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.

A multivariate approach for processing magnetization effects in triggered event-related functional magnetic resonance imaging time series

Triggered event-related functional magnetic resonance imaging requires sparse intervals of temporally resolved functional data acquisitions, whose initiation corresponds to the occurrence of an event, typically an epileptic spike in the electroencephalographic trace. However, conventional fMRI time series are greatly affected by non-steady-state magnetization effects, which obscure initial blood oxygen level-dependent (BOLD) signals. Here, conventional echo-planar imaging and a post-processing solution based on principal component analysis were employed to remove the dominant eigenimages of the time series, to filter out the global signal changes induced by magnetization decay and to recover BOLD signals starting with the first functional volume. This approach was compared with a physical solution using radiofrequency preparation, which nullifies magnetization effects. As an application of the method, the detectability of the initial transient BOLD response in the auditory cortex, which is elicited by the onset of acoustic scanner noise, was used to demonstrate that post-processing-based removal of magnetization effects allows to detect brain activity patterns identical with those obtained using the radiofrequency preparation. Using the auditory responses as an ideal experimental model of triggered brain activity, our results suggest that reducing the initial magnetization effects by removing a few principal components from fMRI data may be potentially useful in the analysis of triggered event-related echo-planar time series. The implications of this study are discussed with special caution to remaining technical limitations and the additional neurophysiological issues of the triggered acquisition.

Rising sound intensity: an intrinsic warning cue activating the amygdala

Human subjects overestimate the change of rising intensity sounds compared with falling intensity sounds. Rising sound intensity has therefore been proposed to be an intrinsic warning cue. In order to test this hypothesis, we presented rising, falling, and constant intensity sounds to healthy humans and gathered psychophysiological and behavioral responses. Brain activity was measured using event-related functional magnetic resonance imaging. We found that rising compared with falling sound intensity facilitates autonomic orienting reflex and phasic alertness to auditory targets. Rising intensity sounds produced neural activity in the amygdala, which was accompanied by activity in intraparietal sulcus, superior temporal sulcus, and temporal plane. Our results indicate that rising sound intensity is an elementary warning cue eliciting adaptive responses by recruiting attentional and physiological resources. Regions involved in cross-modal integration were activated by rising sound intensity, while the right-hemisphere phasic alertness network could not be supported by this study.

BOLD correlates of edge detection in human auditory cortex

Edges are important cues defining coherent auditory objects. As a model of auditory edges, sound on- and offset are particularly suitable to study their neural underpinnings because they contrast a specific physical input against no physical input. Change from silence to sound, that is onset, has extensively been studied and elicits transient neural responses bilaterally in auditory cortex. However, neural activity associated with sound onset is not only related to edge detection but also to novel afferent inputs. Edges at the change from sound to silence, that is offset, are not confounded by novel physical input and thus allow to examine neural activity associated with sound edges per se. In the first experiment, we used silent acquisition functional magnetic resonance imaging and found that the offset of pulsed sound activates planum temporale, superior temporal sulcus and planum polare of the right hemisphere. In the planum temporale and the superior temporal sulcus, offset response amplitudes were related to the pulse repetition rate of the preceding stimulation. In the second experiment, we found that these offset-responsive regions were also activated by single sound pulses, onset of sound pulse sequences and single sound pulse omissions within sound pulse sequences. However, they were not active during sustained sound presentation. Thus, our data show that circumscribed areas in right temporal cortex are specifically involved in identifying auditory edges. This operation is crucial for translating acoustic signal time series into coherent auditory objects.

Neural correlates of antinociception in borderline personality disorder

CONTEXT: A characteristic feature of borderline personality disorder (BPD) is self-injurious behavior in conjunction with stress-induced reduction of pain perception. Reduced pain sensitivity has been experimentally confirmed in patients with BPD, but the neural correlates of antinociceptive mechanisms in BPD are unknown. We predicted that heat stimuli in patients with BPD would activate brain areas concerned with cognitive and emotional evaluation of pain. OBJECTIVE: To assess the psychophysical properties and neural correlates of altered pain processing in patients with BPD. DESIGN: Case-control study. SETTING: A university hospital. PARTICIPANTS: Twelve women with BPD and self-injurious behavior and 12 age-matched control subjects. INTERVENTIONS: Psychophysical assessment and blood oxygen level-dependent functional magnetic resonance imaging during heat stimulation with fixed-temperature heat stimuli and individual-temperature stimuli adjusted for equal subjective pain in all the participants. MAIN OUTCOME MEASURE: Blood oxygen level-dependent functional magnetic resonance imaging signal changes during heat pain stimulation. RESULTS: Patients with BPD had higher pain thresholds and smaller overall volumes of activity than controls in response to identical heat stimuli. When the stimulus temperature was individually adjusted for equal subjective pain level, overall volumes of activity were similar, although regional patterns differed significantly. Patient response was greater in the dorsolateral prefrontal cortex and smaller in the posterior parietal cortex. Pain also produced neural deactivation in the perigenual anterior cingulate gyrus and the amygdala in patients with BPD. CONCLUSION: The interaction between increased pain-induced response in the dorsolateral prefrontal cortex and deactivation in the anterior cingulate and the amygdala is associated with an antinociceptive mechanism in patients with BPD.

