Spatial and temporal differentiation of fMRI BOLD response in primary visual cortex of human brain during sustained visual simulation

The blood oxygenation level dependent (BOLD) response during sustained visual stimulation has been studied by several groups using fMRI with controversial conclusions. This issue was investigated for the human brain at high (4 Tesla) magnetic field strength using a flashing goggle at 8 Hz. The results demonstrate that the overall BOLD response in the primary visual cortex has an initial overshoot after the onset of visual stimulation and an undershoot after the termination of visual stimulation. A significant and positive BOLD response, however, remains constant between the initial and terminal transient responses. The temporal BOLD responses in the primary visual cortex were spatially dependent. The regions identified as draining veins in images displayed proportionately larger initial and terminal transient responses, whereas regions devoid of such vessels and associated mainly with parenchyma exhibited a more time-independent BOLD response. These results reveal that the BOLD effect and, presumably, the uncoupling between cerebral blood flow and cerebral metabolic rate of oxygen consumption, are maintained in the primary visual cortex during sustained visual stimulation, and the temporal characteristics of the BOLD effect are spatially dependent.     

Increased levels of proteoglycan fragments and stromelysin in hip joint fluid in Legg-Calvé-Perthes disease

High response rates in patients with metastatic melanoma have been achieved with combination chemoimmunotherapy. A response rate of 62% in 45 patients has been reported for treatment with dacarbazine, bleomycin, vincristine, lomustine (BOLD) plus interferon alpha (IFN-alpha). We conducted a multicentre phase II study to confirm these results. Melanoma patients with distant metastases were treated as outpatients with dacarbazine 200 mg m(-2) on days 1-5, vincristine 1 mg m(-2) on days 1 and 4, bleomycin 15 mg on days 2 and 5 i.v. and lomustine 80 mg orally on day 1, repeated every 4 weeks. IFN-alpha-2b was initiated s.c. on day 8 at 3 MU daily for 6 weeks, and 6 MU t.i.w. thereafter. Forty-three patients entered the study. The median number of metastatic sites was three (range 1-5), and 81% of patients had visceral metastases. Nine patients had brain metastases, and seven patients were systemically pretreated. Among the 41 patients that were evaluable for response, the response rate was 27% (95% CI 14-3%), with one complete and ten partial remissions. The response rate in 25 previously untreated patients without brain metastases was 40% (95% CI 21-61%). Median duration of response was 6 (range 2-14+) months; median overall survival was 5 (1-26) months. The main toxicity was malaise/fatigue. We confirm that BOLD plus IFN-alpha has activity in metastatic melanoma. The lower response rate in our study compared with the previous report is probably related to patient selection, as in the previous study 46% of patients had stage III disease, whereas all our patients had stage IV disease, which is associated with a worse prognosis.     

The variability of human, BOLD hemodynamic responses

Cerebral hemodynamic responses to brief periods of neural activity are delayed and dispersed in time. The specific shape of these responses is of some importance to the design and analysis of blood oxygenation level-dependent (BOLD), functional magnetic resonance imaging (fMRI) experiments. Using fMRI scanning, we examine here the characteristics and variability of hemodynamic responses from the central sulcus in human subjects during an event-related, simple reaction time task. Specifically, we determine the contribution of subject, day, and scanning session (within a day) to variability in the shape of evoked hemodynamic response. We find that while there is significant and substantial variability in the shape of responses collected across subjects, responses collected during multiple scans within a single subject are less variable. The results are discussed in terms of the impact of response variability upon sensitivity and specificity of analyses of event-related fMRI designs.     

Abnormal error-related antisaccade activation in premanifest and early manifest Huntington disease.

