to identify areas in which the blood oxygenation (BOLD) signal varied with the magnitude of the negativity in each condition. A significant ERP MMN was obtained, with larger peaks to LARGE deviants and with frontocentral scalp distribution, consistent with the MMN reported outside the magnetic field. This result validates the experimental procedures for simultaneous ERP/fMRI of the auditory cortex. Main foci of increased BOLD signal were observed in the right superior temporal gyrus [STG; Brodmann area (BA) 22] and right superior temporal plane (STP; BA 41 and 42). The imaging results provide new information supporting the idea that generators in the right lateral aspect of the STG are implicated in processes of frequency deviant detection, in addition to generators in the right and left STP.

The spatial extent of the BOLD response.

Functional magnetic resonance imaging is routinely used to localize brain function, with multiple brain scans averaged together to reveal activation volumes. In this study, we examine the seldom-studied effect of multiple scan averaging on the extent of activation volume. Using restricted visual field stimulation, we obtained a large number of scan repetitions and analyzed changes in activation volume with progressively increased averaging and across single scans. Activation volume increased monotonically with averaging and failed to asymptote when as many as 22 scans were averaged together. Expansions in the spatial extent of activation were not random; rather, they were centered about activation loci that appear with little or no averaging. Using empirical and simulated data, changes with averaging in activation volumes and cross correlation coefficient distributions revealed the presence of considerably more activated voxels than commonly surmised. Many voxels have low SNR and remain undetected without extensive averaging. The primary source of such voxels was not downstream venous drainage since there was no significant and consistent delay difference between voxels activated at different averaging levels. Voxels with low SNR may reflect a diffuse subthreshold activity centered about spiking neurons, dephasing gradients from distal veins, or simply a blood flow response extending beyond the locus of neuronal firing. Across single scans, as much as twofold changes in activation volume were observed. These changes were not correlated with the order of scan acquisition, subject task performance, or signal and noise properties of activated voxels. Instead, they may reflect subtle changes between overlapping noise and signal frequency components.

Estimation of FMRI response delays.

We present an efficient algorithm using the Hilbert Transform for estimating the delay of the BOLD response to neuronal stimulation. With minimal additional computations, the algorithm estimates parameters generated in the widely used cross-correlation method and simplifies the interpolation required to estimate the response delay from the cross-correlation function. We examined errors in the Hilbert-based delay estimate associated with the use of DFT on short-duration discrete signals and proposed a method for minimizing these errors. Furthermore, we compared the delay estimates obtained with the Hilbert method to those obtained using the onset of the BOLD response. The Hilbert method resulted in less variance in the delay estimate despite the potential for higher variability in the latter part of the BOLD response. This improved delay estimate was attributed to the reduced sensitivity of the Hilbert method to noise contamination compared to the onset method.

Cross-bridge kinetics modeled from myoplasmic [Ca2+] and LV pressure at 17 degrees C and after 37 degrees C and 17 degrees C ischemia.

We modeled changes in contractile element kinetics derived from the cyclic relationship between myoplasmic [Ca(2+)], measured by indo 1 fluorescence, and left ventricular pressure (LVP). We estimated model rate constants of the Ca(2+) affinity for troponin C (TnC) on actin (A) filament (TnCA) and actin and myosin (M) cross-bridge (A x M) cycling in intact guinea pig hearts during baseline 37 degrees C perfusion and evaluated changes at 1) 20 min 17 degrees C pressure, 2) 30-min reperfusion (RP) after 30-min 37 degrees C global ischemia during 37 degrees C RP, and 3) 30-min RP after 240-min 17 degrees C global ischemia during 37 degrees C RP. At 17 degrees C perfusion versus 37 degrees C perfusion, the model predicted: A x M binding was less sensitive; A x M dissociation was slower; Ca(2+) was less likely to bind to TnCA with A x M present; and Ca(2+) and TnCA binding was less sensitive in the absence of A x M. Model results were consistent with a cold-induced fall in heart rate from 260 beats/min (37 degrees C) to 33 beats/min (17 degrees C), increased diastolic LVP, and increased phasic Ca(2+). On RP after 37 degrees C ischemia vs. 37 degrees C perfusion, the model predicted the following: A x M binding was less sensitive; A x M dissociation was slower; and Ca(2+) was less likely to bind to TnCA in the absence of A. M. Model results were consistent with reduced myofilament responsiveness to [Ca(2+)] and diastolic contracture on 37 degrees C RP. In contrast, after cold ischemia versus 37 degrees C perfusion, A x M association and dissociation rates, and Ca(2+) and TnCA association rates, returned to preischemic values, whereas the dissociation rate of Ca(2+) from A x M was ninefold faster. This cardiac muscle kinetic model predicted a better-restored relationship between Ca(2+) and cross-bridge function on RP after an eightfold longer period of 17 degrees C than 37 degrees C ischemia.

Differentiation of atrial rhythms from the electrocardiogram with coherence spectra.

Automated electrocardiogram (ECG) interpretation systems fail to reliably discriminate atrial fibrillation from sinus rhythm and other more regular atrial arrhythmias. Previously, magnitude-squared coherence (MSC), a frequency domain measure of the linear phase relation between 2 signals, has been shown to be a reliable discriminator of fibrillatory and nonfibrillatory cardiac rhythms when applied to intracardiac electrograms. This study determines whether MSC, when applied to the surface electrocardiogram, would discriminate between atrial fibrillation and nonfibrillatory atrial rhythms. MSC was analyzed by using 2 surface leads of a 10-second ECG. For 68 ECG recordings (23 sinus rhythm, 22 atrial flutter, and 23 atrial fibrillation), MSC was computed between leads II and V1 and the mean MSC in several frequency bands was examined. The performance of MSC was compared to previously published measures of ventricular irregularity and percent power in discriminating atrial fibrillation from nonfibrillatory rhythms. As hypothesized, atrial fibrillation exhibited low coherence in the 2 to 9 Hz band while nonfibrillatory atrial rhythms exhibited relatively moderate to high levels of coherence in the same frequency band. Mean MSC in the 2 to 9 Hz band was significantly lower for atrial fibrillation (range, 0.04 to 0.48; mean +/- SD: 0.15 +/- 0.11) than for sinus rhythm (range, 0.18 to 0.81; 0.47 +/- 0.17) (P <.0005) and atrial flutter (range, 0.06 to 0.80; 0.44 +/- 0.21) (P <.0005). Mean MSC in the 2 to 9 Hz band showed less overlap between atrial fibrillation and atrial flutter than R-R variability and percent power. However, R-R variability showed less overlap between atrial fibrillation and sinus rhythm than mean MSC and percent power. Thus, MSC and RRV both discriminate atrial fibrillation from more organized atrial rhythms. Conversely, percent power was highly variable for both atrial fibrillation and organized atrial rhythms. Results suggest that MSC applied to surface ECG may be used to quantify rhythm organization.