Task-induced deactivations during successful paired associates learning: an effect of age but not Alzheimer's disease

Task-induced fMRI deactivations during successful encoding and retrieval of visuospatial paired associates were examined at different levels of task difficulty in younger and older adults (Experiment 1), and older adults with and without mild probable Alzheimer's disease (AD) (Experiment 2). Irrespective of the level of task difficulty, common deactivations (determined through the use of conjunction analyses) were observed in the lateral and medial prefrontal, anterior and posterior cingulate, and temporal brain regions and in the claustrum during both encoding and retrieval in younger and older adults (Experiment 1). In AD patients and healthy older adults, common deactivations were found in posterior cingulate, temporal, and lateral parietal regions and in the insula and claustrum during encoding and retrieval of paired associates (Experiment 2). As task difficulty increased, irrespective of the type of task, the magnitude of task-induced deactivations increased in the medial prefrontal/superior frontal gyrus and middle/posterior cingulate cortex in younger and older adults (Experiment 1), and in the middle cingulate cortex in older adults with and without AD (Experiment 2). In Experiment 1, greater deactivation was observed in the anterior cingulate gyrus in older compared to younger adults during retrieval of paired associates which was attributed to greater suppression of task-unrelated thoughts in the older group. No significant differences in task-induced deactivation, or in the type of relationship exhibited between deactivation and task difficulty, were observed between older adults with and without AD (Experiment 2). It was suggested that this was related to the matching of successful task performance and task difficulty across patient and control groups. Following previous proposals, task-induced deactivations were suggested to underlie a shifting of attentional focus from monitoring of the self and the environment (through attenuation of these activities) to external, goal-directed behaviour.     

Calibrated fMRI during a cognitive Stroop task reveals reduced metabolic response with increasing age

fMRI studies of aging have revealed increased blood oxygenation level dependent (BOLD) response to tasks of executive function with advancing age, which is generally interpreted as increased neural activity. However, changes in the cerebrovascular system with age can alter the BOLD signal, complicating this interpretation. Arterial spin labeling (ASL) allows simultaneous acquisition of BOLD and cerebral blood flow (CBF) information and can be used to quantify the component parts of the BOLD signal. We used this calibrated BOLD approach in 58 healthy participants over an age range of 18-71 years to determine the relative vascular and neuronal contributions to the age-related BOLD changes in response to a Stroop task. The percentage BOLD response increased significantly with increasing age but the percentage CBF response did not alter, such that the BOLD increase is attributed to a significant reduction in the oxygen metabolism response with increasing age. Hence, in this study, the BOLD increase with age should be interpreted as a reduction in neural activity. The greatest percentage BOLD increases with age were found in the left and right medial frontal gyri and the primary motor cortex and were again linked to a reduction in oxygen metabolism. On separating the participants into three groups (young, old high performers and old low performers), age-related differences in percentage BOLD response and oxygen metabolism response could be attributed to the low performing old group. This study demonstrates the need to take into account alterations in vascular-metabolic coupling and resting blood volume when interpreting changes in the BOLD response with aging.     

Temporal dynamics of the BOLD fMRI impulse response

Using computer simulations and high-resolution fMRI experiments in humans (n=6) and rats (n=8), we investigated to what extent BOLD fMRI temporal resolution is limited by dispersion in the venous vasculature. For this purpose, time-to-peak (TTP) and full-width at half-maximum (FWHM) of the BOLD impulse response (IR) function were determined. In fMRI experiments, a binary m-sequence probe method was used to obtain high-sensitivity model-free single-pixel estimates of IR. Simulations of postcapillary flow suggested that flow-related dispersion leads to a TTP and FWHM increase, which can amount to several seconds in larger pial veins. fMRI experiments showed substantial spatial variation in IR timing within human visual cortex, together with a correlation between TTP and FWHM. Averaged across the activated regions and across subjects, TTP and FWHM were 4.51+/-0.52 and 4.04+/-0.42 s, respectively. In regions of interest (ROI) weighted toward the larger venous structures, TTP and FWHM increased to 5.07+/-0.64 and 4.32+/-0.48 s, respectively. In rat somatosensory cortex, TTP and FWHM were substantially shorter than in humans (2.73+/-0.60 and 2.28+/-0.63 s, respectively). These results are consistent with a substantial macrovascular dispersive contribution to BOLD IR in humans, and furthermore suggest that neurovascular coupling is a relatively rapid process, with a resolution below 2.3 s FWHM.     

