Watching social interactions produces dorsomedial prefrontal and medial parietal BOLD fMRI signal increases compared to a resting baseline

Some human brain areas are tonically active in a resting state when subjects are not engaged in any overt task. The activity of these areas decreases when subjects are engaged in a wide variety of laboratory tasks designed to study cognitive operations. It has been suggested that these areas, among them the medial parietal (precyneus) and the dorsomedial prefrontal cortices, may support a "default state" of the human brain. Passive visual observation of laboratory stimuli typically yields no change in activity in these default areas compared to rest. Here we report functional magnetic resonance imaging (fMRI) data on normal subjects watching realistic movie clips depicting everyday social interactions. In contrast with previous findings on default state brain areas, the observation of the relational segment of the movie clip, during which two persons interact, yielded increased activity in the medial parietal (precuneus) and dorsomedial prefrontal cortices, compared to rest and to observation of the segment of the movie clip depicting a single individual engaged in everyday activities. To the best of our knowledge, this is the first report of joint increased activity in medial parietal and dorsomedial prefrontal cortices. We suggest that the default state areas may participate in the processing of social relations in concert with regions previously identified as critical for social cognition that were also activated by our stimuli, including the inferior frontal cortex, the superior temporal cortex, and the fusiform gyrus.     

A calibration method for quantitative BOLD fMRI based on hyperoxia

The estimation of changes in CMR(O2) using functional MRI involves an essential calibration step using a vasoactive agent to induce an isometabolic change in CBF. This calibration procedure is performed most commonly using hypercapnia as the isometabolic stimulus. However, hypercapnia possesses a number of detrimental side effects. Here, a new method is presented using hyperoxia to perform the same calibration step. This procedure requires independent measurement of Pa(O2), the BOLD signal, and CBF. We demonstrate that this method yields results that are comparable to those derived using other methods. Further, the hyperoxia technique is able to provide an estimate of the calibration constant that has lower overall intersubject and intersession variability compared to the hypercapnia approach.     

Baseline BOLD correlation predicts individuals' stimulus-evoked BOLD responses

To investigate whether individuals' ongoing neuronal activity at resting state can affect their response to brain stimulation, fMRI BOLD signals were imaged from the human visual cortex of fifteen healthy subjects in the absence and presence of visual stimulation. It was found that the temporal correlation strength but not amplitude of baseline BOLD signal fluctuations acquired under the eyes-fixed condition is positively correlated with the amplitude of stimulus-evoked BOLD responses across subjects. Moreover, the spatiotemporal correlations of baseline BOLD signals imply a coherent network covering the visual system, which is topographically indistinguishable from the "resting-state visual network" observed under the eyes-closed condition. The overall findings suggest that the synchronization of ongoing brain activity plays an important role in determining stimulus-evoked brain activity even at an early stage of the sensory system. The tight relationship between baseline BOLD correlation and stimulus-evoked BOLD amplitude provides an essential basis for understanding and interpreting the large inter-subject BOLD variability commonly observed in numerous fMRI studies and potentially for improving group fMRI analysis. This study highlights the importance to integrate the information from both resting-state coherent networks and task-evoked neural responses for a better understanding of how the brain functions.     

Influences of negative BOLD responses on positive BOLD responses

Understanding possible interactions between blood oxygenation level-dependent (BOLD) responses is critical for model-based analyses and the interpretation of experiments that deal with stimuli presented close together in time. Such interactions are well documented in the case of successive positive BOLD responses. However, the influence that a stimulus-induced, negative BOLD response exerts on a subsequent positive BOLD response has yet to be investigated and is the focus of the current study. We performed functional magnetic resonance imaging on 10 healthy subjects during bilateral electrical median nerve stimulation using five different time intervals between left- and right-sided stimuli. We found an acute interruption of the ongoing negative BOLD response at the onset of the positive BOLD response. Different parameters characterizing the positive BOLD response were estimated. There was no impact of the preceding negative BOLD response on the parameters describing the subsequent positive BOLD response. These findings indicate that the underlying mechanisms for negative and positive BOLD responses do not engage parallel processes. We hypothesize that the negative BOLD response is caused by a decreased release of the same vasodilatative agents that evoke the positive BOLD response. Additionally, our results demonstrate that there is no need to adjust the model of a positive BOLD response due to a preceding negative BOLD response in the same brain area.     