Objective: Individuals with the trinucleotide CAG expansion (CAG+) that causes Huntington's disease (HD) have impaired performance on antisaccade (AS) tasks that require directing gaze in the mirror opposite direction of visual targets. This study aimed to identify the neural substrates underlying altered antisaccadic performance. Method: Three groups of participants were recruited: (1) Imminent and early manifest HD (early HD, n = 8); (2) premanifest (presymptomatic) CAG+ (preHD, n = 10); and (3) CAG unexpanded (CAG?) controls (n = 12). All participants completed a uniform study visit that included a neurological evaluation, neuropsychological battery, molecular testing, and functional MRI during an AS task. The blood oxygenation level dependent (BOLD) response was obtained during saccade preparation and saccade execution for both correct and incorrect responses using regression analysis. Results: Significant group differences in BOLD response were observed when comparing incorrect AS to correct AS execution. Specifically, as the percentage of incorrect AS increased, BOLD responses in the CAG? group decreased progressively in a well-documented reward detection network that includes the presupplementary motor area and dorsal anterior cingulate cortex. In contrast, AS errors in the preHD and early HD groups lacked this relationship with BOLD signal in the error detection network, and BOLD responses to AS errors were smaller in the two CAG+ groups as compared with the CAG? group. Conclusions: These results are the first to suggest that abnormalities in an error-related response network may underlie early changes in AS eye movements in premanifest and early manifest HD. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Functional magnetic resonance imaging of regional cerebral blood oxygenation changes during breath holding

BACKGROUND and PURPOSE: Recently, noninvasive MRI methods have been developed that are now capable of detecting and mapping regional hemodynamic responses to various stress tests, which involve the use of vasoactive substances such as acetazolamide or inhalation of carbon dioxide. The aim of this study was to assess regional cerebral blood oxygenation changes during breath holding at 1.5 T. METHODS: In 6 healthy volunteers, T2*-weighted gradient echo images were acquired for a total dynamic scanning time of 10 minutes during alternating periods of breath holding and normal breathing at 40-second intervals after inspiration, at 30-second intervals after expiration, and at 18 seconds after expiration. To quantify the relative signal changes, 2.5-minute baseline image sampling with normal breathing was carried out. RESULTS: Repeated challenges of breath holding of various durations induced an overall rise in blood oxygen level-dependent (BOLD) signal intensities. In general, BOLD signal intensity increases were greatest in gray matter and nonsignificant in white matter. Depending on the breath-holding duration and techniques, BOLD signal intensity increases of all activated pixels varied from 0.8% to 3.5%. CONCLUSIONS: The present study demonstrates that cerebral blood oxygenation changes during breath holding can be detected by means of fMRI at 1.5 T. The breath-holding test, a short and noninvasive method to study cerebral hemodynamics with fMRI, could become a useful alternative to the acetazolamide or CO2 test.     

Physiologic aspects of event related paradigms in magnetic resonance functional neuroimaging

In order to substantiate event related paradigms in magnetic resonance functional neuroimaging, we assessed the temporal and spatial characteristics of oxygenation-sensitive MRI responses to 1 s periods of visual activation in repetitive protocols. A main finding is a reduction of the functional contrast between conditions (reversing checkerboard vs. darkness) for decreasing interstimulus intervals yielding 4.5% signal change for 89 s, 4% for 9 s, 3% for 6 s, and 1% for 3 s, respectively. Although rapid repetitions of identical stimuli preclude the development of the full positive and negative MRI signal deflections, pertinent responses leave the spatial pattern of activated brain regions unaffected and result in identical maps. These findings suggest the use of interstimulus intervals of the order of the response time from stimulus onset to maximum signal strength (5-6 s in the visual system). The resulting distinction in time will allow for separate mapping of stimulus-related responses with spatially overlapping cortical representations.     

Linearity and normalization in simple cells of the macaque primary visual cortex

Simple cells in the primary visual cortex often appear to compute a weighted sum of the light intensity distribution of the visual stimuli that fall on their receptive fields. A linear model of these cells has the advantage of simplicity and captures a number of basic aspects of cell function. It, however, fails to account for important response nonlinearities, such as the decrease in response gain and latency observed at high contrasts and the effects of masking by stimuli that fail to elicit responses when presented alone. To account for these nonlinearities we have proposed a normalization model, which extends the linear model to include mutual shunting inhibition among a large number of cortical cells. Shunting inhibition is divisive, and its effect in the model is to normalize the linear responses by a measure of stimulus energy. To test this model we performed extracellular recordings of simple cells in the primary visual cortex of anesthetized macaques. We presented large stimulus sets consisting of (1) drifting gratings of various orientations and spatiotemporal frequencies; (2) plaids composed of two drifting gratings; and (3) gratings masked by full-screen spatiotemporal white noise. We derived expressions for the model predictions and fitted them to the physiological data. Our results support the normalization model, which accounts for both the linear and the nonlinear properties of the cells. An alternative model, in which the linear responses are subject to a compressive nonlinearity, did not perform nearly as well.     