Deconvolution of impulse response in event-related BOLD fMRI

The temporal characteristics of the BOLD response in sensorimotor and auditory cortices were measured in subjects performing finger tapping while listening to metronome pacing tones. A repeated trial paradigm was used with stimulus durations of 167 ms to 16 s and intertrial times of 30 s. Both cortical systems were found to be nonlinear in that the response to a long stimulus could not be predicted by convolving the 1-s response with a rectangular function. In the short-time regime, the amplitude of the response varied only slowly with stimulus duration. It was found that this character was predicted with a modification to Buxton's balloon model. Wiener deconvolution was used to deblur the response to concatenated short episodes of finger tapping at different temporal separations and at rates from 1 to 4 Hz. While the measured response curves were distorted by overlap between the individual episodes, the deconvolved response at each rate was found to agree well with separate scans at each of the individual rates. Thus, although the impulse response cannot predict the response to fully overlapping stimuli, linear deconvolution is effective when the stimuli are separated by at least 4 s. The deconvolution filter must be measured for each subject using a short-stimulus paradigm. It is concluded that deconvolution may be effective in diminishing the hemodynamically imposed temporal blurring and may have potential applications in quantitating responses in eventrelated fMRI.     

Single-trial P3 amplitude and latency informed event-related fMRI models yield different BOLD response patterns to a target detection task

Using single-trial parameters as a regressor in the General Linear Model (GLM) is becoming an increasingly popular method for informing fMRI analysis. However, the parameter used to characterise or to differentiate brain regions involved in the response to a particular task varies across studies (e.g. ERP amplitude, ERP latency, reaction time). Furthermore, the way in which the single-trial information is used in the fMRI analysis is also important. For example, the single-trial parameters can be used as regressors in the GLM or to modify the duration of the events modelled in the GLM. The aim of this study was to investigate the BOLD response to a target detection task when including P3 amplitude, P3 latency and reaction time parameters in the GLM. Simultaneous EEG-fMRI was recorded from fifteen subjects in response to a visual choice reaction time task. Including P3 amplitude as a regressor in the GLM yielded activation in left central opercular cortex, left postcentral gyrus, left insula, left middle frontal gyrus, left insula and left parietal operculum. Using P3 latency and reaction time as an additional regressor yielded no additional activation in comparison with the conventional fMRI analysis. However, when P3 latency or reaction time was used to determine the duration of events at a single-trial level, additional activation was observed in the left postcentral gyrus, left precentral gyrus, anterior cingulate cortex and supramarginal gyrus. Our findings suggest that ERP amplitudes and latencies can yield different activation patterns when used to modify relevant aspects of the GLM.     

Hemodynamic nonlinearities affect BOLD fMRI response timing and amplitude

The interpretation of functional magnetic resonance imaging (fMRI) studies based on blood oxygen-level dependent (BOLD) contrast generally relies on the assumption of a linear relationship between evoked neuronal activity and fMRI response. While nonlinearities in this relationship have been suggested by a number of studies, it remains unclear to what extent they relate to the neurovascular response and are therefore inherent to BOLD fMRI. Full characterization of potential vascular nonlinearities is required for accurate inferences about the neuronal system under study. To investigate the extent of vascular nonlinearities, evoked activity was studied in humans with BOLD fMRI (n = 28) and magnetoencephalography (MEG) (n = 5). Brief (600–800 ms) rapidly repeated (1 Hz) visual stimuli were delivered using a stimulation paradigm that minimized neuronal nonlinearities. Nevertheless, BOLD fMRI experiments showed substantial remaining nonlinearities. The smallest stimulus separation (200–400 ms) resulted in significant response broadening (15–20% amplitude decrease; 10–12% latency increase; 6–14% duration increase) with respect to a linear prediction. The substantial slowing and widening of the response in the presence of preceding stimuli suggest a vascular rather than neuronal origin to the observed nonlinearity. This was confirmed by the MEG data, which showed no significant neuro-electric nonlinear interactions between stimuli as little as 200 ms apart. The presence of substantial vascular nonlinearities has important implications for rapid event-related studies by fMRI and other imaging modalities that infer neuronal activity from hemodynamic parameters.     