A comparison of methods for characterizing the event-related BOLD timeseries in rapid fMRI

Information about the shape and temporal duration of the blood oxygenation level dependent (BOLD) response can inform both functional neuroanatomy and psychological theory. However, the BOLD response evolves over 20 s or more, making it difficult to distinguish the unique characteristics of the response evoked by temporally adjacent stimuli. Fortunately, event-related BOLD signals can be extracted given that there is adequate variance in the distribution of inter-stimulus intervals (ISI). Unfortunately, the ISI distribution that yields the highest statistical efficiency is not always optimal from a psychological perspective; variability in the stimulus timing may complicate the interpretation of neuroimaging data in terms of underlying cognitive operations. In the present paper, Monte Carlo simulations are used to evaluate two techniques for estimating the event-related BOLD timeseries-event-related averaging and deconvolution using the Ordinary Least Squares estimate -with respect to maintaining acceptable levels of statistical power and experimental validity. While the unbiased deconvolution technique more robustly estimates the shape of the BOLD response functions, both methods succeed in accurately re-producing known differences between evoked BOLD responses when the stimulus ordering is randomized. However, the deconvolution method is more effective at preserving differences when there are sequential dependencies in the stimulus presentation order and restricted ISI distributions are used; particularly if the second of two sequentially dependent stimuli is omitted on some portion of the trials. Importantly, the successful re-production of the evoked BOLD response using restricted ISI distributions often maximizes the ability to make psychologically valid experimental conclusions.     

Improved spatial localization of post-stimulus BOLD undershoot relative to positive BOLD

The negative blood oxygenation level-dependent (BOLD) signal following the cessation of stimulation (post-stimulus BOLD undershoot) is observed in functional magnetic resonance imaging (fMRI) studies. However, its spatial characteristics are unknown. To investigate this, gradient-echo BOLD fMRI in response to visual stimulus was obtained in isoflurane-anesthetized cats at 9.4 T. Since the middle cortical layer (layer 4) is known to have the highest metabolic and cerebral blood volume (CBV) responses, images were obtained to view the cortical cross-section. Robust post-stimulus BOLD undershoot was observed in all studies, and lasted longer than 30 s after the cessation of 40-60 s stimulation. The magnitude of post-stimulus BOLD undershoot was linearly dependent on echo time with little intercept when extrapolating to TE = 0, indicating that the T2* change is the major cause of the BOLD undershoot. The post-stimulus BOLD undershoot was observed within the cortex and near the surface of the cortex, while the prolonged CBV elevation was observed only at the middle of the cortex. Within the cortex, the largest post-stimulus undershoot was detected at the middle of the cortex, similar to the CBV increase during the stimulation period. Our findings demonstrate that, even though there is significant contribution from pial vessel signals, the post-stimulus undershoot BOLD signal is useful to improve the spatial localization of fMRI to active cortical sites.     

A BOLD signature of eyeblinks in the visual cortex

We are usually unaware of the brief but large illumination changes caused by blinks, presumably because of blink suppression mechanisms. In fMRI however, increase of the BOLD signal was reported in the visual cortex, e.g. during blocks of voluntary blinks (Bristow, Frith and Rees, 2005) or after spontaneous blinks recorded during the prolonged fixation of a static stimulus (Tse, Baumgartner and Greenlee, 2010). We tested whether such activation, possibly related to illumination changes, was also present during standard fMRI retinotopic and visual experiments and was large enough to contaminate the BOLD signal we are interested in. We monitored in a 3T scanner the eyeblinks of 14 subjects who observed three different types of visual stimuli, including periodic rotating wedges and contracting/expanding rings, event-related Mondrians and graphemes, while fixating. We performed event-related analyses on the set of detected spontaneous blinks. We observed large and widespread BOLD responses related to blinks in the visual cortex of every subject and whatever the visual stimulus. The magnitude of the modulation was comparable to visual stimulation. However, blink-related activations lay mostly in the anterior parts of retinotopic visual areas, coding the periphery of the visual field well beyond the extent of our stimuli. Blinks therefore represent an important source of BOLD variations in the visual cortex and a troublesome source of noise since any correlation, even weak, between the distribution of blinks and a tested protocol could trigger artifactual activities. However, the typical signature of blinks along the anterior calcarine and the parieto-occipital sulcus allows identifying, even in the absence of eyetracking, fMRI protocols possibly contaminated by a heterogeneous distribution of blinks.     

