The critical relationship between the timing of stimulus presentation and data acquisition in blocked designs with fMRI.

This paper concerns the experimental design and statistical models employed by fMRI activation studies which block presentation of linguistic stimuli. In particular, we note that the relationship between the timing of stimulus presentation and data acquisition can have a substantial impact on the ability to detect activations in critical language areas, even when the stimuli are presented in blocks. Using a blocked word rhyming paradigm and repeated investigations on a single subject, activation was observed in Broca's area (left inferior frontal cortex) and Wernicke's area (left posterior temporoparietal cortex) when (i) the timing of data acquisition was distributed throughout the peristimulus time and (ii) an event-related analysis was used to model the phasic nature of the hemodynamic response within each block of repeated word stimuli. In contrast, when the timing of data acquisition relative to stimulus presentation was fixed, activation was detected in Broca's area but not consistently in Wernicke's area. Our results indicate that phasic responses to stimuli occur even in a blocked design and that the sampling and proper modeling of these responses can have profound effects on their detection. Specifically, distributed sampling over peristimulus time is essential in order to detect small activations particularly when they are transient. These findings are likely to generalize to the detection of transient signals in any cognitive paradigm.     

Interleaved silent steady state (ISSS) imaging: a new sparse imaging method applied to auditory fMRI

The acoustic scanner noise that is generated by rapid gradient switching in echo planar imaging (EPI) is an important confounding factor in auditory fMRI. "Sparse imaging" designs overcome the influence of scanner noise on stimulus presentation by acquiring single brain volumes following a silent stimulus presentation period. However, conventional sparse imaging requires assumptions about the time-to-peak of the evoked hemodynamic response and reduces the amount of EPI data which can be acquired and hence statistical power. In this article, we describe an "interleaved silent steady state" (ISSS) sampling scheme in which we rapidly acquire a set of EPI volumes following each silent stimulus presentation period. We avoid T1-related signal decay during the acquisition of the EPI volumes by maintaining the steady state longitudinal magnetization with a train of silent slice-selective excitation pulses during the silent period, ensuring that signal contrast is constant across successive scans. A validation study comparing ISSS to conventional sparse imaging demonstrates that ISSS imaging provides time course information that is absent in conventional sparse imaging data. The ISSS sequence has a temporal resolution like event-related (ER) imaging within a single trial (unlike conventional sparse imaging, where ER-like temporal resolution can only be achieved by compiling data across many jittered trials of the same stimulus type). This temporal resolution within trials makes ISSS particularly suitable for experiments in which a) scanner noise would interfere with the perception and processing of the stimulus; b) stimuli are several seconds in duration, and activation is expected to evolve and change as the stimulus unfolds; and c) it is impractical to present a single stimulus more than once (for example, repetition priming or familiarity effects would be expected).     

Adaptive pacing of visual stimulation for fMRI studies involving overt speech

We report the development of an interactive approach to single-word language production studies in fMRI. The approach, adaptive pacing, involves real-time adjustment of stimulus presentation times based on individual subject performance timing and content. At the same time, it maintains a stochastic distribution of interstimulus intervals to avoid confounding task covariates with speech-related signal variance. Adaptive pacing of overt speech production is an example of a new class of paradigms that require an observational approach to data acquisition and benefit from a "time-aware" acquisition and processing environment. The advantages of adaptive pacing in fMRI of impaired subjects are expected to be the acquisition of more informative data per unit time, less contamination of data by correlates of non-language processes such as emotion, and facilitation of experiments that combine normal and impaired subjects.     

