B. Douglas Ward

Neural correlates of sensory and decision processes in auditory object identification.

Physiological studies of auditory perception have not yet clearly distinguished sensory from decision processes. In this experiment, human participants identified speech sounds masked by varying levels of noise while blood oxygenation signals in the brain were recorded with functional magnetic resonance imaging (fMRI). Accuracy and response time were used to characterize the behavior of sensory and decision components of this perceptual system. Oxygenation signals in a cortical subregion just anterior and lateral to primary auditory cortex predicted accuracy of sound identification, whereas signals in an inferior frontal region predicted response time. Our findings provide neurophysiological evidence for a functional distinction between sensory and decision mechanisms underlying auditory object identification. The present results also indicate a link between inferior frontal lobe activation and response-selection processes during auditory perception tasks.

Classification of Alzheimer Disease, Mild Cognitive Impairment, and Normal Cognitive Status with Large-Scale Network Analysis Based on Resting-State Functional MR Imaging

PURPOSE To use large-scale network (LSN) analysis to classify subjects with Alzheimer disease (AD), those with amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) subjects. MATERIALS AND METHODS The study was conducted with institutional review board approval and was in compliance with HIPAA regulations. Written informed consent was obtained from each participant. Resting-state functional magnetic resonance (MR) imaging was used to acquire the voxelwise time series in 55 subjects with clinically diagnosed AD (n = 20), aMCI (n =15), and normal cognitive function (n = 20). The brains were divided into 116 regions of interest (ROIs). The Pearson product moment correlation coefficients of pairwise ROIs were used to classify these subjects. Error estimation of the classifications was performed with the leave-one-out cross-validation method. Linear regression analysis was performed to analyze the relationship between changes in network connectivity strengths and behavioral scores. RESULTS The area under the receiver operating characteristic curve (AUC) yielded 87% classification power, 85% sensitivity, and 80% specificity between the AD group and the non-AD group (subjects with aMCI and CN subjects) in the first-step classification. For differentiation between subjects with aMCI and CN subjects, AUC was 95%; sensitivity, 93%; and specificity, 90%. The decreased network indexes were significantly correlated with the Mini-Mental State Examination score in all tested subjects. Similarly, changes in network indexes significantly correlated with Rey Auditory Verbal Leaning Test delayed recall scores in subjects with aMCI and CN subjects. CONCLUSION LSN analysis revealed that interconnectivity patterns of brain regions can be used to classify subjects with AD, those with aMCI, and CN subjects. In addition, the altered connectivity networks were significantly correlated with the results of cognitive tests.

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.

Comparison of simultaneously measured perfusion and BOLD signal increases during brain activation with T1‐based tissue identification

Perfusion and blood oxygenation level‐dependent (BOLD) signals were simultaneously measured during a finger‐tapping task at 3T using QUIPSS II with thin‐slice TI1 periodic saturation, a modified pulsed arterial spin labeling technique that provides quantitative measurement of perfusion. Perfusion and BOLD signal changes due to motor activation were obtained and correlated with the T1 values estimated from echo‐planar imaging (EPI)‐based T1 maps on a voxel‐by‐voxel basis. The peak perfusion signal occurs in voxels with a T1 of brain parenchyma while the peak BOLD signal occurs in voxels with a T1 characteristic of blood and cerebrospinal fluid. The locations of the peak signals of functional BOLD and perfusion only partially overlap on the order of 40%. Perfusion activation maps will likely represent the sites of neuronal activity better than do BOLD activation maps. Magn Reson Med 44:137–143, 2000.

MR-derived cerebral blood volume maps: Issues regarding histological validation and assessment of tumor angiogenesis

In an effort to develop MRI methods for the evaluation of tumor angiogenesis (new blood vessel formation), MRI‐derived cerebral blood volume (CBV) information has been compared to histologic measures of microvessel density (MVD). Although MVD is a standard marker of angiogenesis, it is not a direct correlate of the volume measurements made with MRI, and therefore inappropriate for the development and validation of the MR techniques. Therefore, the goal of this study was to develop an approach by which MR measurements of CBV can be directly correlated. To this end, dynamic susceptibility contrast (DSC) MRI experiments were performed in six Fisher rats implanted with 9L gliosarcoma brain tumors. Subsequently, the circulation was perfused with a latex compound (Microfil®), after which 50‐μm tissue sections were analyzed for vessel count, diameter, and the fraction of area comprised of vessels. The results demonstrate that while fractional area (FA) does not provide a good measure of CBV, FA corrected for section thickness effects does. Whereas the FA in normal brain was found to be 13.03 ± 1.83% the corrected FA, or fractional volume (FV), was 1.89 ± 0.39%, a value in agreement with those reported in the literature for normal brain. Furthermore, while no significant difference was found between normal brain and tumor FA (P = 0.55), the difference was significant for FV (P = 0.036), as would be expected. And only with FV does a correlation with the MRI‐derived CBV become apparent (rS = 0.74). There was strong correlation (rs = 0.886) between the tumor / normal blood volume ratios as estimated by each technique, although the MR‐ratio (1.56 ± 0.29) underestimated the histologic‐ratio (2.35 ± 0.75). Thus, the correlation of MRI CBV methods requires a measurement of fractional vessel area and correction of this area for section thickness effects. This new independent correlative measure should enable efficient and accurate progress in the development of MRI methods to evaluate tumor angiogenesis. Magn Reson Med 46:735–747, 2001.