Effects of hypoxia, hyperoxia, and hypercapnia on baseline and stimulus-evoked BOLD, CBF, and CMRO2 in spontaneously breathing animals

Functional magnetic resonance imaging (fMRI) was used to investigate the effects of inspired hypoxic, hyperoxic, and hypercapnic gases on baseline and stimulus-evoked changes in blood oxygenation level-dependent (BOLD) signals, cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen (CMRO2) in spontaneously breathing rats under isoflurane anesthesia. Each animal was subjected to a baseline period of six inspired gas conditions (9% O2, 12% O2, 21% O2, 100% O2, 5% CO2, and 10% CO2) followed by a superimposed period of forepaw stimulation. Significant stimulus-evoked fMRI responses were found in the primary somatosensory cortices. Relative fMRI responses to forepaw stimulation varied across gas conditions and were dependent on baseline physiology, whereas absolute fMRI responses were similar across moderate gas conditions (12% O2, 21% O2 100% O2, and 5% CO2) and were relatively independent of baseline physiology. Consistent with data obtained using well-established techniques, baseline and stimulus-evoked CMRO2 were invariant across moderate physiological perturbations thereby supporting a CMRO2-fMRI technique for non-invasive CMRO2 measurement. However, under 9% O2 and 10% CO2, stimulus-evoked CBF and BOLD were substantially reduced and the CMRO2 formalism appeared invalid, likely due to attenuated neurovascular coupling and/or a failure of the model under extreme physiological perturbations. These findings demonstrate that absolute fMRI measurements help distinguish neural from non-neural contributions to the fMRI signals and may lend a more accurate measure of brain activity during states of altered basal physiology. Moreover, since numerous pharmacologic agents, pathophysiological states, and psychiatric conditions alter baseline physiology independent of neural activity, these results have implications for neuroimaging studies using relative fMRI changes to map brain activity.     

A Delphi study to determine baseline informatics competencies for nurse managers

The objective of this research study was to produce a job-specific list of informatics competencies for generic nurse manager positions. In 2002, Staggers et al (Nurs Res. 2002;51(6):383-390) identified a list of core nursing informatics competencies at four levels of nursing practice but concluded that job-specific competencies still needed to be developed. An expert panel utilized the Master List of Nursing Informatics Competencies produced in the 2002 study by Staggers et al to define the job-specific informatics competencies appropriate for generic nurse manager positions. A three-round Delphi study was utilized to establish the core competencies appropriate for this job-specific position. Participants were expert informatics nurses in the US Veterans' Healthcare System. Based on the Four Levels of Practice defined in the 2002 study by Staggers et al, the panel identified the level 2 experienced nurse as most appropriate for generic nurse manager positions. For the purposes of review, each practice level was considered to include the competencies of the levels below it. Therefore, having selected level 2 experienced nurse, this necessitated the review of levels 1 and 2, which totaled 69 competencies. From the available 69 competencies, the panel selected a total of 49 core competencies appropriate for generic nurse manager positions. This Delphi research study chose to focus on a single job-specific position to take one small step toward the recommendation of Staggers et al to identify job-specific competencies. The generic nurse manager position was selected as it is a vital position in providing leadership and support within all institutions. While the study raises several questions about how the panel elected some competencies over others, it also begins to define which levels of competencies and categories are most appropriate. With this information at hand, the next logical step would be to establish associated tools for competency development and evaluation, which could then be used to properly prepare and review individuals for the associated nurse manager responsibilities.     