Analysis of speech-related variance in rapid event-related fMRI using a time-aware acquisition system

Speech production introduces signal changes in fMRI data that can mimic or mask the task-induced BOLD response. Rapid event-related designs with variable ISIs address these concerns by minimizing the correlation of task and speech-related signal changes without sacrificing efficiency; however, the increase in residual variance due to speech still decreases statistical power and must be explicitly addressed primarily through post-processing techniques. We investigated the timing, magnitude, and location of speech-related variance in an overt picture naming fMRI study with a rapid event-related design, using a data acquisition system that time-stamped image acquisitions, speech, and a pneumatic belt signal on the same clock. Using a spectral subtraction algorithm to remove scanner gradient noise from recorded speech, we related the timing of speech, stimulus presentation, chest wall movement, and image acquisition. We explored the relationship of an extended speech event time course and respiration on signal variance by performing a series of voxelwise regression analyses. Our results demonstrate that these effects are spatially heterogeneous, but their anatomic locations converge across subjects. Affected locations included basal areas (orbitofrontal, mesial temporal, brainstem), areas adjacent to CSF spaces, and lateral frontal areas. If left unmodeled, speech-related variance can result in regional detection bias that affects some areas critically implicated in language function. The results establish the feasibility of detecting and mitigating speech-related variance in rapid event-related fMRI experiments with single word utterances. They further demonstrate the utility of precise timing information about speech and respiration for this purpose.     

Event-related fMRI of the auditory cortex.

An event-related protocol was designed to permit auditory fMRI studies minimally affected by the echo-planar noise artifact; a long time interval (TR = 10 s) between each cerebral volume acquisition was combined with stroboscopic data acquisition, and event-related curves were reconstructed with a 1-s resolution. The cerebral hemodynamic-response time course to a target auditory stimulus was measured in five individual subjects using this method. Clear bell-shaped event-related responses were observed bilaterally in all individuals in primary auditory cortex (A1) as well as in laterally extending secondary cortical fields. Group-average event-related curves attained their maxima (0.5-0.7%) 3 s after stimulus onset in A1 (4 s for more anterior and lateral regions of auditory cortex), and signal had returned to near-baseline level 6 s after stimulus onset. The stroboscopic event-related method appeared effective in minimizing effects of the interaction between scanning noise and experimental auditory stimulation; it adds useful temporal information to the spatial resolution afforded by fMRI in studies of human auditory function, while allowing presentation of auditory stimuli on a silent background.     

Effects of N6-(L-phenylisopropyl)adenosine, caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit

This study examined the effects of caffeine, theophylline and rolipram on the acquisition of conditioned responses in the rabbit and their ability to antagonize the retardant effects of the adenosine analog N6-(L-phenylisopropyl)adenosine (L-PIA) on acquisition. Pavlovian conditioning of nictitating membrane extension was accomplished by pairing the offset of a 800-msec tone- and light-conditioned stimulus with the onset of a 100-msec shock unconditioned stimulus to the skin just lateral to the outer canthus of the eye. L-PIA (5 mumol/kg) retarded the acquisition of conditioned responses to the tone- and light-conditioned stimuli, although theophylline (50-200 mumol/kg), caffeine (3-100 mumol/kg) and rolipram (0.03-3.0 mumol/kg) had no effect. The highest dose of caffeine used (300 mumol/kg) produced a small but significant enhancement of conditioned response acquisition in two of four experiments. The two adenosine antagonists theophylline (200 mumol/kg) and caffeine (300 mumol/kg) completely blocked the retardant effects of L-PIA on acquisition, although the phosphodiesterase inhibitor rolipram (3.0 mumol/kg) did not. In previously trained animals, L-PIA (5 mumol/kg) also increased the intensity threshold of a tone-conditioned stimulus for eliciting conditioned responses by more than 10 db. Theophylline (200 mumol/kg) and caffeine (300 mumol/kg) had no effect on the intensity threshold of the tone-conditioned stimulus but completely antagonized the effects of L-PIA. It was suggested that the depressant effects of the adenosine analog L-PIA on both the acquisition of conditioned responses and on the ability of a conditioned stimulus to elicit conditioned responses as soon as learning had occurred were mediated by adenosine receptors.     