Perforin expression in human cell-mediated luteolysis

For a variety of reasons, small vessels have low signal intensity in magnetic resonance angiography. When the vessel signal intensity is lower than the signal intensity of background tissues, these vessels tend not to be visible on maximum-intensity-projection images. The authors developed a nonlinear second-difference spatial filtering technique that enhances the details of small vessels while suppressing both noise and uniform background tissue. Two similar nonlinear second-difference filters are presented and compared with the linear Laplacian second-difference filter. To evaluate the performance of these filters, they were applied to intracranial three-dimensional time-of-flight MR angiographic data and the results compared with the vessel enhancement obtained with a simple second-difference Laplacian filter and with magnetization transfer contrast (MTC) techniques. The comparisons demonstrated that nonlinear filtering and MTC techniques result in similar improvement in small-vessel visibility and apparent continuity. A quantitative comparison demonstrated that the improvement in the contrast-to-noise ratio is much greater with the nonlinear filters than the Laplacian filter.     

The population dynamics of cercariae of Schistosoma japonicum in Oncomelania hupensis

High resolution functional MRI (fMRI) experiments were performed in human visual cortex at 0.5, 1.5, and 4 T to determine the blood oxygenation level dependent (BOLD) field strength response within regions of obvious venous vessels and cortical gray matter ("tissue"). T2*-weighted FLASH images were collected in single- and multi-echo mode and used to determine the intrinsic BOLD parameters, namely, signal-to-noise ratio (psi), the apparent transverse relaxation rate (R2*) and the change in R2* (deltaR2*) between the activated and baseline states. The authors find the average percentage signal change (deltaS/S, measured at TE = T2*) to be large in vessels (13.3 +/- 2.3%, 18.4 +/- 4.0%, and 15.1 +/- 1.2%) compared with that in tissue (1.4 +/- 0.7%, 1.9 +/- 0.7%, and 3.3 +/- 0.2%) at 0.5, 1.5, and 4 T, respectively. The signal-to-noise ratio in optimized, fully relaxed proton density weighted gradient echo images was found to increase linearly with respect to the static magnetic field strength (B0). The predicted upper bound on BOLD contrast-to-noise ratio (deltaS/R)max as a function of field strength was calculated and found to behave less than linearly in voxels containing vessels larger than the voxel itself and greater than linearly in voxels containing a mixture of capillaries and veins/venules with a diameter less than that of the voxel.     

Characterizing dynamic brain responses with fMRI: a multivariate approach

In this paper we present a multivariate analysis of evoked hemodynamic responses and their spatiotemporal dynamics as measured with fast fMRI. This analysis uses standard multivariate statistics (MANCOVA) and the general linear model to make inferences about effects of interest and canonical variates analysis (CVA) to describe the important features of these effects. We have used these techniques to characterize the form of hemodynamic transients that are evoked during a cognitive or sensorimotor task. In particular we do not assume that the neural or hemodynamic response reaches some "steady state" but acknowledge that these physiological changes could show profound task-dependent adaptation and time-dependent changes during the task. To address this issue we have modeled hemodynamic responses using appropriate temporal basis functions and estimated their exact form within the general linear model using MANCOVA. We do not propose that this analysis is a particularly powerful way to make inferences about functional specialization (or more generally functional anatomy) because it only provides statistical inferences about the distributed (whole brain) responses evoked by different conditions. However, its application to characterizing the temporal aspects of evoked hemodynamic responses reveals some compelling and somewhat unexpected perspectives on transient but stereotyped responses to changes in cognitive or sensorimotor processing. The most remarkable observation is that these responses can be biphasic and show profound differences in their form depending on the extant task or condition. Furthermore these differences can be seen in the absence of changes in mean signal.     

