Kátia C. Andrade

Development of a Large-Scale Functional Brain Network during Human Non-Rapid Eye Movement Sleep

Graph theoretical analysis of functional magnetic resonance imaging (fMRI) time series has revealed a small-world organization of slow-frequency blood oxygen level-dependent (BOLD) signal fluctuations during wakeful resting. In this study, we used graph theoretical measures to explore how physiological changes during sleep are reflected in functional connectivity and small-world network properties of a large-scale, low-frequency functional brain network. Twenty-five young and healthy participants fell asleep during a 26.7 min fMRI scan with simultaneous polysomnography. A maximum overlap discrete wavelet transformation was applied to fMRI time series extracted from 90 cortical and subcortical regions in normalized space after residualization of the raw signal against unspecific sources of signal fluctuations; functional connectivity analysis focused on the slow-frequency BOLD signal fluctuations between 0.03 and 0.06 Hz. We observed that in the transition from wakefulness to light sleep, thalamocortical connectivity was sharply reduced, whereas corticocortical connectivity increased; corticocortical connectivity subsequently broke down in slow-wave sleep. Local clustering values were closest to random values in light sleep, whereas slow-wave sleep was characterized by the highest clustering ratio (gamma). Our findings support the hypothesis that changes in consciousness in the descent to sleep are subserved by reduced thalamocortical connectivity at sleep onset and a breakdown of general connectivity in slow-wave sleep, with both processes limiting the capacity of the brain to integrate information across functional modules.

Sleep Spindles and Hippocampal Functional Connectivity in Human NREM Sleep

We investigated human hippocampal functional connectivity in wakefulness and throughout non-rapid eye movement sleep. Young healthy subjects underwent simultaneous EEG and functional magnetic resonance imaging (fMRI) measurements at 1.5 T under resting conditions in the descent to deep sleep. Continuous 5 min epochs representing a unique sleep stage (i.e., wakefulness, sleep stages 1 and 2, or slow-wave sleep) were extracted. fMRI time series of subregions of the hippocampal formation (HF) (cornu ammonis, dentate gyrus, and subiculum) were extracted based on cytoarchitectonical probability maps. We observed sleep stage-dependent changes in HF functional coupling. The HF was integrated to variable strength in the default mode network (DMN) in wakefulness and light sleep stages but not in slow-wave sleep. The strongest functional connectivity between the HF and neocortex was observed in sleep stage 2 (compared with both slow-wave sleep and wakefulness). We observed a strong interaction of sleep spindle occurrence and HF functional connectivity in sleep stage 2, with increased HF/neocortical connectivity during spindles. Moreover, the cornu ammonis exhibited strongest functional connectivity with the DMN during wakefulness, while the subiculum dominated hippocampal functional connectivity to frontal brain regions during sleep stage 2. Increased connectivity between HF and neocortical regions in sleep stage 2 suggests an increased capacity for possible global information transfer, while connectivity in slow-wave sleep is reflecting a functional system optimal for segregated information reprocessing. Our data may be relevant to differentiating sleep stage-specific contributions to neural plasticity as proposed in sleep-dependent memory consolidation.

Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling

In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three‐day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time‐course in the left middle temporal gyrus. Post‐hoc contrasts corrected for measures of NREM sleep variability also revealed between‐group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep. Hum Brain Mapp 33:2362–2376, 2012.

The neural correlates and temporal sequence of the relationship between shock exposure, disturbed sleep and impaired consolidation of fear extinction

Consolidation of extinction learning is a primary mechanism disrupted in posttraumatic stress disorder (PTSD), associated with hypoactivity of the ventromedial prefrontal cortex and hippocampus. A role for rapid eye movement (REM) sleep disturbances in this failure to consolidate extinction learning has been proposed. We performed functional magnetic resonance imaging (fMRI) with simultaneous skin conductance response (SCR) measurements in 16 healthy participants during conditioning/extinction and later recall of extinction. The visual stimuli were basic geometric forms and electrical shocks functioned as the unconditioned stimulus. Between the conditioning/extinction and recall sessions, participants received a 90-min sleep window in the sleep laboratory. This daytime sleep was polysomnographically recorded and scored by professionals blind to the study design. Only seven out of 16 participants had REM sleep; participants without REM sleep had a significantly slower decline of both SCR and neural activity of the laterodorsal tegmentum in response to electrical shocks during conditioning. At recall of fear extinction, participants with preceding REM sleep had a reduced SCR and stronger activation of the left ventromedial prefrontal cortex and bilateral lingual gyrus in response to the extinguished stimulus than participants lacking REM sleep. This study indicates that trait-like differences in shock reactivity/habituation (mediated by the brainstem) are predictive of REM sleep disruption, which in turn is associated with impaired consolidation of extinction (mediated by the ventromedial prefrontal cortex). These findings help understand the neurobiological basis and the temporal sequence of the relationship between shock exposure, disturbed sleep and impaired consolidation of extinction, as observed in PTSD.