Comparative evaluation of sponsored and unsponsored continuing medical education]

BACKGROUND AND PURPOSE: Continuing medical education (CME), by law, has to be free of commercial influences. Sponsoring of CME in Germany has never been evaluated regarding potential influences on presentation of data and perception of participants. The present paper evaluates the impact of sponsoring on accredited CME events. MATERIAL UND METHODS: All CME events accredited by the Chamber of Physicians North Rhine have to be evaluated by a standard evaluation form. The data of 23,240 physicians participating in 1,019 consecutive CME events (representing 13.5% of all accredited events in the sampling period from February 2002 to May 2003) have been analyzed. RESULTS: Nearly two thirds of all participants were specialists. 64.6% of all evaluation forms had been sent back from sponsored CME events. Participants in sponsored events were older and, regarding the topic of the presentation, they were more often familiar with and had a diagnostic and therapeutic strategy for the clinical problem presented. Both types of CME events were rated good to excellent regarding a set of evaluation categories, about 28% of all participants felt their personal strategy had been changed by the event. On 7.7% of all evaluation forms (10% in sponsored and 3.4% in sponsored events; p<0.001), the participants noted a commercial bias. The participants who noted a commercial bias were more experienced in the topic discussed, found the presentation of data more often incomplete, and felt a negative impact on their learning behavior. CONCLUSION: Sponsored and unsponsored CME events are rated as equally satisfactory by the great majority of participants. Only in about 8% of the evaluation forms a commercial bias was noted, which had a negative impact on the educational value of the CME event. Thus, it seems most likely that the regulatory framework for accreditation is able to prevent large-scale commercial influence on CME events.     

Effect of spatial attention on stimulus-specific haemodynamic repetition effects

The aim of this fMRI study was to investigate whether spatial attention to the initial and/or repeated presentation of a stimulus is necessary to observe repetition-related modulations of the neural responses evoked by that stimulus. During each trial, two stimuli were presented simultaneously, one left and one right of fixation. During each block, participants were instructed to attend covertly to stimuli in one of the two hemifields and respond whether each was a face or house, ignoring the contralateral stimulus. Regions that preferred one stimulus category over the other, such as the fusiform face area and parahippocampal place area, showed evidence of some processing of the ignored stimuli. However, a reduced response to repeated stimuli (repetition suppression) was only reliable for preferred stimuli when both their initial and repeated presentations were attended. This suggests that attention is necessary for both the acquisition and expression of the neural mechanisms that underlie repetition suppression, at least over the lags of 2-16 intervening trials used here.     

Time‐course of attentional bias for threat‐related cues in patients with chronic daily headache–tension type: Evidence for the role of anger

This study investigated the role of anger in attentional bias for linguistic threat‐related stimuli in individuals with chronic daily headache (CDH) tension type and healthy controls. Attentional bias was assessed using a visual probe task which presented pain‐related (sensory and affective), social threat, anger‐related, and neutral words at two exposure duration conditions: 500ms and 1250ms. Compared to healthy controls, individuals with CDH showed significantly greater attentional bias towards pain‐related words at 1250ms, indicating a bias in maintained attention to pain cues in this group. No significant differences between groups were found in attentional bias scores at the shorter stimulus duration of 500ms. No significant differences between groups were found in attentional bias scores to social threat and anger‐related words at either stimulus presentation duration. When compared to 0, in all group and duration combinations there was significant positive bias towards anger. Across the whole sample, pain bias scores at 1250ms were significantly associated with anger out, whilst anger bias scores at both 500ms and 1250ms correlated significantly with trait anger. The results of the present investigation support the content‐specificity hypothesis, according to which attentional bias in patients with chronic pain is shown only towards pain‐related cues. Moreover, the current pattern of results highlights the importance of exploring further the role of anger in the aetiology and maintenance of chronic pain in general, and CDH tension type in particular.     