How does spatial extent of fMRI datasets affect independent component analysis decomposition?

Spatial independent component analysis (sICA) of functional magnetic resonance imaging (fMRI) time series can generate meaningful activation maps and associated descriptive signals, which are useful to evaluate datasets of the entire brain or selected portions of it. Besides computational implications, variations in the input dataset combined with the multivariate nature of ICA may lead to different spatial or temporal readouts of brain activation phenomena. By reducing and increasing a volume of interest (VOI), we applied sICA to different datasets from real activation experiments with multislice acquisition and single or multiple sensory-motor task-induced blood oxygenation level-dependent (BOLD) signal sources with different spatial and temporal structure. Using receiver operating characteristics (ROC) methodology for accuracy evaluation and multiple regression analysis as benchmark, we compared sICA decompositions of reduced and increased VOI fMRI time-series containing auditory, motor and hemifield visual activation occurring separately or simultaneously in time. Both approaches yielded valid results; however, the results of the increased VOI approach were spatially more accurate compared to the results of the decreased VOI approach. This is consistent with the capability of sICA to take advantage of extended samples of statistical observations and suggests that sICA is more powerful with extended rather than reduced VOI datasets to delineate brain activity.

Processing of temporal unpredictability in human and animal amygdala

The amygdala has been studied extensively for its critical role in associative fear conditioning in animals and humans. Noxious stimuli, such as those used for fear conditioning, are most effective in eliciting behavioral responses and amygdala activation when experienced in an unpredictable manner. Here, we show, using a translational approach in mice and humans, that unpredictability per se without interaction with motivational information is sufficient to induce sustained neural activity in the amygdala and to elicit anxiety-like behavior. Exposing mice to mere temporal unpredictability within a time series of neutral sound pulses in an otherwise neutral sensory environment increased expression of the immediate-early gene c-fos and prevented rapid habituation of single neuron activity in the basolateral amygdala. At the behavioral level, unpredictable, but not predictable, auditory stimulation induced avoidance and anxiety-like behavior. In humans, functional magnetic resonance imaging revealed that temporal unpredictably causes sustained neural activity in amygdala and anxiety-like behavior as quantified by enhanced attention toward emotional faces. Our findings show that unpredictability per se is an important feature of the sensory environment influencing habituation of neuronal activity in amygdala and emotional behavior and indicate that regulation of amygdala habituation represents an evolutionary-conserved mechanism for adapting behavior in anticipation of temporally unpredictable events.

Brain responses to auditory and visual stimulus offset: Shared representations of temporal edges

Edges are crucial for the formation of coherent objects from sequential sensory inputs within a single modality. Moreover, temporally coincident boundaries of perceptual objects across different sensory modalities facilitate crossmodal integration. Here, we used functional magnetic resonance imaging in order to examine the neural basis of temporal edge detection across modalities. Onsets of sensory inputs are not only related to the detection of an edge but also to the processing of novel sensory inputs. Thus, we used transitions from input to rest (offsets) as convenient stimuli for studying the neural underpinnings of visual and acoustic edge detection per se. We found, besides modality-specific patterns, shared visual and auditory offset-related activity in the superior temporal sulcus and insula of the right hemisphere. Our data suggest that right hemispheric regions known to be involved in multisensory processing are crucial for detection of edges in the temporal domain across both visual and auditory modalities. This operation is likely to facilitate cross-modal object feature binding based on temporal coincidence. Hum Brain Mapp, 2008. (c) 2008 Wiley-Liss, Inc.