'Derived nonlinear' versus 'linear' click-evoked otoacoustic emissions

Recordings of emission evoked in response to transient stimuli (TEOAE) are partially contaminated by the initial stimulus artifact. For this reason, a nonlinear estimation method is widely used (derived nonlinear response, DNLR). The aims of this paper are: (1) to analyse some very basic properties of the derived nonlinear emissions such as the short-time input/output relationships; and (2) to show similarities and differences between the classical averaging (linear) and the derived nonlinear recording techniques, in the same ears, both in time and in the frequency domain. At latencies greater than about 6 ms, responses which are recorded using the derived nonlinear technique exhibit no additional features in comparison with linear recordings, at all stimulus levels. At latencies less than 6 ms, the derived nonlinear technique greatly reduces the linear content of the acoustic artifact, and the response may be considered as the initial part of the emission. However, the derived nonlinear responses tend to be considerably noisier than the linear emissions, thus reducing the effectiveness of the technique. The linear responses show a strikingly similar frequency content with respect to the derived nonlinear responses, at least at a high stimulus level and around the main peaks of the spectrum.     

Spike train encoding by regular-spiking cells of the visual cortex

1. To study the encoding of input currents into output spike trains by regular-spiking cells, we recorded intracellularly from slices of the guinea pig visual cortex while injecting step, sinusoidal, and broadband noise currents. 2. When measured with sinusoidal currents, the frequency tuning of the spike responses was markedly band-pass. The preferred frequency was between 8 and 30 Hz, and grew with stimulus amplitude and mean intensity. 3. Stimulation with broadband noise currents dramatically enhanced the gain of the spike responses at low and high frequencies, yielding an essentially flat frequency tuning between 0.1 and 130 Hz. 4. The averaged spike responses to sinusoidal currents exhibited two nonlinearities: rectification and spike synchronization. By contrast, no nonlinearity was evident in the averaged responses to broadband noise stimuli. 5. These properties of the spike responses were not present in the membrane potential responses. The latter were roughly linear, and their frequency tuning was low-pass and well fit by a single-compartment passive model of the cell membrane composed of a resistance and a capacitance in parallel (RC circuit). 6. To account for the spike responses, we used a "sandwich model" consisting of a low-pass linear filter (the RC circuit), a rectification nonlinearity, and a high-pass linear filter. The model is described by six parameters and predicts analog firing rates rather than discrete spikes. It provided satisfactory fits to the firing rate responses to steps, sinusoids, and broadband noise currents. 7. The properties of spike encoding are consistent with temporal nonlinearities of the visual responses in V1, such as the dependence of response frequency tuning and latency on stimulus contrast and bandwidth. We speculate that one of the roles of the high-frequency membrane potential fluctuations observed in vivo could be to amplify and linearize the responses to lower, stimulus-related frequencies.     

Simultaneous oxygenation and perfusion imaging study of functional activity in primary visual cortex at different visual stimulation frequency: quantitative correlation between BOLD and CBF changes

A relationship between regional cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) changes in the primary visual cortex (V1) at varied visual stimulation frequency has been examined quantitatively using the multislice FAIR technique. A linear correlation in the common activation areas between functional BOLD and CBF maps was observed. This supports the hypothesis that the task-stimulated BOLD changes in microvasculature are correlated with the CBF changes that presumably reflect the degree of neuronal activity. The linear correlation coefficients for intrasubject comparisons are more significant than those for intersubject comparisons. This suggests that using intrasubject comparisons for quantitative studies of neuronal activity related to different task stimuli and task performances should be more reliable than using intersubject comparisons.     