Attentional bias to pain and social threat in pediatric patients with functional abdominal pain and pain-free youth before and after performance evaluation

This study investigated attentional biases for pain and social threat versus neutral stimuli in 54 youth with functional abdominal pain (FAP) and 53 healthy control subjects (ages 10 to 16 years). We assessed attentional bias using a visual probe detection task (PDT) that presented pain and social threat words in comparison to neutral words at conscious (1250 ms) and preconscious (20 ms) presentation rates. We administered the PDT before and after random assignment of participants to a laboratory stressor—failure versus success feedback regarding their performance on a challenging computer game. All analyses controlled for trait anxiety. At the conscious rate of stimulus presentation, FAP patients exhibited preferential attention toward pain compared with neutral stimuli and compared with the control group. FAP patients maintained preferential attention toward conscious pain stimuli after performance feedback in both failure and success conditions. At the preconscious rate of stimulus presentation, FAP patients’ attention was neutral at baseline but increased significantly toward pain stimuli after performance feedback in both failure and success conditions. FAP patients’ somatic symptoms increased in both failure and success conditions; control youth’s somatic symptoms only increased after failure. Regarding social threat, neither FAP nor control youth exhibited attentional bias toward social threat compared with neutral stimuli at baseline, but both FAP and control youth in the failure condition significantly increased attention away from social threat after failure feedback. Results suggest that FAP patients preferentially attend to pain stimuli in conscious awareness. Moreover, performance evaluation may activate their preconscious attention to pain stimuli.     

Real-time high-speed volumetric imaging using compressive sampling optical coherence tomography

Volumetric imaging of the Optic Nerve Head (ONH) morphometry with Optical Coherence Tomography (OCT) requires dense sampling and relatively long acquisition times. Compressive Sampling (CS) is an emerging technique to reduce volume acquisition time with minimal image degradation by sparsely sampling the object and reconstructing the missing data in software. In this report, we demonstrated real-time CS-OCT for volumetric imaging of the ONH using a 1060nm Swept-Source OCT prototype. We also showed that registration and averaging of CS-recovered volumes enhanced visualization of deep structures of the sclera and lamina cribrosa. This work validates CS-OCT as a means for reducing volume acquisition time and for preserving high-resolution in volume-averaged images. Compressive sampling can be integrated into new and existing OCT systems without changes to the optics, requiring only software changes and post-processing of acquired data.     

Attentional Biases Towards Body Expressions of Pain in Men and Women

This study investigated whether there are gender differences in attention to bodily expressions of pain and core emotions. Three experiments are reported using the attentional dot probe task. Images of men and women displaying bodily expressions, including pain, were presented. The task was used to determine whether participants’ attention was drawn towards or away from target expressions. Inconsistent evidence was found for an attentional bias towards body expressions, including pain. While biases were affected by gender, patterns varied across the Experiments. Experiment 1, which had a presentation duration of 500 ms, found a relative bias towards the location of male body expressions compared to female expressions. Experiments 2 and 3 varied stimulus exposure times by including both shorter and longer duration conditions (e.g., 100 vs. 500 vs. 1250 ms). In these experiments, a bias towards pain was confirmed. Gender differences were also found, especially in the longer presentation conditions. Expressive body postures captured the attention of women for longer compared to men. These results are discussed in light of their implications for why there are gender differences in attention to pain, and what impact this has on pain behaviour.PerspectiveWe show that men and women might differ in how they direct their attention towards bodily expressions, including pain. These results have relevance to understanding how carers might attend to the pain of others, as well as highlighting the wider role that social-contextual factors have in pain.     

5-Hydroxytryptamine (serotonin)2A receptors in rat anterior cingulate cortex mediate the discriminative stimulus properties of d-lysergic acid diethylamide