Complex spatio-temporal dynamics of fMRI BOLD: A study of motor learning

Many studies have investigated the temporal properties of BOLD signal responses to task performance in regions of interest, often noting significant departures from the conventionally modelled response shape, and significant variation between regions. However, these investigations are rarely extended across the whole brain nor incorporated into the routine analysis of fMRI studies. As a result, little is known about the range of response shapes generated in the brain by common paradigms. The present study finds such temporal dynamics can be complex. We made a detailed investigation of BOLD signal responses across the whole brain during a two minute motor-sequence task, and tracked changes due to learning. The multi-component OSORU (Onset, Sustained, Offset, Ramp, Undershoot) linear model, developed by Harms and Melcher (J.Neurophysiology, 2003), was extended to characterise responses. In many regions, signal transients persisted for over thirty seconds, with large signal spikes at onset often followed by a dip in signal below the final sustained level of activation. Training altered certain features of the response shape, suggesting that different features of the response may reflect different aspects of neuro-vascular dynamics. Unmodelled, this may give rise to inconsistent results across paradigms of varying task durations. Few of the observed effects have been thoroughly addressed in physiological models of the BOLD response. The complex, extended dynamics generated by this simple, often employed task, suggests characterisation and modelling of temporal aspects of BOLD responses needs to be carried out routinely, informing experimental design and analysis, and physiological modelling.     

Impaired hemodynamic response in the ischemic brain assessed with BOLD fMRI

The study aims to investigate the effect of cerebral ischemia or hypoperfusion in the evaluation of neural activity with blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI), and to examine whether the severity of the compromised hemodynamic status in patients with major cerebral artery diseases could, conversely, be assessed with the use of neural activity as endogenous vasodilator. 28 neurological impairment-free patients with anterior-circulation-territory ischemia performed a bimanual hand-grasping task. Magnitude and temporal shift of evoked BOLD response, baseline cerebral blood flow (CBF) and its increment, and the severity of hemodynamic impairment stratified by blood flow pattern were evaluated. For fMRI data, both conventional analysis with a canonical HRF and an HRF-model-free analysis were performed. The severity of hemodynamic impairment was significantly correlated (p<0.0001) with baseline CBF, CBF increment, and magnitude and delay of BOLD response. BOLD response delay was also significantly correlated (p<0.0001) with baseline CBF, CBF increment, and response magnitude. In 10 out of 45 ischemic motor cortices, conventional analysis completely failed to detect areas of activation that were demonstrated by HRF-model-free analysis. These data suggest that delay and reduced magnitude of BOLD response can be an indicator of the severity of compromised hemodynamic status, and that reduced regional baseline CBF and its increment underlie impaired BOLD response, which necessitates an alternative approach to conventional analysis with any single HRF.     

Investigating the source of BOLD nonlinearity in human visual cortex in response to paired visual stimuli

Several studies have demonstrated significant nonlinearity in the blood-oxygenation-level-dependent (BOLD) signal. Completely understanding the nature of this nonlinear behavior is important in the interpretation of the BOLD signal. However, this task is hindered by the uncertainty of the source of BOLD nonlinearity which could come from neuronal and/or vascular origin. The obscurity of this issue not only impedes accurate modeling of BOLD nonlinearity, but also limits generalization of the conclusions regarding BOLD nonlinearity. To examine this issue, we eliminated nonlinear contributions from the neuronal response and selectively study BOLD nonlinearity under only the vascular effect by employing a paired-stimulus paradigm composed of two ultra-short visual stimuli separated by a variable inter-stimulus interval (ISI). ISIs chosen were long enough (> or = 1s) to ensure invariant neuronal activity to all stimuli. Under this circumstance, we still observed significant nonlinearity in the BOLD signal reflected by a progressive recovery of BOLD response to the second stimuli as ISI gets longer and delayed BOLD onset latency. These nonlinear behaviors identified in the BOLD signal originate entirely from the vascular responses as the neuronal responses to all stimuli are identical. More importantly, we found that BOLD nonlinearity became much less significant after we removed activated pixels from large vessels. These finds reveal that the dominant component, if not all, of the source of BOLD nonlinearity comes from large-vessel hemodynamic response. They also suggest a possible mechanism to improve the spatial specificity of gradient-echo BOLD signal for fMRI mapping based on the characteristics of vascular refractoriness.     

Enhancing BOLD response in the auditory system by neurophysiologically tuned fMRI sequence

Auditory neuroscience has not tapped fMRI's full potential because of acoustic scanner noise emitted by the gradient switches of conventional echoplanar fMRI sequences. The scanner noise is pulsed, and auditory cortex is particularly sensitive to pulsed sounds. Current fMRI approaches to avoid stimulus-noise interactions are temporally inefficient. Since the sustained BOLD response to pulsed sounds decreases with repetition rate and becomes minimal with unpulsed sounds, we developed an fMRI sequence emitting continuous rather than pulsed gradient sound by implementing a novel quasi-continuous gradient switch pattern. Compared to conventional fMRI, continuous-sound fMRI reduced auditory cortex BOLD baseline and increased BOLD amplitude with graded sound stimuli, short sound events, and sounds as complex as orchestra music with preserved temporal resolution. Response in subcortical auditory nuclei was enhanced, but not the response to light in visual cortex. Finally, tonotopic mapping using continuous-sound fMRI demonstrates that enhanced functional signal-to-noise in BOLD response translates into improved spatial separability of specific sound representations.     