Spatial correlations of laminar BOLD and CBV responses to rat whisker stimulation with neuronal activity localized by Fos expression.

The spatial relationship between a measured fMRI signal and its underlying neuronal activity remains unclear. One obstacle is the localization of neuronal activity; another is the spatial resolution of fMRI. In the present study, high‐resolution BOLD and CBV fMRI experiments (voxel size: 156 × 156 × 2000 μm3) were conducted in the rat whisker barrel cortex at 3 T; neuronal activity across cortical layers was mapped using the Fos expression technique. Results show that BOLD response is weighted by blood volume and that pixels with high BOLD response can be located at the cortical surface or in deep layers, depending on local vasculature. In contrast to BOLD response, the pixels with high CBV response were consistently clustered in the deep cortical layers. Percentage‐CBV change in cortical layers IV–V was 7.3 ± 1.5%, which was significantly higher than in layers I–III (4.1 ± 0.9%) and VI (4.3 ± 0.7%) (mean ± SEM). The laminar distribution of CBV response correlates well with neuronal activity localized by Fos expression. We conclude that neuronal activity can be inferred from CBV fMRI data with high spatial accuracy. The data indicate that both intracolumn functional connectivity and neurovascular coupling can be studied using CBV fMRI. Magn Reson Med 52:1060–1068, 2004.

Differential effects of deep sedation with propofol on the specific and nonspecific thalamocortical systems: a functional magnetic resonance imaging study.

Background:The current state of knowledge suggests that disruption of neuronal information integration may be a common mechanism of anesthetic-induced unconsciousness. A neural system critical for information integration is the thalamocortical system whose specific and nonspecific divisions may play the roles for representing and integrating information, respectively. How anesthetics affect the function of these systems individually is not completely understood. The authors studied the effect of propofol on thalamocortical functional connectivity in the specific and nonspecific systems, using functional magnetic resonance imaging. Methods:Eight healthy volunteers were instructed to listen to and encode 40 English words during wakeful baseline, light sedation, deep sedation, and recovery in the scanner. Functional connectivity was determined as the temporal correlation of blood oxygen level-dependent signals with seed regions defined within the specific and nonspecific thalamic nuclei. Results:Thalamocortical connectivity at baseline was dominantly medial and bilateral frontal and temporal for the specific system, and medial frontal and medial parietal for the nonspecific system. During deep sedation, propofol reduced functional connectivity by 43% (specific) and 79% (nonspecific), a significantly greater reduction in the nonspecific than in the specific system and in the left hemisphere than in the right. Upon regaining consciousness, functional connectivity increased by 58% (specific) and 123% (nonspecific) during recovery, exceeding their values at baseline. Conclusions:Propofol conferred differential changes in functional connectivity of the specific and nonspecific thalamocortical systems, particularly in left hemisphere, consistent with the verbal nature of stimuli and task. The changes in nonspecific thalamocortical connectivity may correlate with the loss and return of consciousness.

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment.

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimers disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimers disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.

Volatile anesthetics enhance flash-induced γ oscillations in rat visual cortex

Background: The authors sought to understand neural correlates of anesthetic-induced unconsciousness. Cortical &ggr; 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 &ggr; oscillations in terms of equivalent concentrations producing the loss of righting reflex (1 minimum alveolar concentration for the loss of righting [MACLR]). 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 MACLR). 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) &ggr; power was calculated using multitaper power spectral technique. Wavelet decomposition was used to determine spectral and temporal distributions of &ggr; 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) &ggr; oscillations was augmented at intermediate concentrations of all three anesthetic agents; and (4) flash-induced &ggr; power was not reduced below waking baseline even in deep anesthesia. Conclusions: These findings suggest that a reduction in flash-induced &ggr; oscillations in rat visual cortex is not a unitary correlate of anesthetic-induced unconsciousness.

A novel technique for modeling susceptibility-based contrast mechanisms for arbitrary microvascular geometries: The finite perturber method

Recently, we demonstrated that vessel geometry is a significant determinant of susceptibility-induced contrast in MRI. This is especially relevant for susceptibility-contrast enhanced MRI of tumors with their characteristically abnormal vessel morphology. In order to better understand the biophysics of this contrast mechanism, it is of interest to model how various factors, including microvessel morphology contribute to the measured MR signal, and was the primary motivation for developing a novel computer modeling approach called the Finite Perturber Method (FPM). The FPM circumvents the limitations of traditional fixed-geometry approaches, and enables us to study susceptibility-induced contrast arising from arbitrary microvascular morphologies in 3D, such as those typically observed with brain tumor angiogenesis. Here we describe this new modeling methodology and some of its applications. The excellent agreement of the FPM with theory and the extant susceptibility modeling data, coupled with its computational efficiency demonstrates its potential to transform our understanding of the factors that engender susceptibility contrast in MRI.