Effect of lesions of the ascending 5-hydroxytryptaminergic pathways on timing behaviour investigated with the fixed-interval peak procedure

Twelve rats received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei; 12 rats received sham lesions. The rats were then trained for 60 sessions under a discrete-trials fixed-interval schedule (peak procedure). In half the trials, a reinforcer became available 40 s after trial onset, and the trial was terminated upon reinforcer delivery; the remaining trials were 120 s in duration, and reinforcement did not occur in these trials. Performance during the 120-s trials was characterized by increasing response rate during the first 40 s of the trial, declining response rate between 40 s and 80 s, and a secondary increase in response rate during the final 40 s of the trial. The lesioned group showed a broader "spread" of the response rate function than the control group (time between attainment of 70% of the peak response rate and subsequent decline of response rate below this level); however, the peak response rate and the time from trial onset until attainment of the peak response rate did not differ significantly between the groups; the spread/peak-time ratio was significantly greater in the lesioned group than in the control group. The levels of 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid in the parietal cortex, hippocampus, amygdala, nucleus accumbens and hypothalamus were markedly reduced in the lesioned group, but the levels of noradrenaline and dopamine were not significantly affected by the lesion. The results confirm the involvement of 5HTergic function in timing behaviour.     

Double-evoked otoacoustic emissions. II. Intermittent noise rejection, calibration and ear-canal measurements

Measurements of double-click-evoked otoacoustics emissions (2CEOAEs) and double-chirp distortion products (2ChDPs) are reported for normal-hearing adults based upon theory presented in an earlier report [Keefe, J. Acoust, Soc. Am. 103, 3489-3498 (1998)]. The nonlinear acoustic response of a probe assembly used in ear-canal measurements in tested in a calibration cavity to compare the double-evoked (2E) technique with existing OAE techniques. The 2E technique reduces the peak distortion by approximately 30 dB relative to existing click-evoked techniques. The 2E subtraction of click responses is partially analogous to current techniques in that the linear response is eliminated, but differs in that high-frequency measurements are improved by eliminating time gating of the cochlear response, and low-frequency measurements are improved by reducing probe distortion, especially when two acoustic sources are used. Because time gating is eliminated, it is straightforward to measure the onset of a click-evoked OAE. The nonlinear coherence function is used to measure the nonlinear distortion signal-to-noise ratio (DNR) for the 2ChDPs and 2CEOAEs. The DNR is typically 20-30 dB. An intermittent noise rejection technique is implemented in real time that compares a currently acquired ear-canal response with a stored response. Dissimilar responses indicate the presence of intermittent noise, and the noise-contaminated responses are thereby discarded before ensemble averaging.     

The receptive field of the primate P retinal ganglion cell, II: Nonlinear dynamics

The ganglion cells of the primate retina include two major anatomical and functional classes: P cells which project to the four parvocellular layers of the lateral geniculate nucleus (LGN), and M cells which project to the two magnocellular layers. The characteristics of the P-cell receptive field are central to understanding early form and color vision processing (Kaplan et al., 1990; Schiller & Logothetis, 1990). In this and in the following paper, P-cell dynamics are systematically analyzed in terms of linear and nonlinear response properties. Stimuli that favor either the center or the surround of the receptive field were produced on a CRT and modulated with a broadband signal composed of multiple m-sequences (Benardete et al., 1992b; Benardete & Victor, 1994). The first-order responses were calculated and analyzed in this paper (part I). The findings are: (1) The first-order responses of the center and surround depend linearly on contrast. (2) The dynamics of the center and surround are well described by a bandpass filter model. The most significant difference between center and surround dynamics is a delay of approximately 8 ms in the surround response. (3) In the LGN, these responses are attenuated and delayed by an additional 1-5 ms. (4) The spatial transfer function of the P cell in response to drifting sine gratings at three temporal frequencies was measured. This independent method confirmed the delay between the (first-order) responses of the center and surround. This delay accounts for the dependence of the spatial transfer function on the frequency of stimulation.     