The neural correlates of negative prediction error signaling in human fear conditioning.

In a temporal difference (TD) learning approach to classical conditioning, a prediction error (PE) signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative PE signal, which is the initial step towards successful extinction. In order to visualize negative PE signaling during fear conditioning, we employed combined functional magnetic resonance (fMRI) and skin conductance response (SCR) measurements in a conditioning task with visual stimuli and mild electrical shocks. Positive PE signaling was associated with increased activation in the bilateral insula, supplementary motor area, brainstem, and visual cortices. Negative PE signaling was associated with increased activation in the ventromedial and dorsolateral prefrontal cortices, the left lateral orbital gyrus, the middle temporal gyri, angular gyri, and visual cortices. The involvement of the ventromedial prefrontal and orbitofrontal cortex in extinction learning has been well documented, and this study provides evidence for the notion that these regions are already involved in negative PE signaling during fear conditioning.

Acoustic Oddball during NREM Sleep: A Combined EEG/ fMRI Study

Background A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. Methodology/Principal Findings Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. Conclusions/Significance We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state with relatively increased stimulus processing, revealing an activity pattern resembling novelty processing as previously reported during wakefulness. The KC itself is not reflected by increased metabolic demand in BOLD based imaging, arguing that evoked KCs result from increased neural synchronicity without altered metabolic demand.

Resting state functional MRI connectivity predicts hypothalamus-pituitary-axis status in healthy males

Homeostasis of the human stress response system is critically maintained by a hierarchical system of neural and endocrine elements for which intact negative feedback is important to prevent maladaptation towards stress. Such feedback is efficiently probed by the established combined dexamethasone-suppression/corticotropin-releasing hormone stimulation (dex/CRH) test. Here we investigate which suprahypothalamic networks might modulate the response assessed by this neuroendocrine test. Combined resting state fMRI (rs-fMRI)/EEG was acquired in 20 healthy male volunteers along with dex/CRH profiles obtained on a different day outside the scanner. Seed-based network analysis and inter-seed cross correlation analysis for selected atlas-based limbic, paralimbic and medial prefrontal cortex seeds were correlated with stimulated cortisol and adrenocorticotropin hormone (ACTH) concentrations. Lower connectivity between a left hippocampus-based network and the right hippocampus significantly predicted stimulated cortisol concentration (R(2)=0.70, corrected pcluster=0.001). Six further significantly negative correlations were detected mainly in the left anterior cingulate cortex (ACC) and the medial prefrontal cortex (mPFC). The strongest positive correlation with stimulated hormone concentration was detected for the left subcallosal ACC (ACTH, R(2)=0.57, corrected pcluster=0.009). Inter-seed connectivity mainly pointed to hippocampal/amygdala interactions as correlates of the dex/CRH response. In conclusion, resting state functional connectivity patterns of limbic, particularly hippocampal, as well as cingulate and medial prefrontal areas can explain some of the variance of the dex/CRH test in healthy subjects. Functional connectivity analysis can be considered useful to study supra-hypothalamic control systems of the HPA axis.

Statistical evaluation of recurrence quantification analysis applied on single trial evoked potential studies

OBJECTIVE We evaluated the potential of recurrence quantification analysis (RQA) to improve the analysis of trial-by-trial-variability in event-related potentials (ERPs) experiments. METHODS We use an acoustic oddball paradigm to compare the efficiency of RQA with a linear amplitude based analysis of single trial ERPs with regard to the power to distinguish responses to different tone types. We further probed the robustness of both analyses towards structured noise induced by parallel magnetic resonance imaging (MRI). RESULTS RQA provided robust discrimination of responses to different tone types, even when EEG data were contaminated by structured noise. Yet, its power to discriminate responses to different tone types was not significantly superior to a linear amplitude analysis. RQA measures were only moderately correlated with EEG amplitudes, suggesting that RQA may extract additional information from single trial responses not detected by amplitude evaluation. CONCLUSIONS RQA allows quantifying signal characteristics of single trial ERPs measured with and without noise induced by parallel MRI. RQA power to discriminate responses to different tone types was similar to linear amplitude based analysis. SIGNIFICANCE RQA has the potential to detect differences of signal features in response to a standard oddball paradigm and provide additional trial-by-trial information compared to classical amplitude based analysis.