A component based noise correction method (CompCor) for BOLD and perfusion based fMRI

A component based method (CompCor) for the reduction of noise in both blood oxygenation level-dependent (BOLD) and perfusion-based functional magnetic resonance imaging (fMRI) data is presented. In the proposed method, significant principal components are derived from noise regions-of-interest (ROI) in which the time series data are unlikely to be modulated by neural activity. These components are then included as nuisance parameters within general linear models for BOLD and perfusion-based fMRI time series data. Two approaches for the determination of the noise ROI are considered. The first method uses high-resolution anatomical data to define a region of interest composed primarily of white matter and cerebrospinal fluid, while the second method defines a region based upon the temporal standard deviation of the time series data. With the application of CompCor, the temporal standard deviation of resting-state perfusion and BOLD data in gray matter regions was significantly reduced as compared to either no correction or the application of a previously described retrospective image based correction scheme (RETROICOR). For both functional perfusion and BOLD data, the application of CompCor significantly increased the number of activated voxels as compared to no correction. In addition, for functional BOLD data, there were significantly more activated voxels detected with CompCor as compared to RETROICOR. In comparison to RETROICOR, CompCor has the advantage of not requiring external monitoring of physiological fluctuations.     

Improved characterization of BOLD responses for evoked sensory stimuli

Pain and somatosensory processing involves an interaction of multiple neuronal networks. One result of these complex interactions is the presence of differential responses across brain regions that may be incompletely modeled by a straightforward application of standard general linear model (GLM) approaches based solely on the applied stimulus. We examined temporal blood oxygenation-level dependent (BOLD) signatures elicited by two stimulation paradigms (brush and heat) providing innocuous and noxious stimuli. Data were acquired from 32 healthy male subjects (2 independent cohorts). Regional time courses and model-free analyses of the first cohort revealed distinct temporal features of the BOLD responses elicited during noxious versus innocuous stimulation. Specifically, a biphasic (dual peak) BOLD signal was observed in response to heat but much less so in response to brush stimuli. This signal was characterized by a stimulus-locked response along with a second peak delayed by ～12.5 s. A cross-validation error analysis determined a modified design matrix comprising two explanatory variables (EVs) as a parsimonious means to model the biphasic responses within a GLM framework. One EV was directly derived from the stimulation paradigm (EV1), while the second EV (EV2) was EV1 shifted by 12.5 s. The 2EV GLM analysis enabled a more detailed characterization of the elicited BOLD responses, particularly during pain processing. This was confirmed by application of the model to a second, independent cohort[AU1]. Furthermore, the delayed component of the biphasic response was strongly associated with the noxious heat stimuli, suggesting that this may represent a sensitive fMRI link of pain processing.     

A comparison of nonparametric and parametric methods to adjust for baseline measures

When analyzing the randomized controlled trial, we may employ various statistical methods to adjust for baseline measures. Depending on the method chosen to adjust for baseline measures, inferential results can vary. We investigate the Type 1 error and statistical power of tests comparing treatment outcomes based on parametric and nonparametic methods. We also explore the increasing levels of correlation between baseline and changes from the baseline, with or without underlying normality. These methods are illustrated and compared via simulations.     

Dynamic models of BOLD contrast

This personal recollection looks at the evolution of ideas about the dynamics of the blood oxygenation level dependent (BOLD) signal, with an emphasis on the balloon model. From the first detection of the BOLD response it has been clear that the signal exhibits interesting dynamics, such as a pronounced and long-lasting post-stimulus undershoot. The BOLD response, reflecting a change in local deoxyhemoglobin, is a combination of a hemodynamic response, related to changes in blood flow and venous blood volume, and a metabolic response related to oxygen metabolism. Modeling is potentially a way to understand the complex path from changes in neural activity to the BOLD signal. In the early days of fMRI it was hoped that the hemodynamic/metabolic response could be modeled in a unitary way, with blood flow, oxygen metabolism, and venous blood volume-the physiological factors that affect local deoxyhemoglobin-all tightly linked. The balloon model was an attempt to do this, based on the physiological ideas of limited oxygen delivery at baseline and a slow recovery of venous blood volume after the stimulus (the balloon effect), and this simple model of the physiology worked well to simulate the BOLD response. However, subsequent experiments suggest a more complicated picture of the underlying physiology, with blood flow and oxygen metabolism driven in parallel, possibly by different aspects of neural activity. In addition, it is still not clear whether the post-stimulus undershoot is a hemodynamic or a metabolic phenomenon, although the original venous balloon effect is unlikely to be the full explanation, and a flow undershoot is likely to be important. Although our understanding of the physics of the BOLD response is now reasonably solid, our understanding of the underlying physiological relationships is still relatively poor, and this is the primary hurdle for future models of BOLD dynamics.     