Acute tryptophan depletion improves performance and modulates the BOLD response during a Stroop task in healthy females

To gain more insight into the effect of low brain serotonin (5-HT) on brain activation related to conflict, the present study examined the effect of acute tryptophan depletion (ATD) on performance and the blood oxygen level dependent (BOLD) response during a combined cognitive and emotional Stroop task. Fifteen healthy female volunteers were tested during a placebo and tryptophan depletion session in an event-related fMRI design. ATD improved performance during Stroop interference. Two effects of ATD on the BOLD response were found. Firstly, ATD increased the BOLD response in the anterior cingulate cortex (ACC) (BA 32) when incongruent color words were compared with congruent color words in the first Stroop block the participants performed. Secondly, ATD increased the BOLD response in the left precuneus (BA 31) and cuneus (BA 18) during congruent color words. ATD did not affect the BOLD response accompanying emotional stimuli. However, we showed that ATD increased the interference of negative words on color naming. This finding was explained in terms of an emotional processing bias in favor of negative words, which leads to stronger interference of these words. In line with previous studies, the present study showed that a temporary reduction of 5-HT improved Stroop performance and changed the underlying brain activation pattern in healthy female participants. Moreover, we replicated our previous finding that ATD modulated the BOLD response in the dorsomedial prefrontal cortex during tasks that require cognitive control.     

Source of nonlinearity of the BOLD response revealed by simultaneous fMRI and NIRS

The nonlinearity of the blood oxygenation level-dependent (BOLD) response to stimuli of different duration, particularly those of short duration, has been well studied by functional magnetic resonance imaging (fMRI). This nonlinearity is assumed to be due to neural adaptation and the nonlinearity of the response in the oxygen extraction fraction (OEF); the latter has not been examined quantitatively in humans. To evaluate how the OEF response contributes to the nonlinearity of the BOLD response to neural activity, we used simultaneous fMRI and near-infrared spectroscopy (NIRS). The responses to visual stimuli of four different durations were measured as changes in the BOLD signal and the NIRS-derived hemoglobin concentrations. The hemodynamic response nonlinearity was quantified using an impulse response function model with saturation nonlinearity scaling in the response amplitude, assuming that the unknown neural adaptation parameters varied within a physiologically feasible range. Independent of the degree of neural adaptation, the BOLD response consistently showed saturation nonlinearity similar to that of the OEF response estimated from the NIRS measures, the nonlinearity of which was greater than that of the response in the total hemoglobin concentration representing the cerebral blood volume (CBV). We also found that the contribution of the OEF response to the BOLD response was four to seven times greater than the contribution of the CBV response. Thus, we conclude that the nonlinearity of the BOLD response to neural activity originates mainly from that of the OEF response.     

Neural correlates of high and craving during cocaine self-administration using BOLD fMRI

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.     

Comparison of BOLD fMRI and MEG characteristics to vibrotactile stimulation

The characteristics of blood oxygenation level-dependent (BOLD) fMRI and magnetoencephalographic (MEG) responses to vibrotactile stimuli in humans were studied and compared. The stimuli, presented with interstimulus intervals (ISIs) ranging from 1 to 5 s, yielded highly reproducible MEG responses, with current dipoles in the primary somatosensory (SI) cortex in all subjects. BOLD fMRI responses to similar stimuli showed substantial intrasubject variation in the activation sites around the SI cortex. BOLD responses were detected in all subjects in the secondary somatosensory (SII) cortices as well, with comparable BOLD response amplitudes to those in the SI cortex. Current dipoles, used to model the MEG signals, were stronger at longer ISIs than shorter ISIs. The BOLD response amplitudes did not show a similar dependence on ISI, but the activated brain area was larger when longer ISIs or longer stimuli were applied. Our results support the view that combined use of brain mapping methods provides complementary information and should be considered in functional brain examinations.     