d-Lysergic acid diethylamide (LSD), an indoleamine hallucinogen, produces profound alterations in mood, thought, and perception in humans. The brain site(s) that mediates the effects of LSD is currently unknown. In this study, we combine the drug discrimination paradigm with intracerebral microinjections to investigate the anatomical localization of the discriminative stimulus of LSD in rats. Based on our previous findings, we targeted the anterior cingulate cortex (ACC) to test its involvement in mediating the discriminative stimulus properties of LSD. Rats were trained to discriminate systemically administered LSD (0.085 mg/kg s.c.) from saline. Following acquisition of the discrimination, bilateral cannulae were implanted into the ACC (AP, +1.2 mm; ML, +/-1.0 mm; DV, -2.0 mm relative to bregma). Rats were tested for their ability to discriminate varying doses of locally infused LSD (0.1875, 0.375, and 0.75 microg/side) or artificial cerebrospinal fluid (n = 3-7). LSD locally infused into ACC dose-dependently substituted for systemically administered LSD, with 0.75 microg/side LSD substituting completely (89% correct). Systemic administration of the selective 5-hydroxytryptamine (serotonin) (5-HT)(2A) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907; 0.4 mg/kg) blocked the discriminative cue of LSD (0.375 microg/side) infused into ACC (from 68 to 16% drug lever responding). Furthermore, M100907 (0.5 microg/microl/side) locally infused into ACC completely blocked the stimulus effects of systemic LSD (0.04 mg/kg; from 80 to 12% on the LSD lever). Taken together, these data indicate that 5-HT(2A) receptors in the ACC are a primary target mediating the discriminative stimulus properties of LSD.     

An improved method for mapping cerebrovascular reserve using concurrent fMRI and near-infrared spectroscopy with Regressor Interpolation at Progressive Time Delays (RIPTiDe)

Cerebrovascular reserve (CVR) reflects the compensatory dilatory capacity of cerebral vasculature to a dilatory stimulus. Blood oxygen-level dependent (BOLD) fMRI has been proven to be an effective imaging technique to obtain CVR maps when subjects perform CO(2) inhalation or a breath-holding (BH) task. Here we propose a novel way to process the fMRI data obtained during a blocked BH task by using simultaneously collected near-infrared spectroscopy (NIRS) data as regressors to estimate the vascular contribution to the BOLD signal. Six healthy subjects underwent a 6min 30s resting state (RS) fMRI scan, followed by a scan of the same duration with a blocked BH task (5 breath holds with 20s durations separated by ~50s of regular breathing). NIRS data were recorded from a probe over the subjects' right prefrontal area. For each scan, the time course of changes in total hemoglobin (Δ[tHb]) was calculated from the NIRS data, time shifted by various amounts, and resampled to the fMRI acquisition rate. Each shifted time course was used as regressor in a general linear model analysis. The maximum parameter estimate across all time shifts was calculated at all voxels in both the BH and RS scans, and then converted into signal percentage changes. The ratio of these signal changes generates a CVR map of the BH response, normalized to the resting state. The NIRS regressor method makes no assumptions about the shape (or presence) of the BH response, and allows direct, quantitative comparison of the vascular BOLD response to BH to the baseline map obtained in the resting state.     

Nonlinearities in rapid event-related fMRI explained by stimulus scaling

Because of well-known nonlinearities in fMRI, responses measured with rapid event-related designs are smaller than responses measured with spaced designs. Surprisingly, no study to date has tested whether rapid designs also change the pattern of responses across different stimulus conditions. Here we report the results of such a test. We measured cortical responses to a flickering checkerboard at different contrasts using rapid and spaced event-related fMRI. The relative magnitude of responses across contrast conditions differed between rapid and spaced designs. Modeling the effect of the rapid design as a scaling of stimulus strength provided a good account of the data. The data were less well fit by a model that scaled the strength of responses. A similar stimulus scaling model has explained effects of neural adaptation, which suggests that adaptation may account for the observed difference between rapid and spaced designs. In a second experiment, we changed the stimulus in ways known to reduce neural adaptation and found much smaller differences between the two designs. Stimulus scaling provides a simple way to account for nonlinearities in event-related fMRI and relate data from rapid designs to data gathered using slower presentation rates.     

Detection versus estimation in event-related fMRI: choosing the optimal stimulus timing.