The spatiotemporal pattern of auditory cortical responses during verbal hallucinations

Functional magnetic resonance imaging (fMRI) studies can provide insight into the neural correlates of hallucinations. Commonly, such studies require self-reports about the timing of the hallucination events. While many studies have found activity in higher-order sensory cortical areas, only a few have demonstrated activity of the primary auditory cortex during auditory verbal hallucinations. In this case, using self-reports as a model of brain activity may not be sensitive enough to capture all neurophysiological signals related to hallucinations. We used spatial independent component analysis (sICA) to extract the activity patterns associated with auditory verbal hallucinations in six schizophrenia patients. SICA decomposes the functional data set into a set of spatial maps without the use of any input function. The resulting activity patterns from auditory and sensorimotor components were further analyzed in a single-subject fashion using a visualization tool that allows for easy inspection of the variability of regional brain responses. We found bilateral auditory cortex activity, including Heschl's gyrus, during hallucinations of one patient, and unilateral auditory cortex activity in two more patients. The associated time courses showed a large variability in the shape, amplitude, and time of onset relative to the self-reports. However, the average of the time courses during hallucinations showed a clear association with this clinical phenomenon. We suggest that detection of this activity may be facilitated by examining hallucination epochs of sufficient length, in combination with a data-driven approach.

Cortical and subcortical correlates of electroencephalographic alpha rhythm modulation

Neural correlates of electroencephalographic (EEG) alpha rhythm are poorly understood. Here, we related EEG alpha rhythm in awake humans to blood-oxygen-level-dependent (BOLD) signal change determined by functional magnetic resonance imaging (fMRI). Topographical EEG was recorded simultaneously with fMRI during an open versus closed eyes and an auditory stimulation versus silence condition. EEG was separated into spatial components of maximal temporal independence using independent component analysis. Alpha component amplitudes and stimulus conditions served as general linear model regressors of the fMRI signal time course. In both paradigms, EEG alpha component amplitudes were associated with BOLD signal decreases in occipital areas, but not in thalamus, when a standard BOLD response curve (maximum effect at approximately 6 s) was assumed. The part of the alpha regressor independent of the protocol condition, however, revealed significant positive thalamic and mesencephalic correlations with a mean time delay of approximately 2.5 s between EEG and BOLD signals. The inverse relationship between EEG alpha amplitude and BOLD signals in primary and secondary visual areas suggests that widespread thalamocortical synchronization is associated with decreased brain metabolism. While the temporal relationship of this association is consistent with metabolic changes occurring simultaneously with changes in the alpha rhythm, sites in the medial thalamus and in the anterior midbrain were found to correlate with short time lag. Assuming a canonical hemodynamic response function, this finding is indicative of activity preceding the actual EEG change by some seconds.

Cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy--a technique in its infancy but already successful in fertility preservation

Increasing survival rates in young cancer patients, new reproductive techniques and the growing interest in quality of life after gonadotoxic cancer therapies have placed fertility preservation as an important issue to oncologists, fertility specialists and patients. Several techniques are now available for fertility preservation in these patients. A new promising method is cryopreservation and transplantation of ovarian cortex. Ovarian tissue can be extracted by laparoscopy without any significant delay of gonadotoxic therapy. The tissue can be cryopreserved by specialised centres of reproductive medicine and transplanted in case the women experience premature ovarian failure (POF). This review summarises the European expertise on cryopreservation and transplantation of ovarian tissue, following around 30 reported transplantations globally, resulting in six live births and several ongoing pregnancies. It emphasises that fertility preservation by the cryopreservation of ovarian tissue is a new but already a successful clinical option, which can be considered for selected cancer patients.

Molecular genetics and functional anomalies in a series of 248 Brugada cases with 11 mutations in the TRPM4 channel.

Brugada syndrome (BrS) is a condition defined by ST-segment alteration in right precordial leads and a risk of sudden death. Because BrS is often associated with right bundle branch block and the TRPM4 gene is involved in conduction blocks, we screened TRPM4 for anomalies in BrS cases. The DNA of 248 BrS cases with no SCN5A mutations were screened for TRPM4 mutations. Among this cohort, 20 patients had 11 TRPM4 mutations. Two mutations were previously associated with cardiac conduction blocks and 9 were new mutations (5 absent from ~14'000 control alleles and 4 statistically more prevalent in this BrS cohort than in control alleles). In addition to Brugada, three patients had a bifascicular block and 2 had a complete right bundle branch block. Functional and biochemical studies of 4 selected mutants revealed that these mutations resulted in either a decreased expression (p.Pro779Arg and p.Lys914X) or an increased expression (p.Thr873Ile and p.Leu1075Pro) of TRPM4 channel. TRPM4 mutations account for about 6% of BrS. Consequences of these mutations are diverse on channel electrophysiological and cellular expression. Because of its effect on the resting membrane potential, reduction or increase of TRPM4 channel function may both reduce the availability of sodium channel and thus lead to BrS.