Testing for Neural Responses during Temporal Components of Trials with BOLD fMRI

Some cognitive neuroscientific hypotheses might concern neural responses occurring during particular periods of time in a behavioral trial. Here, these particular periods of time are referred to as temporal components of the trial. A difficulty in using BOLD fMRI to test hypotheses about neural responses during temporal components is that some information is irretrievably lost when neural responses are hemodynamically transformed. As a result, one cannot in general use the fMRI signal to unambiguously specify if there was a neural response during a given temporal component. However, adoption of a linear-time invariant model for the transform from neural signal to fMRI signal and constraint of the space of underlying neural waveforms might allow one to ask such questions. Here, the basic theory relevant to this issue and a corresponding method are discussed. The application of this method to fMRI time series data collected during the performance of a delayed-response trial is provided as an illustrative example.     

A direct comparison between whole-brain PET and BOLD fMRI measurements of single-subject activation response

We present the results of a direct comparison of single-subject activation using identical tasks for both functional PET and fMRI whole-brain studies. We examined the most commonly employed methods for each modality. For fMRI this is the blood oxygenation level-dependent (BOLD) contrast method with echo-planar imaging. In PET single-subject activation studies are based on the development of high sensitivity 3D imaging of regional cerebral blood flow from multiple [15O]water injections. The identical activation paradigm of a visually cued sequential finger opposition was used for PET and fMRI. For both modalities the entire brain volume difference images were smoothed to the same final resolution and the peak t value within the primary sensory/motor (PSM) area was then identified. All contiguous voxels in the PSM above a predetermined threshold of statistical significance were determined. Finally, the difference-weighted centroid location was calculated for the PSM region for each modality. These studies showed a very similar pattern of activation, with the volume of activation greater in fMRI and higher levels of statistical significance. The centroids of activation, however, differed by 9 +/- 3 mm between the modalities, with the fMRI centroid location dorsal to that for PET. These results were stable across all processing options including differing levels of image smoothing and thresholds of statistical significance. These results are consistent with the hypothesis that draining veins contribute a substantial signal for fMRI activation studies and indicate caution for the interpretation of BOLD fMRI images with activation sites near draining veins.     

Network analysis of single-subject fMRI during a finger opposition task

The analysis of functional magnetic resonance imaging (fMRI) data has typically relied on univariate methods to identify areas of brain activity related to cognitive and behavioral task performance. We investigated the ability of multivariate network analysis using a modified form of principal component analysis, the Scaled Subprofile Model (SSM), applied to single-subject fMRI data to identify patterns of interactions among brain regions over time during an anatomically well-characterized simple motor task. We hypothesized that each subject would exhibit correlated patterns of brain activation in several regions known to participate in the regulation of movement including the contralateral motor cortex and the ipsilateral cerebellum. EPI BOLD images were acquired in six healthy participants as they performed a visually and auditorally paced finger opposition task. SSM analysis was applied to the fMR time series on a single-subject basis. Linear combinations of the major principal components that predicted the expected hemodynamic response to the order of experimental conditions were identified for each participant. These combinations of SSM patterns were highly associated with the expected hemodynamic response, an indicator of local neuronal activity, in each participant (0.84 相似文献   

BOLD response during uncoupling of neuronal activity and CBF

The widely used technique of functional magnetic resonance imaging (fMRI) based on the blood oxygenation level-dependent (BOLD) effect is a tool for the investigation of changes in local brain activity upon stimulation. The principle of measurement is based on the assumption that there is a strong coupling between changes in neural activity, metabolism, vascular response and oxygen extraction in the area under investigation. As fMRI is on the way to become a routine tool in clinical examinations, we wanted to investigate whether, generally and under a variety of conditions, there is a strong link between the BOLD signal and neural activity. For clinical and experimental application of the method, it is crucial, whether the absence of changes in BOLD signal intensity upon stimulation can always be interpreted as an absence of changes in brain activity. We approached this question by inhibiting the nitric oxide mediated 'neurovascular coupling' via application of 7 nitroindazole. Before and after inhibition of this neurovascular coupling, we acquired evoked potentials and performed fMRI during somatosensory stimulation in rats. Cerebral blood flow response as well as BOLD signal intensity changes following electrical stimulation were abolished within 10 min after application of 7 nitroindazole, whereas somatosensory-evoked potentials were only slightly affected but still clearly detectable. Even 1 h after injection of 7 nitroindazole, there was still remaining electrical activity. Thus, we observed an uncoupling between electrical, i.e., neural activity and the BOLD signal. According to our results, the absence of BOLD signal changes did not permit the conclusion that there was no neural activity in the area under investigation. Our findings are especially relevant for the clinical application of fMRI in patients suffering from cerebrovascular and other brain diseases.