With the advent of event-related paradigms in functional MRI, there has been interest in finding the optimal stimulus timing, especially when the interstimulus interval is varied during the imaging run. Previous works have proposed stimulus timings to optimize either the estimation of the impulse response function (IRF) or the detection of signal changes. The purpose of this paper is to clarify that estimation and detection are fundamentally different goals and to determine the optimal stimulus timing and distribution with respect to both the accuracy of estimating the IRF and the power of detection assuming a particular hemodynamic model. Simulated stimulus distributions are varied systematically, from traditional blocked designs to rapidly varying event related designs. These simulations indicate that estimation of the hemodynamic impulse response function is optimized when stimuli are frequently alternated between task and control states, with shorter interstimulus intervals and stimulus durations, whereas the detection of activated areas is optimized by blocked designs. The stimulus timing for a given experiment should therefore be generated with the required detectability and estimation accuracy.     

Alteration in the response properties of primary somatosensory cortex related to differential aversive Pavlovian conditioning

The effects of differential aversive Pavlovian conditioning on the functional organization of primary somatosensory cortex (SI) were examined in 17 healthy participants. Neuroelectric source imaging from 60 electrodes was employed while nine subjects received an innocuous electric stimulus (conditioned stimulus, CS) to one finger (left or right) that was followed by painful electric shock to the lower back (unconditioned stimulus, US) and an innocuous stimulus to the other finger that was never followed by pain. Eight subjects received a presentation of the innocuous and painful stimuli with equal probability to both fingers (control group). The data included the electromyogram (EMG) from the left m. corrugator, and judgments of intensity, aversiveness, and CS-US contingency. Only the experimental group displayed EMG conditioning, differential contingency judgments, as well as a change of dipole orientation for the CS and an enhanced dipole moment for the US in the electroencephalogram. Intensity and unpleasantness ratings were altered in a more unspecific manner and did not differ between groups and stimulus conditions. The data suggest that SI contributes to memory processes in associative learning. Pavlovian conditioning of tactile responses might be important in the altered processing of painful stimuli in chronic pain patients where enhanced conditioning has been demonstrated.     

Acquisition and presentation of follicular dendritic cell-bound antigen by lymph node-resident dendritic cells

Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node-resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen-antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance.     

Relaxation training and cognitive redirection strategies in the treatment of acute pain

Relaxation training, relaxation instructions, and redirection of attention techniques were compared to a no-treatment control in the treatment of acute ischemic pain. Relaxation instructions were ineffective in reducing state anxiety, verbally reported pain or distress or pain measured during presentation of the stimulus by cross-modality matching. Relaxation training was effective in reducing distress during presentation of the stimulus and verbally reported pain. The attention-redirection technique reduced pain as measured by cross-modality matching. The interaction hypothesis was supported, re. the two measures of distress during presentation of the painful stimulus. As externality increased, the effectiveness of relaxation training increased. However, there was no consistent decrease in distress for subjects high on externality in the relaxation instruction group.     

The acquisition of fear of movement-related pain and associative learning: a novel pain-relevant human fear conditioning paradigm

Current fear-avoidance models consider fear of pain as a key factor in the development of chronic musculoskeletal pain. Generally, the idea is that by virtue of the formation of associations or acquired propositional knowledge about the relation between neutral movements and pain, these movements may signal pain, and hence start to elicit defensive fear responses (eg, avoidance behavior). This assumption has never been investigated experimentally. Therefore, we developed a pain-relevant fear conditioning paradigm using a movement as a conditioned stimulus (CS) and a painful electrocutaneous stimulus as an unconditioned stimulus (US) to examine the acquisition of fear of movement-related pain in healthy subjects. In a within-subjects design, participants manipulated a joystick to the left/right in the experimental (predictable) condition, and upward/downward in the control (unpredictable) condition or vice versa. In the predictable condition, one movement direction (CS+), and not the other (CS−), was followed by painful stimuli. In the unpredictable condition, painful stimuli were always delivered during the intertrial interval. Both fear of movement-related pain ratings and eyeblink startle measures were more elevated in response to the CS+ than to the CS−, whereas no differences occurred between both unreinforced CSs in the control condition. Participants were slower initiating a CS+ movement than a CS− movement, while response latencies to CSs in the control condition did not differ. These data support the acquisition of fear of movement-related pain by associative learning. Results are discussed in the broader context of the acquisition of pain-related fear in patients with musculoskeletal pain.