Improved shimming for fMRI specifically optimizing the local BOLD sensitivity

In functional MRI, magnetic field inhomogeneities due to air-tissue susceptibility differences may lead to severe signal dropouts and geometric distortions in echo-planar images. Therefore, the inhomogeneities in the field are routinely minimized by shimming prior to imaging. However in fMRI, the Blood Oxygen Level Dependent (BOLD) effect is the measure of interest, so the BOLD sensitivity (BS) should be optimized rather than the magnetic field homogeneity. The analytical expression for an estimate of the BOLD sensitivity has been recently developed, allowing for the computation of BOLD sensitivity maps from echo-planar images and field maps. This report describes a novel shimming procedure that optimizes the local BOLD sensitivity over a region of interest. The method is applied in vivo and compared to a standard global shimming procedure. A breath-holding experiment was carried out and demonstrated that the BS-based shimming significantly improved the detection of activation in a target region of interest, the medial orbitofrontal cortex.     

IRON fMRI measurements of CBV and implications for BOLD signal

Changes in cerebral blood volume (CBV) and blood magnetization each induce changes in the transverse relaxation rate of MRI signal that are associated with changes in cerebral activity. BOLD signal, the preeminent method for non-invasive localization of task-induced brain function in human subjects, reflects a combination of changes in CBV and blood magnetization. Intravenous injection of paramagnetic contrast media, usually iron oxide particles surrounded by larger macromolecules, can overwhelm the BOLD response and sensitize signal to blood plasma volume, a method we have deemed "IRON" fMRI. The practical advantage of this technique is the ability to optimize blood magnetization at any echo time, enabling high detection power and the use of short echo times; for these reasons, IRON fMRI has become a valuable imaging tool in animal models. The temporal response of blood plasma volume is quite different from blood flow and BOLD signal; thus, CBV has been identified as a prominent source of transient features of the BOLD response. This article reviews the methodological advantages of the IRON method and how CBV measurements have informed our understanding of the BOLD response.     

Linear coupling of undershoot with BOLD response in ER-fMRI and nonlinear BOLD response in rapid-presentation ER-fMRI

In event-related (ER) BOLD-fMRI brain activation studies, understanding the relationship between the elicited BOLD signal and its underlying neuronal activity is essential for any quantitative interpretation of the neural events from the BOLD measurements. This requires a better understanding of the dynamic BOLD response. Besides the neuronal activity-induced positive BOLD response, the dynamic response is also characterized by a profound post-stimulus undershoot. The relationship between the positive response and the post-stimulus undershoot, however, remains poorly understood. Earlier studies using block-design paradigms with long stimulation durations (>10s) do not suggest a quantitative relationship. Using an ER paradigm, this study revealed a linear coupling between the positive BOLD response and the post-stimulus undershoot across the human visual cortex. The voxelwise linear coupling across the visual cortex strongly supports a homogeneous hemodynamic response in ER paradigms, though the BOLD response magnitude varies substantially over a wide range across the visual cortex. Although underlying neuronal activity is responsible for a BOLD response, the blood volume fraction affects the magnitude of the BOLD response; the larger the blood volume fraction, the larger the magnitude. This effect needs to be accounted for in any quantitative interpretation of the BOLD measurements. In the absence of nonlinear neuronal activities, the nonlinear vascular response renders the estimated BOLD responses smaller in rapid presentation (RP) ER paradigms compared to that in ER paradigms, and this reduction effect also needs to be considered when interpreting the estimated BOLD responses in RP-ER paradigms. Interestingly, this nonlinear effect might be simply accounted for by a scaling factor across the visual cortex.     

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.