Cocaine decreases cortical cerebral blood flow but does not obscure regional activation in functional magnetic resonance imaging in human subjects

The authors used functional magnetic resonance imaging (fMRI) to determine whether acute intravenous (i.v.) cocaine use would change global cerebral blood flow (CBF) or visual stimulation-induced functional activation. They used flow-sensitive alternating inversion recovery (FAIR) scan sequences to measure CBF and blood oxygen level-dependent (BOLD) sensitive T2* scan sequences during visual stimulation to measure neuronal activation before and after cocaine and saline infusions. Cocaine (0.6 mg/kg i.v. over 30 seconds) increased heart rate and mean blood pressure and decreased end tidal carbon dioxide (CO2). All measures returned to baseline by 2 hours, the interinfusion interval, and were unchanged by saline. Flow-sensitive alternating inversion recovery imaging demonstrated that cortical gray matter CBF was unchanged after saline infusion (-2.4 +/- 6.5%) but decreased (-14.1 +/- 8.5%) after cocaine infusion (n = 8, P < 0.01). No decreases were detected in white matter, nor were changes found comparing BOLD signal intensity in cortical gray matter immediately before cocaine infusion with that measured 10 minutes after infusion. Visual stimulation resulted in comparable BOLD signal increases in visual cortex in all conditions (before and after cocaine and saline infusion). Despite a small (14%) but significant decrease in global cortical gray matter CBF after acute cocaine infusion, specific regional increases in BOLD imaging, mediated by neurons, can be measured reliably.     

Stimulus compounding in interval timing: The modality–duration relationship of the anchor durations results in qualitatively different response patterns to the compound cue.

We have previously demonstrated that rats trained on a two-duration peak procedure in which two modal signals (i.e., tone and houselight) predicted probabilistic reinforcement availability at two times (10 s and 20 s) would respond in a scalar manner at a time between the trained durations in response to the simultaneous compound cue (tone + houselight). In these experiments, we evaluated whether this scalar response pattern would remain with greater relative separation between the anchor durations. Results revealed an effect of the modality–duration relationship, such that scalar responding was seen on compound trials in rats trained that the auditory stimulus signaled the shorter duration, whereas the visual stimulus signaled the longer duration, but not in the reverse condition. In rats showing scalar responding on compound trials, post hoc analyses demonstrated that the peak time of compound responding was most accurately predicted by the reinforcement probability weighted average of anchor peak times. In contrast, rats trained that the visual stimulus signaled the shorter duration, whereas the auditory stimulus signaled the longer duration, responded in a highly rightward skewed manner. In these rats, initiation of responding to the compound stimulus appeared to be controlled by the visual stimulus only, whereas response terminations reflected control by both modal stimuli. These latter data provide evidence of separate determinants of response initiation and termination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dynamic functional imaging of relative cerebral blood volume during rat forepaw stimulation

Dynamic measurements of regional changes in cerebral blood volume (CBV) were performed in rat models of hypercarbia and focal neuronal activation using T2-weighted imaging after injection of an intravascular contrast agent with a very long blood half-life. Calculated percent CBV change during hypercarbia was consistent with literature results from other non-invasive modalities. Equivalent percent CBV increases were found using spin- and gradient-echo images, suggesting proportional changes in blood volume for capillaries and small veins. During electrical stimulation of rat forepaw, focal CBV response to stimulation (24+/-4%) was significantly delayed relative to blood oxygen level dependent (BOLD) signal after both onset and cessation of stimulation. Poststimulus CBV decay was temporally consistent with the BOLD poststimulus undershoot. The use of exogenous agent increased the functional contrast-to-noise ratio relative to BOLD imaging by 5.7+/-1.3 at a magnetic field strength of 2 Tesla and 1.5+/-0.2 at 4.7 Tesla.     

Orientation bias in the response of kitten LGNd neurons to moving light bars

The orientation sensitivity to moving light bars was determined for 113 neurons in laminae A, A1 and C of the dorsal part of the lateral geniculate nucleus (LGNd) of kittens 7-42 days old. Forty neurons (35.4%) were biased to contrast orientation (OB neurons), i.e. their response to an optimally oriented bar was 2-10 times stronger than their response to a bar oriented orthogonally to the optimal. The remaining 73 neurons were not sensitive to contrast orientation. Evidence is presented that orientation bias in the LGNd develops prior to visual experience. Orientation biased responses in the LGNd strongly depended on stimulus parameters; preferred stimuli were light bars having a length of 5 degrees or more and moving at velocities slower than 5 degrees/s. Our findings suggest that the OB neurons of the LGNd could be effective in generating the early orientation sensitivity in the visual cortex.